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Lupine Publishers | The Optimal Pain Management Methods Post Thoracic Surgery: A Literature Review

Abstract

Post-operative pain control is one of the key factors that can aid in fast and safe recovery after any surgical interventions. Thoracic surgery can cause significant postoperative pain which can lead to delayed recovery, delayed hospital discharge and possibly increased risk of chest complications in the form of atelectasis and even lower respiratory infections. Therefore, appropriate pain management following thoracic surgery is mandatory to prevent development of such morbidities including chronic pain.

Keywords: Thoracic Surgery, Analgesia, VATS, Robotics, Thoracotomy

Introduction

Thoracic surgical procedures can result in severe pain which can present as a challenge to be appropriately managed postoperatively. In particular, thoracotomies are well known for their severity of pain due to the incision, manipulation of muscles and ligaments, retraction of the ribs with compression, stretching of the intercostal nerves, possible rib fractures, pleural irritation, and postoperative tube thoracotomy [1]. Recognition of this has contributed to the development of minimally invasive techniques such as video assisted thoracoscopic surgeries (VATS) and lately robotic surgery [1]. These techniques not only aim to produce better aesthetic results, but also reduce post-operative pain and enhance recovery without compromising the quality of treatment offered. Poor pain management can lead to several and serious complications such as lung atelectasis, hypostatic pneumonia due to avoidance of deep breathing in these patients as a result of pain and superimposed infection [1]. Pain management as a result, does not only lead to greater patient satisfaction, but it also reduces morbidity and mortality in patients undergoing thoracic surgery [2]. Historically, post-operative pain management for thoracic surgery involved the use of narcotics alongside parenteral or oral anti-inflammatory agents [2]. Post chest tube removal patients typically are transitioned to oral analgesia. Multiple additional pain control adjuncts were also implemented with differing levels of success [1]. Over time, intra-operative techniques have been developed which aims to target pain reduction postoperatively [2]. As our understanding of both pain management and the factors that play a role in the development of pain has increased, we have been able to target these and improve postoperative pulmonary morbidity and pain scores [1,2]. We aim to review different means of pain control in this paper in order to assess their effectiveness in achieving optimum results.

Thoracotomy

The mechanism of pain in thoracotomy involves the innervation of the intercostal, sympathetic, vagus and phrenic nerves [3]. Additionally, shoulder pain may result from stretching of the joints during the operation.

After a thoracotomy, pain can persist for two months or more, and in certain incidences it recurs after a period of cessation. The incidence of chronic pain post thoracotomy is reported to be 22-67% in the population [4]. Good surgical technique and effective acute post-operative pain treatment are evident means of preventing post-thoracotomy pain and consequent pulmonary complications [4]. Due to the multifactorial character of the pain, a multimodal approach to target pain is advised. Typically, both regional and systemic anaesthesia are administered. A combination of opioids such as fentanyl or morphine are typically used [5]. A variety of techniques for the administration of local anaesthetics are available at present, and the effectiveness of each is assessed in this paper.

a) Thoracic Epidural Analgesia (TEA)

TEA was the most widely used method of means of analgesia. It was the gold standard means of pain relief [6,7]. It is typically inserted prior to general anaesthesia, at the level of T5-T6, midway along the dermatomal distribution of the thoracotomy incision. A study by Tiippana et al. [8] measured the visual analogue scale (VAS) in order to assess the presence of pain during rest and at the time at which they coughed in 114 patients of whom 89 had TEA and 22 who had other methods of pain control. TEA was effective in alleviating pain at rest and during coughing. In TEA patients, the incidence of chronic pain of at least moderate severity was 11% and 12% at 3 and 6 months, respectively. The study found that at one week after discharge, 92% of all patients needed daily pain medication. The study advised for extended postoperative analgesia for up to the week post-discharge to be administered in order to manage this. The study however concluded overall, that TEA was effective in controlling evoked post-operative pain. However, the study did encounter problems of technical form in 24% of the epidural catheters. The incidence of chronic pain, however, was lower compared with previous studies where TEA was not used. Several other studies support that TEA is superior to less invasive methods. According to Shelley B. et al. [9] TEA was preferred by 62% of the respondents over paravertebral block (PVB) with 30% and other analgesic techniques with 8%. Limitations of this technique included hypotension and urinary retention. Certain patients with active infection and on anticoagulation are excluded from epidural placement.

b) Paravertebral Block (PVB)

PVB is considered an effective method for pain management and its use has been increased in the recent years. This technique involves injecting local anaesthetic into the paravertebral space and it is able to block unilateral multi-segmental spinal and sympathetic nerves. Previous studies have shown that it is effective in achieving analgesia and is associated with a lower incidence of side effects such as nausea, vomiting, hypotension and urinary retention [10,11]. As the lungs are collapsed, it is associated with a lower risk of pneumothorax.

In a study by Davies R.G. et al. [10] there was no significant difference in pain scores, morphine consumption and supplementary use of analgesia between TEA and PVB. The rate of failed technique was lower in PVB (OR =0.28, p=0.007). Respiratory function was improved at both 24 and 48 hours with PVB but only significantly improved at 24 hours.

c) Intercostal Nerve Block (ICNB)

ICNBs are generally administered as single injections at least two dermatomes above and below the thoracotomy incision [12]. It is performed percutaneously or under direct vision, using single injections or through placement of an intercostal catheter. It can also be formed using cryotherapy. It is associated with reduced post-operative pain scores; however, it is less effective than TEA in controlling chronic pain [12]. This was illustrated by a study by Sanjay et al. [12] which found that patients that underwent ICNB had higher pain scores 4 hours post-operatively, than those who received epidural anaesthesia using 0.25% bupivacaine (p<0.05). The study concluded that in the early post-operative period there was significant impact in pain relief for both techniques, but thereafter, epidural anaesthesia was proven to significantly reduce post thoracotomy pain over ICNB. Due to the multifactorial nature of post-thoracotomy pain, various approaches are required in order to target pain. ICNBs are useful in the blockade of intercostal nerves, whilst PVB and TEA appear to block the intercostal and sympathetic nerves. Due to the inability of regional anaesthesia to block the vagus and phrenic nerves which are implicated in the pathophysiology of pain, NSAIDs and opioids are required as adjuncts. TEA is proven to be the most effective means of treating pain alongside PVB; however, it is associated with more side effects than PVB. At present, there are a limited number of studies directly comparing pain control and post-operative outcomes between PVB and TEA. There is no conclusive evidence that either method is superior to the other regarding pain control.

Video-Assisted Thoracoscopic Surgery (VATS)

Existing evidence supports the noninferiority of thoracic PVB when compared to TEA for postoperative analgesia [13]. PVB is versatile and may be applied both unilaterally or bilaterally. It can be used to avoid contralateral sympathectomy, consequently minimising hypotension. This is an apparent advantage it has over thoracic epidural. Furthermore, it offers a more favourable side effect profile when compared to epidural anaesthesia. At present, the factors taken into consideration when selecting a regional technique include tolerance of side effects associated with TEA, consensus on best practice/technique, and operator experience [13]. A randomised controlled trial by Kosiński et al. [14] compared the analgesic efficacy of continuous thoracic epidural block and percutaneous continuous PVB in 51 patients undergoing VATS lobectomy. The primary outcome measures were postoperative static (at rest) and dynamic (coughing) visual analogue pain scores (VAS), patient-controlled morphine use and side-effect profile. The study found that pain control (VAS) was superior in the PVB group at 24 hours, both at rest (1.7 vs3.3, p=0.01) and on coughing (5.8 vs 6.6, p=0.023), and control of pain at rest was also superior in the PVB group at 36 hours (3.0 vs 3.7 (p=0.025) and at 48 hours (1.2 vs 2.0, p=0.026). There were no significant differences in the postoperative morphine requirements. In regard to side-effect profile, the study showed that the incidence of postoperative urinary retention (defined as no spontaneous micturition for 8 hours or ultrasound-assessed volume of the urinary bladder >500ml) was greater in the epidural group (64.0% vs 34.6%, p=0.0036), as was the incidence of hypotension (32.0% vs 7.7%, p=0.0031). There was no significant difference in the incidence of atelectasis (4.0% vs 7.7%, p=0.0542). However, the incidence of pneumonia was significantly more frequent in the PVB group (3.8% vs 0%, p=0/0331). Kosiński et al. concluded that PVB is as effective as thoracic epidural block in regard to pain management as it offers a superior safety profile with minimal postoperative complications. A further randomised controlled trial by Okajima et al. [15] compared the requirements for postoperative supplemental analgesia in 90 patients who received wither a PVB or thoracic epidural infusion for VATS lobectomy, segmentectomy or wedge resection. The main outcome measures were pain scores at rest (verbal rating scale 0= none and 10=maximum pain), blood pressure, side effects and overall satisfaction scores relating to pain control (1=dissatisfied and 5=satisfied). The study found a similar frequency of supplemental analgesia (50mg diclofenac sodium suppository or 15mg pentazocine intramuscularly) for moderate pain in both groups, with 56% of those in the PVB group requiring ≥2 doses, compared to 48% in the epidural group (p=0.26). Hypotension, defined as a systolic blood pressure <90mmHg, occurred more frequently in the epidural group (21.2% vs 2.8%, p=0.02). There was no difference in the incidence of pruritus (3.0% vs 0%, p=0.29) and post-operative nausea and vomiting (30.3% vs 25.0%, p=0.62) between both groups. The study found no statistical difference between patient-reported satisfaction in pain control between epidural and PVB using the verbal rating scale (5.0 vs 4.5, p=0.36). The study concluded that PVB offered additional to equivalent analgesia to epidural, a lower incidence of haemodynamic instability postoperatively. A further study by Khoshbin et al. [16] performed an analysis on 81 patients undergoing VATS for pleural aspiration +/- pleurodesis, lung biopsies or bullectomy. The main outcome was postoperative pain levels, documented every 6 hours and scored against the Visual analogue Scale (0= no pain, 10= worst possible pain). In both PVB and epidural groups, bupivacaine 0.125% was the local anaesthetic of choice, with clonidine added to the epidural infusion at 300μg in 500ml. The study showed that there was no significant difference in mean pain scores between PVB or EP (2.1 vs 2.9, p=0.899), therefore concluding that PVB is as effective as epidural in controlling pain post-VATS.

Robotic Lung Surgery

Minimally invasive techniques are considered advantageous over open surgical approaches due to their shorter recovery times, reduced perceived levels of pain post-operatively and shorter postoperative length of stay in hospital [17-19]. Robotic surgery has become a popular method in recent years. Debate remains regarding whether robotic surgery is superior to VATS in regard with pain reduction. A case control study by Louie et al. [19] compared 45 robotic assisted lobectomies (RAL) to 34 VATS lobectomies. The study showed that both groups had a similar mean ICU stay (0.9 vs 0.6 days) and a mean total length of stay (4.0 vs 4.5 days). The study showed that patients that underwent robotic lobectomies had a shorter duration of analgesic use post-operatively (p=0.039) and a shorter time resuming to normal everyday activities (p=0.001). A limitation in this study was an inaccurate record of the amount of pain relief used by the patients, ultimately working as a confounding factor when interpreting the results. In a separate study by Jang et al. [18] 40 patients undergoing RAL were compared retrospectively to 80 VATS patients (40 initial patients and 40 most recent patients), all with resectable non-small cell lung cancer. The study showed that the post-operative median length of stay was significantly shorter in RAL patients compared to the initial VATS patients. The rate of post-operative complications was significantly lower in the RAL group (10%) compared to the initial VATS group (32.5%) and similar to the recent VATS group (17.5%). Post-operative recovery was easier for patients in both the RAL and VATS group due to earlier mobilisation, allowing them to return to their everyday activities quicker. In a retrospective review by Kwon et al. [17] 74 patients undergoing robotic surgery, 227 patients undergoing VATS and 201 patients undergoing anatomical pulmonary resection were assessed and compared with regard to acute (visual pain score) and chronic pain (Pain DETECT questionnaire). The study showed that there was no significant difference in acute or chronic pain between patients undergoing robotic assisted surgery and VATS. Despite no significant difference in pain scores, 69.2% of patients who underwent robotic-assisted surgery felt the approach affected their pain versus 44.2% of the patients who underwent VATS (p=0.0330). These results all support the superiority of robotic surgery over VATS and open approaches with regard to pain, length of hospital stay and recovery times. Both robotic surgery and VATS have their benefits i.e. two-versus three-dimensional view, instrument manoeuvrability, and reduced post-operative pain.

Conclusion

Since post-thoracotomy pain is multifactorial, a multimodal approach is required. In particular, ICNB blocks the intercostal nerves, and PVB and TEA appear to block the intercostal and sympathetic nerves. NSAIDs and opioids are required as valgus and phrenic nerve cannot be blocked by regional anaesthesia. TEA is evident to be the most effective in treating pain alongside with PVB. It is however associated with more side effects than PVB.

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The Effects of Freeze-Thaw Cycles and of Storage Time on the Stability of Proakap4 Polypeptide in Raw Sperm Samples: Implications for Semen Analysis Assessment in Breeding Activities

Abstract

Evaluation of the concentrations of the sperm macromolecule called proAKAP4, has been successfully introduced as a pertinent sperm parameter to assess sperm quality and high concentrations of proAKAP4 was shown to be highly correlated with sperm motility and fertility in large mammals. The sandwich ELISA kits known as Pig 4MID® Kits allowed the artificial insemination stations to monitor sperm quality more accurately with threshold values qualifying each ejaculate and animal. Introducing new methods and procedures are always challenging and sperm frozen collections have been suggested to standardize sperm assessment in daily routine. We thus have designed an experimental study to assess proAKAP4 stability and integrity in neat frozen ejaculates. Following baseline measurements, fresh ejaculates were aliquoted and stored at -20 °C for stability experiments up to 6 months and following up to 10 freeze-thawing cycles. ProAKAP4 concentrations were assayed at each time point using the Pig 4MID® Kit and western blot. Median or mean changes from baseline concentrations were evaluated statistically. We showed that the frozen storage conditions neither modified the total proAKAP4 concentrations nor changed the degradation rates of the proAKAP4 into mature AKAP4, that should in turn ensures signaling, capacitation and motility. This sperm parameter was shown then to be robust for semen quality analysis on fresh and on frozen neat semen. Taken together, proAKAP4 polypeptide can be considered as a highly stable analyte when kept frozen in raw semen up to the semen quality analysis using the Pig 4MID® Kit

Keywords: Boar; Proakap4; 4MID®; Fertility; Stability; Precursor; Freeze-thaw cycle; Storage; Semen processing

Abbrevations: AKAP4: A-kinase Anchor Protein 4; PKA: Protein Kinase A; CASA: Computer Assisted Semen Analysis

Introduction

ProAKAP4 concentrations are considered as a new sperm parameter that have been validated by field studies for sperm analysis assessment in large mammals [1-6]. Measurement of proAKAP4 concentrations was thus reported to generate pertinent information to guide the prognosis of sow fertility and prolificity in highly competitive breeding activities [1,4]. This quantitative approach of semen assessment is based on a sandwich ELISA method that allow to compare up to 87 semen simultaneously and is commercialized under the brand name of the 4MID® Kits (4BioDx, France). The Pig 4MID® Kits provide then a reliable and valuable figure reflecting the amount of proAKAP4 in pig ejaculates, with threshold values that are allowing a follow-up of the sperm quality inside and between pig breeding centers. Structurally, proAKAP4 is a precursor protein and will have to be converted by motile and alive spermatozoa in AKAP4 (A-kinase anchor protein 4) that in turn, coordinate the main transduction signals regulating sperm motility, capacitation and fertility [1,7-11]. ProAKAP4 concentrations has been reported to be correlated with total and progressive motility in stallion, in human and in bull [2,3,6,12,13]. Clearly the proAKAP4 concentrations is a reflect of the sperm motility giving a more objective figure compared to microscopic observations of the spermatozoa that are motile only at the time of analysis. In contrast, with the Pig 4MID® Kit, the more the proAKAP4 concentration is high in the ejaculate, the more the spermatozoa will be motile and efficient to go up to the site of fecundation. They have been evidences that spermatozoa with few or without proAKAP4 will be less motile or immotile and then infertile [14-18]. Therefore, we considered as essential to determine the stability and integrity of the full-length proAKAP4 in frozen storage conditions before the critical step of the sperm quality analysis. Data concerning the effects of freezing, thawing, and long-term storage effect on sperm proAKAP4 concentrations were not yet available in the literature. In this study, we aimed then to examine the analytical stability of proAKAP4 in fresh boar semen. We then assess the variations of proAKAP4 concentrations and proAKAP4 degradation rates in following freeze-thaw cycles and in long-term storage at minus 20 °C, in a final goal to improve operating procedures for semen analysis in swine breeding centers.

Materials and Methods

Sperm Preparation

Fresh boar sperm samples (Large White strain) were obtained from a boar stud and was first checked for total volume. They were then aliquoted into 1.5-mL polypropylene cryovials for the stability experiment. For stability assessment, the sampling of each ejaculate was then composed of 5 aliquots (2 for freezethaw cycle experiment and 3 for long-term storage experiment). Following baseline measurement (T0), they were all maintained frozen until analysis. The remaining boar ejaculates were either processed for the control quality experiment or for proAKAP4 expression controls. Samples stored at -20 °C were kept in a freezer equipped with a temperature recorder.

Freeze thaw Cycles and Long-term Storage Experiments

After 24 hours, 2 frozen sperm aliquots were thawed at room temperature until completely thawed, and then mixed properly with a micropipette before analysis (freeze-thaw 1). Samples were immediately re-frozen at -20 °C. This cycle was repeated for ten consecutive time points (T1, T2, T3, T4, T5, T6, T7, T8, T9, T10) to yield freeze- thaw processing. A group of 3 semen aliquots were stored at -20 °C for up to 1, 3 and 6 months, and then analyzed for stability at three-time intervals (T1M, T3M, T6M). As described below, the concentrations of proAKAP4 were assessed at each time point using the Pig 4MID® Kit (4BioDx, France). In parallel, proAKAP4 expressions and metabolism of the same aliquot were examined by western blotting. The results were compared with those obtained from the initial analysis of fresh samples. Median or mean changes from baseline (T0) concentrations were evaluated statistically.

Spermatozoa and Seminal Plasma Preparation from Boar Semen

A volume of 500μL of the remaining fresh semen was added in a 1.5mL Eppendorf tube and then centrifuged during 10 min at 2000rpm. The supernatant over the spermatozoa pellet was recovered with a 200μL micropipette and corresponded to the seminal plasma fraction. One volume of Tris Buffer (10 mM Tris HCl pH 6.8) with 2% SDS was added to the seminal plasma and sonicated at 22kHz (15 Watts) for 30 seconds. In parallel, 250μL of Tris Buffer with 2% SDS was added to the spermatozoa pellet, mix thoroughly with a vortex and then sonicated for 30 seconds (22 kHz, 15 Watts). Protein concentrations were determined using the Bradford’s method (BioRad, France). Then 50μL of the Tris-SDS sample was added to 1 volume of 2x concentrated NuPAGE LDS Sample Buffer (ThermoFisher, USA) and 10μL of NuPAGE Sample Reducing Agent (ThermoFisher, USA). Samples were vortexed and heated at 80 °C for 10 min.

Analysis of pig ProAKAP4 Expression and Metabolism by Western Blot

Equal protein concentrations of each sperm preparation were loaded on polyacrylamide gel (4-12% NuPage Precast Gels) and then transferred onto 0.45μm nitrocellulose membranes (G&E Healthcare, USA) using the Liquid Transfer System (Life Technologies, USA). Membranes were incubated overnight at 4 °C with the first antibody at a dilution of 1:4000 in 25 mM Tris-HCl (pH 8.0), 150 mM NaCl, 0.1% (v/v) Tween 20 (TNT Buffer), either with the clone 7E10, a monoclonal antibody anti-AKAP4 (4BioDx, 4BDX-1602, France), or with the clone 6F12, a monoclonal antibody anti-proAKAP4 (4BioDx, 4BDX-1701, France). After washing 3 times in TNT (10 min), each membrane was incubated with the secondary anti-mouse antibody coupled to horseradish peroxidase at 1:50000 diluted (Vector Laboratories, Burlingame, CA USA) and revealed with the ECL™ chemioluminescence kit (G&E Healthcare, USA). Images were acquired using the Image Quant™ LAS 4000 system (G&E Healthcare, USA).

The Pig 4MID® ProAKAP4 ELISA Assays

Thawed semen samples (respectively 50, 25 and 12μL) were mix with the Pig Lysis Buffer (450, 475 and 488μL) and then proceeded for ELISA quantification using the Pig 4MID® Kit (4VDX-18K2) according to the manufacturer’s instructions (4BioDx, France). Briefly, 100μL of semen lysates was then added to each well of the antibody-coated plate. A solution with conjugated proAKAP4 antibody was then added and after appropriate washing, the complexed sandwich was incubated with a substrate solution. The resulting color intensity was proportional to the amount of proAKAP4 present in each semen sample and could be measured by spectrophotometry at 450nm. A standard curve was determined in parallel for precise concentrations of proAKAP4 in the pig semen sample. Results of proAKAP4 concentrations were always expressed in ng/mL.

Statistical Analysis

Statistical analysis was achieved using Prism 8.2 GraphPad software (GraphPad Software, USA). D’Agostino and Pearson normality tests were performed to determine if the populations were following a Gaussian distribution and Pearson correlation coefficients were determined for each proAKAP4 concentration. The threshold for statistical significance was set to be p<0.05. In normally distributed groups, results were presented as mean ± standard deviation. The significant differences from T0 value were determined by a non-parametric paired samples t-test Mann Whitney U-test. Stabilities of proAKAP4 after freeze thaw cycles and after long term storage were assessed by the percentage change from T0 for paired groups (T0-T1, T0 -T2, etc. and T0 – T1M, T0 -T3M, etc.). Bias was calculated by the formula: [(CX - C1)/C1] × 100%, with C1: the mean or median of the T0 sample; and Cx: the mean or median of the experimented sample. For non- Gaussian groups, median variations from T0 were determined by non-parametric Friedman test and Wilcoxon signed rank test

Results

ProAKAP4 Expression in Boar Raw Semen

As observed previously from other mammals [1-3] proAKAP4 was only expressed in spermatozoa preparation and not in the seminal liquid as revealed with the monoclonal antibody (clone 6F12) against proAKAP4 (Figure 1). The proAKAP4 was cleaved in AKAP4 mature protein and the prodomain was released (Figure 1A). This cleavage and metabolism of the precursor proAKAP4 can also be followed by western blotting using specific monoclonal antibodies such as the clone 7E10 which recognized the C-terminus of both proAKAP4 and AKAP4 (Figure 1B). Therefore, in this initial T0 experiment, we observed the same amount of proAKAP4 and AKAP4 in the spermatozoa preparation sample of the fresh pig ejaculate. As expected, we confirmed that proAKAP4 is a spermatozoa specific protein expressed in the flagellum of pig spermatozoa

Stability of Boar proAKAP4 during Freeze-Thaw Cycles of the Same Aliquot

The concentration of proAKAP4 was measured in the ejaculate using the Pig 4MID® Kit as T0 value for the stability experiments. The initial mean concentration of ProAKAP4 was of 50.7 ± 1.3ng / mL, reflecting a high-quality semen [1]. After semen aliquots have been frozen and thawed up to ten times, there were no statistically significant differences in proAKAP4 concentrations as quantified using the Pig 4MID® Kit from T0 to T10 (Table 1).

All concentrations were in ng /mL and indicated as a mean± SD and median (interquatile ranges). Clearly, the proAKAP4 concentrations were not modified statistically after ten freezethaw cycles and the global percentage of variations was at 9.54%. Dilutions of the neat semen (half and quarter dilution factor) had no effect on the recovery of proAKAP4 concentrations as shown graphically on Figure 2. These dilutions highlighted the robustness of the Pig 4MID® Kit to quantify accurately the amount of the proAKAP4 polypeptide in neat pig semen. We checked then the expression and metabolism of proAKAP4 by western blotting (Figure 3). None of proAKAP4 and AKAP4 expressions or metabolisms were altered by the freeze-thaw cycles. Neither the integrity of proAKAP4 or AKAP4 was shown to be altered along the 10 freeze-thawing cycles and proAKAP4 was not further converted into AKAP4 showing that proAKAP4 and AKAP4 processing were not modified by freeze thawing cycles. The proAKAP4 was therefore considered as a very stable analyte when kept frozen in raw semen until we performed the Pig 4MID® Kit analysis

Stability of the Frozen proAKAP4 Polypeptide in longterm Storage Conditions

They were no significant variation in proAKAP4 concentrations as measured with the Pig 4MID® Kit for fresh pig sperm when stored until 6 months at -20 °C (Table 2). No variations were obtained when stored at - 80 °C (data not shown). Statistical significances were evaluated as described in the Materials and methods section. Our results showed that total proAKAP4 concentrations were clearly stable up to six months of storage at -20 °C with the variation in proAKAP4 concentration always below 5%. The western-blot analysis displayed no degradation of the sample stored at -20 °C from up to 6 months highlighting the robustness of the protein when kept frozen in raw semen (data not shown).

Intra-assay and Inter-Assay of the Pig 4MID® Kit

We further assess the robustness of the Pig 4MID® Kit by evaluation of the intra-assay and inter-assay CV’s on the Pig 4MID® Kit with neat pig semen as in the design of our study. These intra-assay and inter-assay CV’s were performed with two different ejaculates of the same animal (Table 3). Inter-assay variation was assessed from 10 determinations (with 2 aliquots each day) on ten consecutive study days, and intra-assay variation was calculated from eight sequential determinations obtained from the first day of the study period

Discussion

This study examined the storage effects and repeated freezethaw cycles on pig proAKAP4 sperm protein integrity in preanalytical conditions (meaning before the 4MID® Kit procedures) to evaluate the robustness of this new parameter in daily routine of semen analysis for swine breeding activities. We clearly show that proAKAP4 polypeptide is highly stable when frozen at minus 20 °C, for a long time period (up to 6 months) and will not be altered by multiple freeze-thaw cycles in neat semen. These data are of importance as they highlighted for the first time, that specimens of one ejaculate can be aliquoted and kept at minus 20 °C until their analysis and shipped from AI stations to central laboratories without loss of proAKAP4 integrity.

The reason of this stability could be due to the localization and the inherent functionality of the proAKAP4 itself. As shown on Figure 1, the proAKAP4 is a sperm specific protein that is neither found on the membrane nor released in the seminal plasma. The proAKAP4 polypeptide is inside the spermatozoa, more precisely in the fibrous sheath of the principle piece of the flagellum [19-22] and will need to be released from the fibrous sheath to be further quantified using the 4MID® assay. ProAKAP4 has been shown to be strictly localized to the principal piece of the flagellum and not in other spermatozoa compartments [20-21], tightly anchored to the fibrous sheath, along the longitudinal columns and ribs of the sperm tail [2,3,20-21].

According to the Pig 4MID® assay procedure, the proAKAP4 has then first to be extracted from the spermatozoa. Proteins markers described in sera or in seminal fluids [1,23] are frequently reported to suffer from the shear stress induced in buffered solutions and from long-term storage conditions. In contrast of what we reported with sperm proAKAP4, proteins in buffer solution can be fragile and they may even acquire conformations susceptible to degradation during frozen and post-thawed conditions. Clearly, proAKAP4 concentrations appears to be stable as long as the polypeptide is maintained in neat semen within the spermatozoa flagellum, with the fibrous sheath bringing stability for proAKAP4 integrity. The maintenance of proAKAP4 as a fulllength precursor is then important for the aliquot processed for the initial quality assessment of the ejaculate and at further steps, for the quality control during dose processing in AI stations. High proAKAP4 concentrations in the ejaculate and then in doses, will ensure to have enough motile and functional spermatozoa populations in the hours post the artificial insemination

The total amount of proAKAP4 per spermatozoa is fully synthetized within the testis and before ejaculation. Therefore, an aliquot of the ejaculate could be frozen immediately after semen collection in boar studs as this will represent the exact picture of the long-term motility of the spermatozoa. Freezing of an aliquot of ejaculate at collection point will then facilitate the analysis of semen (related to the proAKAP4 concentration) and favors also transport of such aliquot up to external laboratories. Our results clearly showed that degradation rates of the proAKAP4 were not impacted by frozen storage conditions of the aliquot and are in favor of such collection for delocalized sperm quality assessments. Furthermore, proAKAP4 stability when stored in aliquots in sperm frozen collections, will allow to better take in account technical and logistical constraints such as i) delays in shipping frozen aliquot when in need to analyze hypofertile animal; ii) being less dependent of any power cut or voltage fluctuations of the low-cost freezers; or the use of frost-free freezer that goes through numerous defrost cycles, as may happen in small breeding centers.

In boar stud, the storage of frozen aliquoted samples could also be convenient to process all the semen in the same time to compare ejaculates of different animals at the end of collection time. The dose semen processing will then not be impacted as the 4MID® analysis will be completely run in 2 hours. The amount of proAKAP4 as a read out of sperm quality should add marketing values for AI stations by ensuring high quality semen. In swine industry, there is also a real interest to identify the best male and then to follow up the sperm production during exploitation. Boars are usually kept from 6 to 9 months in the AI stations. That will be of importance to have a stable parameter to follow animal along all his career and keeping a safe measure of the initial quality of the first ejaculate after quarantine. In this context, the storage of frozen aliquoted samples may allow likewise to identify genetical traits of interest in a particular pig strains, such as fertility, death at birth or litter size, that may be related to proAKAP4 levels of expression [1,24-27].

Finally, keeping frozen aliquots of pig semen could allow to reanalyze the same samples stored to confirm previous results or to perform additional analysis, establishing new path for boar sperm preservation investigations. Better understanding proAKAP4 stability allows now to compare ejaculates at different collection points and compared to extended semen which is being shipped and used many days later. The storage capacity of extenders should be then further explored in relation with proAKAP4 consumption and degradation rates, during several days and in chilled conditions, when spermatozoa will stay alive.

Conclusion

One of current challenge of the swine industry is to standardize the semen processing procedures within boar studs. The proAKAP4 parameter have been initially introduced to facilitate the identification of ejaculates of inferior motility and quality, that were not identified by classical sperm parameters, and that could then be withheld before their release into the field. Having a stable sperm parameter such as proAKAP4 that can be kept stable as frozen up to the analysis time should be further interesting for quality check control and to follow up this parameter evolution during all the boar career. Taken together, the proAKAP4 parameter stability present then multiple advantages in favor of harmonizing sperm quality assessment between laboratory and AI centers.

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Influence of oligochitosans and highly molecular chitosan on Lactobacillus bulgaricus cultivation

Abstract

It was established that decrease of oligochitosans with molecular masses 7.0, 25.4, 45.3 kDa concentration in the process of Lactobacillus bulgaricus cultivation leads to fermented dairy product pH reduction and titratable acidity increase. Further increase in titratable acidity and decrease of lactic acid microorganisms’ amount was determined during the fermented dairy product storage process. Oligochitosans with molecular masses 7.0, 25.4, 45.3 kDa in concentrations interval from 0.0025 to 0.01 per cent did not exhibit prebiotic properties. Active acidity elevation and titratable acidity depression was observed at the chitosan with molecular mass 350 kDa concentration rises. Also increase of highly molecular chitosan concentration leads to elevation of lactic acid microorganisms’ total amount, which was more than three degree as many as total count of lactic acid bacteria in control sample.

Keywords: Chitosan; Oligochitosan; Lactic acidbacteria; Lactose, Lactic acid fermentation; Lactic acid

Introduction

Starters of the Lactobacillus bulgaricus species pure cultures are widely used for manufacturing of functional fermented dairy products with dietary and health-promoting properties. The prospective way of fermented milks production technological development is enrichment with chitosan [1-3]. Chitosan is a biogenic heteropolymer consists of N-acetylglucosaminaine and glucosaminresidues [2,4]. Chitosan has high molecular mass and soluble in organic acids [5,6]. Low-molecular derivatives of chitosan are represented byolygochitosans with a molecular mass from 2 to 50 kDa, which are well soluble in water. Chitosan and olygochitosans are able to interact with Lactobacillus bulgaricus cells by a different mechanism depending of their molecular mass [7-9]. Teichoic acid negatively charged molecules of lactic acidbacteria cells are capable to multi-point ion binding with positively charged high-molecular chitosan, whereas their cytoplasmic membrane proteins interact with oligochitosans [4,9]. The consequence of this process may be a change in metabolic processes in lactic acid bacteria cells. The goal of research was to study the effect of different concentrations of high-molecular chitosan and oligochitosans with varying molecular mass on lactic acid fermentation process driven by Lactobacillus bulgaricus.

Materials and Methods

Targets of research were skim milk, starter culture of lactic acid bacteria Lactobacillus bulgaricus (producer: Dairy Plant “Stavropolsky”, Russia), chitosan with a molecular mass of 350 kDa and a 95 per cent degree of deacetylation (manufacturer: “Bioprogress LLC”, Russia). Oligochitosans with molecular masses of 7.0, 25.4, 45.3 kDa and 96 per cent degree of deacetyration was prepared by the previously described technique [5]. Dry skim milk was reconstituted to a dry mass concentration of (10 ± 0.2) % by dissolving in distilled water at temperature 30 to 35 °C. Reconstituted skim milk after recombination was characterized by the following parameters: mass concentration of fat 0.15 per cent, mass concentration of protein 3.2 per cent,mass concentration of lactose 5 per cent. The solution of chitosan with molecular mass 350kDa in 2 per cent concentration lactic acid aqueous solution with mass concentration 1 per cent was added into skim milk experimental samples for preparation of mixture with final concentration of chitosan 0.0025, 0.005, 0.0075 and 0.01 per cent respectively. Similar experiments were carried out using oligohitosans with molecular masses of 7.0, 25.4, 45.3 kDa in above mentioned concentrations. The starter culture of Lactobacillus bulgaricus was inoculated in the amount of 3 per cent of the total samples volume after pasteurization of the mixture and cooling to the fermentation temperature of (43 - 45) °C. The end of the fermentation process was determined by organoleptic curd density, as well as by titratable and active acidity. Experimental and control samples were stored during 17 days at 4 ± 2 °С after completion of fermentation process. Following parameters were tested in triplicate during storage of control and experimental samples: pH by potentiometry, titratable acidity by titrimetric analysis and total count of lactic acid bacteria (CFU per gram).

Results and Discussions

The effect of highly molecular chitosan and oligohitosans with a molecular weight of 7.0, 25.4, 45.3 kDa various concentrations on fermented dairy products physical and chemical properties during the cultivation of Lactobacillus bulgaricus and long-term storage process was studied.

As shown in Tables 1 &2, decrease in the concentration of oligochitosans leads to significant decrease in pH and increase of titratable acidity after 20 hours of cultivation.

This is explained by the fact that oligohitosans with molecular masses of 7.0, 25.4, 45.3 kDa in concentrations of 0.0025 and 0.005 percent effectively interact with the proteins of the lactic acid bacteria cytoplasmic membrane. This interaction induces bacterial stress [10]. Consequently, lactose enzymatic hydrolysis and lactic acid production are accelerated resulting in titratable acidity increase. The elevation of oligohitosans concentration leads to promotion of their interaction with bacterial cells teichoic acid molecules. This type of interaction influences on lactic acid bacteria cells cytoplasmic membrane permeability and as a result inhibit rate of lactose metabolism. Highly molecular chitosan concentration variation did not lead to significant changes of pH and titratable acidity of fermented skim milk in comparison with control samples. Chitosan with a molecular mass of 350 kDa puts into effective multi-point ion binding with negatively charged teichoic acid molecules of Lactobacillus bulgaricus cells. This is due to the presence into highly molecular chitosan structure of about 1850 amino groups. Lactose assimilation and lactic acid formation rates are changed depending on highly molecular chitosan concentration.

Physical and chemical properties of fermented dairy products during long-term storage at 4 ± 2 °С were studied after the completion of the Lactobacillus bulgaricus cultivation process. It was established that optimal organoleptic attributes (taste and odor) of fermented product control sample are achieved after 5 days of storage at pH 4.2 - 4.5 and titratable acidity 70 - 140 °T. Organoleptic attributes of this product deteriorated during the further storage.

As shown in Table 3, optimal titratable acidity of fermented milks experimental samples containing oligochitosans at a concentration of 0.01 per cent persisted for up to 17 days. Further increase of titratable acidity of experimental samples containing oligochitosans at a concentration 0.0025, 0.005 and 0.0075 per cent was observed during the storage after the completion of the fermentation process.

Decrease in titratable acidity of fermented dairy product experimental samples was detected when concentration of chitosan with molecular mass 350 kDa increased in interval from 0.0025 to 0.01 percent. Therefore high-molecular chitosan concentration elevation reduces the intensity of lactic acid fermentation in experimental samples. The most powerful process of lactose homo fermentative fermentation inhibition occurred in a sample containing high-molecular chitosan in concentration of 0.01 per cent. The decrease of lactose assimilation intensity by Lactobacillus bulgaricus cells may be propelled by two reasons. The interaction between chitosan molecules and lactic acid bacteria cells cytoplasmic membrane leads to disturbance of membrane permeability for β-galactosidase enzyme, which catalases the reaction of lactose into glucose and galactose hydrolysis. At the same time structural changes in cell cytoplasmic membrane cause retardation of lactose hydrolysis products active transport into bacterial cells.

Thus, there is an inhibition of lactic acid formation in the process of fermented dairy product containing high-molecular chitosan storage, which stimulates the preservation of a large number of lactic acid bacteria. This is confirmed by the data of lactic acid microorganisms ‘quantitative accounting in control and experimental samples after 17 days of storage, as shown in Table 4.

The data presented in Table 4 indicates that oligohitosans with molecular masses of 7.0, 25.4, 45.3 kDa did not affect significantly on Lactobacillus bulgaricus grows rates during fermented dairy products storage process. Addition of highly molecular chitosan in concentrations of 0.0075 and 0.01 per cent in fermented milks increased the content of lactic acid microorganisms,which was more than three degree as many as total count of lactic acid bacteria in control sample.

Thus, tested samples ofoligohitosans with varying degrees of polymerization did not exhibit prebiotic properties and did not prolong the shelf life of fermented dairy products. High-molecular chitosan in a concentration of 0.01 per cent can be recommended as a prebiotic, prolonging the shelf life of fermented milks, manufactured with application of Lactobacillus bulgaricus starter cultures.

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Governments should endorse a global moratorium on mRNA vaccines until all questions about their safety have been thoroughly investigated, according to the authors of a new, peer-reviewed article on the COVID-19 vaccine trials and the global vaccination campaign published last week in Cureus, Journal of Medical Science.

Cureus is a web-based peer-reviewed open-access general medical journal using prepublication peer review.

The authors surveyed published research on the pharmaceutical companies’ vaccine trials and related adverse events. They also called for the COVID-19 vaccines to be removed immediately from the childhood immunization schedule.

After the first reports from vaccine trials claimed they were 95% effective in preventing COVID-19, serious problems with method, execution and reporting in the trials became public, which the paper reviewed in detail.

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Authors M. Nathaniel Mead, Stephanie Seneff, Ph.D., Russ Wolfinger, Ph.D., Jessica Rose, Ph.D., Kris Denhaerynck, Ph.D., Steve Kirsch and Dr. Peter McCullough detailed the vaccines’ potential serious harms to humans, vaccine control and processing issues, the mechanisms behind AEs, the immunological reasons for vaccine inefficacy and the mortality data from the registrational trials.

They concluded, “Federal agency approval of the COVID-19 mRNA injectable products on a blanket-coverage population-wide basis had no support from an honest assessment of all relevant registrational data and commensurate consideration of risks versus benefits.”

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Related Journals: The New England Journal of Medicine, Blood Transfusion, Medicine and Healthcare Journal, Iron Chelation Therapy Journal, Blood Journal, Scientific World Journal, Global Journal of Medical Research, Occupational Medicine & Health Affairs Journal, Journal of Experimental Botany, Iranian Journal of Toxicology, Journal of Heavy Metals Toxicity and the Environment, International Journal of Toxicology Heavy Metal Poisoning and Cardiovascular Disease, Heavy metal poisoning from Ayurvedic medicines.

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Related journals of Medical Imaging Clinical Images and Case Reports Journal, International Journal of Clinical & Medical Imaging, Clinical & Medical Biochemistry: Open Access, Imaging and Interventional Radiology, Medical Diagnostic Methods, BMC Medical Imaging, Journal of Medical Imaging, Open Journal of Medical Imaging, International Journal of Medical Image, Medical Imaging and Radiology, Journal of Medical Imaging and Radiation Sciences

Image Journal in Emergency Medicine Emergency medicine is a medical specialty and is the practice of medicine concerned with the diagnosis and treatment of unforeseen illness or injury that require immediate medical attention. The emergency physician’s role is to assess; treat, admit, or discharge any patient that seeks medical attention at any time of day or night.

Related journals of Emergency Medicine Evidence based medicine and practice, Emergency Medicine Journal, The Journal of Emergency Medicine, American Journal of Emergency Medicine, European Journal of Emergency Medicine, The American Journal of Emergency Medicine, Academic Emergency Medicine and International Journal of Emergency Medicine.

Image Journal in Laboratory Medicine Laboratory medicine is also called as clinical pathology. In laboratory medicine the pathologists will perform tests on patient samples (usually blood or urine) in several different areas.

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Exploring Innovations in Pharmaceutical Science: A Glimpse into the Indian Journal of Pharmaceutical Science

Introduction:

The field of pharmaceutical science is a dynamic and ever-evolving domain that plays a crucial role in advancing healthcare globally. In this context, the Indian Journal of Pharmaceutical Science (IJPS) stands out as a beacon of knowledge, providing a platform for researchers, scientists, and practitioners to contribute to the growth and development of pharmaceutical sciences in India and beyond.

Background:

The Indian Journal of Pharmaceutical Science, often abbreviated as IJPS, is a peer-reviewed, open-access journal that covers a wide spectrum of topics within the pharmaceutical sciences. Established with the mission of fostering research and innovation in the field, the journal serves as a valuable resource for academics, researchers, and industry professionals. It provides a platform for the dissemination of cutting-edge research, reviews, and advancements in pharmaceutical science.

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Pharmacology and Toxicology: IJPS explores the effects of drugs on biological systems, highlighting their therapeutic benefits and potential risks. This section includes studies on pharmacokinetics, pharmacodynamics, and toxicological assessments.

Pharmaceutical Chemistry: Researchers contribute to the understanding of the chemical aspects of drug design, synthesis, and analysis, paving the way for the development of novel and more effective pharmaceuticals.

Pharmacognosy and Phytochemistry: The journal delves into the study of medicinal plants and natural products, exploring their therapeutic properties and potential applications in drug development.

Clinical Pharmacy and Pharmacy Practice: IJPS features research on the clinical aspects of pharmacy, including patient care, medication management, and the role of pharmacists in healthcare.

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[naresh12-08-2002]

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Introduction:

The field of pharmaceutical science is a dynamic and ever-evolving realm that plays a crucial role in improving healthcare globally. Among the plethora of resources available to researchers, scholars, and practitioners, the Indian Journal of Pharmaceutical Science  stands out as a distinguished platform for disseminating cutting-edge research and advancements in this domain.

Overview of the Indian Journal of Pharmaceutical Sciences:

The Indian Journal of Pharmaceutical Science, established with the aim of fostering scientific research and innovation in the field, serves as a beacon for pharmaceutical professionals. It is a peer-reviewed, open-access journal that publishes original research articles, reviews, and scientific commentaries covering a broad spectrum of pharmaceutical sciences.

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The journal explores the pharmacological effects and toxicological aspects of pharmaceutical substances. It delves into the mechanisms of action, side effects, and safety profiles of drugs, contributing valuable knowledge to ensure the well-being of patients.

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Bridging the gap between research and practice, IJPS includes articles on clinical pharmacy, patient care, and pharmacy practice. These contributions aim to enhance the role of pharmacists in patient care and healthcare systems.

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Image Journal: Image of Journal: Imaging Journal publishes clinical images, medical images, clinical imaging, medical imaging, medical illustrations etc. Journal also accepting case reports, case series and clinical videos in the areas of medical research. This is a quality controlled, peer-reviewed, open access INTERNATIONAL journal. Image Journal: Image of Journal: Imaging Journal publish research reports, and articles of various research processes like study protocols, pilot studies and pre-protocols.

Journal Homepage: https://www.literaturepublishers.org/

The journal is novel, attractive, open minded, and a peer-reviewed medical periodical designed to serve as a platform for both veteran and ammeter researchers with their path breaking works as long as they are technically correct and scientifically motivated. Subject areas include studies in fields of immunology, anesthesia, cardiovascular medicine, complementary medicine, dentistry and oral medicine, pathology, pharmacology and therapeutics, dermatology, respiratory medicine, rheumatology, drugs and medicines, ear, nose and throat/otolaryngology, emergency medicine, infectious diseases, neurology, nutrition and metabolism, obstetrics and gynecology, endocrinology, gastroenterology, genetics, geriatric medicine, hematology, oncology, ophthalmology, pediatrics, psychiatry, radiology, renal medicine, pharmacognosy, sexual health, urology, epidemiology, ethnic studies, health policy, occupational health, medical education, legal and forensic medicine, environmental medicine and public health, medicine development and safety testing, drug legislation and safety.

Manuscript Submission

Authors are requested to submit their manuscript by using Online Manuscript Submission Portal:

https://www.literaturepublishers.org/submit.html

(or) also invited to submit through the Journal E-mail Id: editor.cicrj@literaturepublishers.org

Medical Imaging Journal Medical imaging is the technique and the process creating of visual representations of body parts, tissues, or organs, for use in clinical diagnosis; encompasses x-ray methods, magnetic resonance imaging, single-photon-emission and positron-emission tomography, and ultrasound. Medical imaging, especially X-ray based examinations and ultrasonography, is crucial in every medical setting and at all levels of health care.

Related journals of Medical Imaging Clinical Images and Case Reports Journal, International Journal of Clinical & Medical Imaging, Clinical & Medical Biochemistry: Open Access, Imaging and Interventional Radiology, Medical Diagnostic Methods, BMC Medical Imaging, Journal of Medical Imaging, Open Journal of Medical Imaging, International Journal of Medical Image, Medical Imaging and Radiology, Journal of Medical Imaging and Radiation Sciences

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Related journals of Emergency Medicine Evidence based medicine and practice, Emergency Medicine Journal, The Journal of Emergency Medicine, American Journal of Emergency Medicine, European Journal of Emergency Medicine, The American Journal of Emergency Medicine, Academic Emergency Medicine and International Journal of Emergency Medicine.

Image Journal in Laboratory Medicine Laboratory medicine is also called as clinical pathology. In laboratory medicine the pathologists will perform tests on patient samples (usually blood or urine) in several different areas.

Related journals of Laboratory Medicine Annals of Clinical and Laboratory Research, La Prensa Medica, Drug Metabolism & Toxicology, Pharmaceutics & Drug Delivery Research, Drug Intoxication & Detoxification: Novel Approaches, The Journal of Laboratory and Clinical Medicine, African Journal of Laboratory Medicine, Pathology & Lab Medicine Journals, Journal of Pathology and Laboratory Medicine International, Archives of Pathology & Laboratory Medicine, Archive of "The Korean Journal of Laboratory Medicine", Journal of Medical Laboratory and Diagnosis, Clinical Chemistry and Laboratory Medicine

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A Review on Diabetic Nephropathy: New Insight into Established Therapeutic Approach

Abstract

Background: Diabetic nephropathy (DN) is a principle cause of morbidity and mortality in both type 1 and type 2 diabetes mellitus. DN plays a major role in development of cardiovascular disease, in particular heart failure, the incidence of which is about 15-fold greater in patient with diabetic nephropathy. Approximately 30-35% of patients with type 1 type 2 diabetes develops diabetic nephropathy. DN is represented by microalbuminuria and macroalbuminuria and morphological changes as like glomerular thickening, interstitial fibrosis, formation of nodular glomerulosclerosis and decreased endothelial cell fenestration. Additionally, the association of renin-angiotensin-aldosterone system, wnt signaling pathway and genetic factors are the major pathway in the progression of diabetic nephropathy.

Conclusion: This review is intended to establish a new insight into traditional therapeutic approach for diabetic nephropathy. Along with potential targets, novel approach such as epigenetic drugs and miRNA modulators may compliment the current therapeutic approach to improve renal function.

Keywords: Diabetic nephropathy; Microalbuminurea; Macroalbuminuria; Glomerulosclerosis

Introduction

Diabetic nephropathy is associated with increased albumin excretion, decreased glomerular filtration rate, glomerular lesion and increased arterial blood pressure [1]. DN can be divided into 5 stages of kidney dilapidation, and symptoms appear in stage 4. All patient should be screened for albuminuria at least once per year for kidney complication. The significant signs of step 4 are swelling of ankles, legs and hands because of water retention, hematuria, fatigue and nausea. If this condition remains untreated may lead stage 5, end-stage renal disease (ESRD) [2]. In stage 5, the kidney can no longer function to meet the daily requirement and microalbuminuria (>300mg/24h), progress to extensive proteinuria (>500mg in 24 h). Various factors linked with end-stage renal diseases are hemodynamic changes, inflammation and hyperglycemia [3]. The mechanism involved in the progression of DN is still on the question. Many researchers have determined an interrelationship between the degree of hyperglycemia and progression of DN complications [4]. As because a number of pathways involved in diabetic nephropathy, treatment should be multi-targeted, encouraging a healthy lifestyle and molecular targets associated in progression of DN. Available treatment procures only symptomatic alleviation and incapable of treating the underlying pathophysiology of diabetic nephropathy.

Pathogenesis of Diabetic Nephropathy

Role cytokines in diabetic nephropathy

Studies suggested that patient suffering from diabetic nephropathy have increased serum and urine level of tumor necrosis (TNF)-alpha [5]. It had been reported that TNF-alpha, IL-6, IL-1 associated in the progression of DN, found to be involved in the impairment of interglomerular hemodynamic [6].

Genetic association in diabetic nephropathy

Angiotensin-converting enzymes (ACE)

The dysfunctional ACE gene produce excess amount of aldosterone which causes fibrosis of blood vessels and aldosterone is also found to be associated with formation of extracellular matrix and fibronectin by mesangial cells by activation of the smad2-dependent TGFB1 pathway [7].

Oxidative stress in diabetic nephropathy

Oxidant species produced by oxygen metabolism and are required in different biological operation such as cell signalling, degenerative disease, aging etc [8]. Various pathophysiological mechanisms involved in DN pathogenesis in which increased oxidant species have been recognized as the single underlying strenuous event therefore, elevated oxidant species accommodates a decisive central and significant role in the pathogenesis of diabetic nephropathy. In vitro and in vivo experimental models of diabetes have determined that metabolic (hyperglycemia, dyslipidaemia) and hemodynamic (systemic and glomerular hypertension) insults define the two principal drivers of oxidative stress in the diabetic kidney [9]. Overexpression of glucose transport because of metabolic- hemodynamic interaction, synergistically fuels an increase in oxidant species production and development of DN and other diabetic microvascular diseases. Oxidant species causes the damage in all the layers of the glomerular filtration barrier, functional alterations of the interaction between glomerular endothelial cells with glycocalyx layer and podocyte [10].

Conventional Drugs for Diabetic Nephropathy

Glucose lowering agent in diabetic nephropathy

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been used for reducing hyperglycemia because SGLT2 is responsible for reabsorbing of the glucose in the glomerular infiltrate. Empagliflozin, an SGLT2 inhibitor, slower the progression of kidney diseases [11]. Dipeptidyl peptidase -4(DPP-4) inhibitors such as linagliptin and saxagliptin (SAVOR-TIMI 53 trial) known to reduce the amount of albuminuria [12].

Cyclooxygenase (COX) and Xanthine oxidase (XO) inhibitor in diabetic nephropathy

Aspirin as a non-specific and others specific COX-2 inhibitors improve glomerular lesion, in pre-clinical models of diabetes [13]. Purine xanthine oxidase (XO) inhibitor reduce inflammation and oxidative stress in diabetic nephropathy [14].

Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and diabetic nephropathy

It was reported that statins amend renal dysfunction and reduce renal injury by inhibition of isoprenylation of Ras and Rho GTPases. Which may lead to decreased monocyte/macrophage infiltration and activating protein-1 (AP-1) in the glomerulus, adhesion of molecules, decreased mesangial proliferation and decreased accumulation of extracellular matrix and fibrosis [15].

Endothelin receptor antagonist in diabetic nephropathy

Avosentan, an endothelin-1 receptor A antagonist, found to reduce albuminuria. A study conducted on randomized controlled trial on 56 patients treated with oral bosentan for 4 weeks improves peripheral endothelial function [16].

Antioxidants against diabetic nephropathy

Pyridoxamine can remove free radicals and carbonyl product, and block the synthesis of AGEs. Pyridoxamine phase II trials showed the normal renal function had lower average serum creatinine level. Currently PIONEER -CSG -17 trial investigating to prove such benefit about use of pyridoxamine [17]. It has been reported that teneligliptin is a DPP-4 inhibitor with antioxidant.

MicroRNA and diabetic nephropathy

Under hyperglycemia conditions, up regulated micrRNAs result in pathogenesis of diabetic nephropathy [18]. It was suggested, miR-192 & miR-200 contribute to stimulate of TGFbeta 1 and fibrosis, which may consequently cause renal damage [19]. Therefore, miRNA may inhibit diabetic nephropathy by regulating various biological processes. Application of kidney protective miRNAs and knockout of inducing miRNA could be some of the approaches to restoring renal function in diabetic nephropathy [20].

Future Prospect of Drugs for Diabetic Nephropathy

Recent studies are gathering the evidence about involvement of autophagy with DN because of its cryoprotective activity in the kidney [21]. mTOR may suppress autophagy. mTORC1 inhibitors such as rapamycin or sirolimus have been found to be effective as renoprotective agents except for the negative effect on renal function and proteinuria [22].

Update on Recent Clinical Trials

Due to the distinct and complicated pathogenic mechanism associated with DN the failure rate of potential new drugs in clinical trials above 90% with only a fistful of these therapies achieving phase III trials. Summarizing the outcome of recently completed clinical trials in the past 5 years (2013-2018) and shown in Table 1 [23].

Conclusion

Diabetic nephropathy remains one of the most prevalent and life-threatening complications of diabetes. Diabetic nephropathy cases increasing rapidly around the world. Recently available therapies provide only symptomatic relief and not capable to treat underlying pathophysiology of diabetic nephropathy. This review has discussed the many factors and pathophysiological mechanisms associated with the progression of diabetic nephropathy, targets and therapeutic approaches to reduce renal impairment and improve kidney function. It also provided with new insights into the treatment of diabetic nephropathy. Novel biomarkers holding strong potential requires further clinical studies. The review also focused on the future prospect of drug for the treatment of diabetic nephropathy and update of recent clinical trials of targets for the treatment of diabetic nephropathy. A combination of therapies with epigenetic drugs and miRNAs modulators may fulfil the current treatment strategy of diabetic nephropathy.

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Cardiovascular Therapy: Cardiovascular Disorders Journal

Cardiovascular Therapy: Case Reports Journal publishes Images in Cardiovascular Therapy, Case Reports in Cardiovascular Therapy, Cardiovascular Disorders Journal, Cardiovascular Cases etc. Cardiovascular Therapy is a scientific, peer-reviewed journal that presents original articles on topics covering the entire spectrum of practical, clinical approach to the diagnosis and treatment of cardiovascular disease. 

Cardiovascular Therapy: Case Reports Journal also publishes timely and informative reviews on scientific areas in cardiovascular therapy as well as case reports, book reviews, clinical images, hypotheses and letters to the Editors.

Cardiovascular Therapy: Case Reports Journal focuses on the topics disease-oriented morphology and pathogenesis from clinicians and scientists in the cardiovascular field. Subjects covers all Cardiovascular Diseases such as Coronary Heart Disease, Angina, Heart attack, Congenital Heart Disease, Stroke, Cardiovascular Biology and Diseases, Ischemic Heart Disease, Coronary Artery Diseases which includes angina and myocardial infarction etc.

Cardiovascular Biology Case Reports Journal

Cardiovascular biology is the study of the mechanisms of cardiovascular physiology and pathophysiology like functions and activities of the cardiovascular system as a whole or of any of its parts.

Related Journals of Cardiovascular Biology: Cardiovascular Disorders Journal, cardiovascular research journals, cardiovascular disorder journals, cardiovascular journal list, cardiovascular disorders, common cardiovascular disease, Cardiovascular Pathology Journal Anatomy & Physiology: Current Research, Advanced Techniques in Biology & Medicine, Biology and Medicine, International Journal of Cardiovascular Research, Cardiovascular Research, Journal of Cardiovascular Electrophysiology, Catheterization and Cardiovascular Interventions, Journal of Cardiovascular Pharmacology, CardioVascular and Interventional Radiology

Cardiotoxicity Case Reports Journal

Cardiotoxicity is a condition when there is damage to the heart muscle. It is the occurrence of heart electrophysiology dysfunction or muscle damage. The heart becomes weaker and is not as efficient in pumping and therefore circulating blood. This may be due to chemotherapy drugs, or other medications used to control respective diseases.

Related Journals of Cardiotoxicity: Cardiovascular Journals, Cardiovascular research Journals, Cardiovascular disorder Journals, Cardiovascular Journal list,Cardiovascular disorders, Common Cardiovascular disease, Cardiovascular Pathology Journal,Cardiovascular Pharmacology: Open Access, Anatomy & Physiology: Current Research, Cellular & Molecular Pathology, Journal of Clinical Toxicology, Journal of the American College of Cardiology, American Journal of Cardiology, Cardiovascular Research, Journal of Thoracic and Cardiovascular Surgery, Journal of Molecular and Cellular Cardiology

Paediatric Cardiology Case Reports Journal

Paediatric Cardiology is that branch of medicine concerned with the study of congenital cardiac malformations, acquired heart diseases and abnormalities of the systemic and pulmonary circulations in the foetus, newborn, child and young adult. It is the specialty concerned with diseases of the heart in the growing and developing individual.

Related Journals of Paediatric Cardiology: Cardiovascular Journals, Cardiovascular Research Journals, Cardiovascular Disorder Journals, Cardiovascular Journal List, Cardiovascular Disorders, Common Cardiovascular Disease, Cardiovascular Pathology Journal, Clinical Paediatrics: Open Access, Paediatric Emergency care and medicine- Open Access, Interventional Pediatrics & Research, Pediatrics & Therapeutics, Pediatric Cardiology, Progress in Pediatric Cardiology, Annals of Pediatric Cardiology

Atherosclerotic Cardiovascular Disease Case Reports Journal

Atherosclerosis is a disease in which plaque builds up inside arteries. Arteries are blood vessels that carry oxygen-rich blood to the heart and other parts of the body. Plaque is made up of fat, cholesterol, calcium, and other substances found in the blood. It is hardening and narrowing of the arteries which get a lot of bad press but with good reason. This progressive process silently and slowly blocks arteries, putting blood flow at risk.

Related Journals of Atherosclerotic Cardiovascular Disease: Cardiovascular Journals, Cardiovascular Research Journals, Cardiovascular Disorder Journals, Cardiovascular Journal List, Cardiovascular Disorders, Common Cardiovascular Disease, Cardiovascular Pathology Journal, Atherosclerosis: Open Access, Internal Medicine: Open Access, Current Synthetic and Systems Biology, Journal of Clinical & Experimental Cardiology, Atherosclerosis, Journal of Atherosclerosis and Thrombosis, Current Atherosclerosis Reports, Atherosclerosis Supplements, ARYA Atherosclerosis

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Publish your paper: Global Research Journal of Pharmacology & Toxicology

Publish your paper: Global Research Journal of Pharmacology & ToxicologyPharmacology is a field of study that examines how medications and naturally occurring mediators affect cells and the entire organism. Pharmacy is a distinct field of study in the health sciences that is frequently confused with pharmacology. Pharmacy makes use of the information from pharmacology to properly prepare and dispense medications in order to get the best therapeutic results.

The science of pharmacology integrates several other fields, including genetics, molecular biology, biochemistry, and physiology. The molecular understanding of signal transduction and transmission processes that control and obstruct particular cell functions is the primary goal of the pharmaceutical sciences. The development of novel medicines and treatment plans for a variety of disease processes is a key goal of our research programmes. This can be done, for instance, by disrupting particular cell surface receptor and signalling systems or by utilising brand-new gene-directed techniques.

There are two main branches of pharmacology:

The study of medication absorption, distribution, metabolism, and excretion is known as pharmacokinetics.

Drug molecular, biochemical, and physiological effects, including drug mode of action, are referred to as pharmacodynamics.

Pharmacodynamics, to put it simply, is what a drug does to the body, and pharmacokinetics, to put it simply, is what the body does to a drug.

Pharmacology has greatly benefited from the advancement of information regarding the cellular receptors that medications interact with. The phases in this process that are modulation-sensitive have been the focus of the creation of novel medicines. Pharmacologists can create more selective medications with fewer negative side effects by understanding how pharmaceuticals interact with biological targets.

Pharmacology is a field of study that examines how medications and naturally occurring mediators affect cells and the entire organism. Pharmacy is a distinct field of study in the health sciences that is frequently confused with pharmacology. Pharmacy makes use of the information from pharmacology to properly prepare and dispense medications in order to get the best therapeutic results.

Some of the most fascinating advancements in contemporary medicine are being led by the science of pharmacology, including:

Genomic and proteomic methods for personalised precision medicine and gene therapy

Regenerative medicine to enhance the growth of bioengineered tissues

Modeling and computation as tools for drug discovery

Biotechnology-based methods for battling disease

Toxicology and pharmacology

Toxicology is the study of how pharmaceuticals and substances in the environment cause adverse consequences, while pharmacology is the branch of science that examines how drugs modify biological systems in an effort to promote health and treat disease. Together, these fields cover the genetic differences in drug action, the molecular foundation of drug action, the effects of medications on cells, organs, and organisms, and drug discovery.

Research in pharmacology and toxicology is at the cutting edge of medical science because more medications will be launched in the next ten years than have been discovered in the last one hundred, and because there is a growing need for selective pharmacological therapies. Indiana University School of Medicine's Department of Pharmacology and Toxicology

Current Trends in Toxicology and Pharmacology Research

Developments in Pharmacology and Toxicology Today An open access, peer-reviewed magazine called Research accepts submissions on all facets of pharmacology, including toxicology, drug mechanisms of action, pharmacodynamics, pharmacokinetics, and hazardous substances. As long as the research makes a valuable contribution to the subject, journals have a policy of publishing work that is regarded by peer reviewers to be a logical and sound addition to scientific knowledge and to place less weight on interest levels. CTPTR welcomes your valuable original articles as part of its goal to provide credible sources of knowledge.

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Global Health Investigations

Global health research is a branch of study that aims to promote the health and well-being of people all over the globe. Its goals include illness prevention, life extension, and the promotion of physical, mental, and social well-being.

Most global health research focuses on illnesses and problems affecting individuals in high-income nations. However, global health is a burgeoning field focusing on issues in low-income nations.

The global health research ecosystem, which includes academic institutions, research networks, and other organizations, is based on an ethical commitment to balancing risks and benefits. This includes preserving and improving the public scientific record's integrity, communicating justifiable concerns about publishing ethics to authorities who can investigate, and safeguarding and encouraging various perspectives within the research community.

The US government's worldwide health research funding advantages include considerable domestic economic activity and scientific innovation. NIH Director Francis Collins said before Congress that every dollar invested in global health research creates $2.21 in products and services while producing an average of seven high-quality employment each year.

Researchers and policymakers often use randomized trials to examine the success of health initiatives, which may then be used to change global health policies. The decisions that researchers make when publishing the outcomes of these studies, on the other hand, may have a significant effect on how the public views the impact of these treatments.

The International Publication of Environmental Research and Public Health is an open-access journal that covers a broad range of global health topics. This publication offers a one-of-a-kind forum for scholars to communicate their knowledge of the environment and its influence on human health.

This journal has published original articles, review pieces, and brief communications. It also includes famous academics' guest essays and reviews.

MDPI publishes it online semi-monthly and covers Environmental Sciences and Engineering, Public Health, Occupational Hygiene, Health Economics, and Global Health Research.

The International Publication of Environmental Research and Public Health (IJERPH) is a peer-reviewed scientific journal that publishes research papers, critical reviews, research notes, and brief communications in environmental health science and public health. It integrates several scientific disciplines to solve environmental and health challenges, including biology, biochemistry, chemistry, microbiology, epidemiology, ecology, engineering, pharmacology, and toxicology.

The International Journal of Medical Sciences is a monthly peer-reviewed international online journal. It encompasses all aspects of medicine and health sciences research.

The journal's primary goal is to publish research that adds considerably to scientific knowledge in medicine and health science. The International Journal of Medical Sciences seeks to encourage the speedy publishing of high-quality, influential research in all fields of Medical Science, Clinical Research, and allied disciplines.

The journal is published under the Open Access format, which ensures that all papers are freely available to the public. This implies that as long as the source is correctly mentioned, users may read, download, copy, distribute, print, search, or link to the entire contents of the articles. This is advantageous for researchers since it assures that their work will be widely accessible.

The International Journal of Environmental Health Sciences accepts submissions on significant environmental and occupational medicine elements, as well as associated toxicology and epidemiological investigations. It aims to enhance the prevention of environmental hazards to human health.

This interdisciplinary journal brings together researchers from biology, biochemistry, chemistry, cell and molecular biology, genetics, microbiology, physiology, epidemiology, environmental toxicology, pharmacology, ecology, engineering, computer science, and social sciences to address environmental quality and public health issues holistically.

The journal is open-access and adheres to a rigorous peer-review procedure. Original research pieces, critical reviews, notes, and brief messages are welcome. At least three anonymous reviewers read the manuscripts and offered feedback to the editors. This procedure enables writers to make educated choices concerning their contributions.