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mcatmemoranda · 4 years

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Going through questions:

Chédiak–Higashi syndrome[1] (CHS) is a rare autosomal recessive disorder that arises from a mutation of a lysosomal trafficking regulator protein,[2] which leads to a decrease in phagocytosis. The decrease in phagocytosis results in recurrent pyogenic infections, albinism, and peripheral neuropathy.

Defect in neutrophil phagosome-lysosome fusion. Pyogenic bacteria = staph, strep, pneumococcus.

Cytotoxic (CD8+) T cells have a PD-1 receptor. Tumor cells can express programmed death ligand-1 (PD-L1), which binds to the PD-1 receptors on cytotoxic T cells. PD-L1 binding to the PD-1 receptor prevents cytotoxic T cells from doing their apoptotic function. This is how cancer cells evade destruction by cytotoxic T cells. The binding of PD-L1 to PD-1 receptor causes T cell exhaustion (inability of the T cell to induce apoptosis). Monoclonal antibodies against PD-1 or PD-L1 prevent PD-L1 interaction with PD-1 receptor, so cancer cells can't evade cytotoxic T cell destruction. Pembrolizumab, nivolizumab = PD-1 antibodies. Atezolizumab = PD-L1 antibody.

T lymphocytes release interferon gamma, which activates macrophages to express MHC-> Th1 differentiation. Viral and bacterial infection result in interferon gamma release from T lymphocytes and NK cells. Interferon Gamma Release Assay (IGRA) tests for latent TB; measures amount of interferon gamma released by T lymphs in response to M. tuberculosis antigens; measures cell-mediated immunity.

Mast cells release tryptase. Tryptase is released by mast cells in anaphylactic reactions. Serum tryptase level is used to diagnose anaphylaxis after the pt is stabilized.

The FceRI IgE on mast cells and basophils bind to the Fc portion of circulating IgE antibodies. Antigen binds to multiple IgEs, which causes aggregation of the FceRI receptors (the IgEs on basophils and mast cells)-> degranulation of histamine and tryptase from basophils and mast cells. Ok so this is more complex than I remember learning. I thought it was the IgEs that aggregate. It's specifically the FceRIs (high affinity IgEs) that aggregate. FceRI receptor on mast cells bind to the circulating IgEs. The the FceRIs aggregate via the antigen and that causes degranulation. Aggregation of the FceRIs activates a tyrosine kinase, which then causes degranulation.

Question 14 of my first immunology quiz has an explanation I want to draw a table from

Etanercept is a TNF-alpha inhibitor it links the Fc portion of human IgG1 to soluble TNF alpha receptors, functioning as a fusion protein. It functions as a decoy receptor, which binds all TNF alpha to keep it from binding to TNF alpha receptors. It treats rheumatoid arthritis when MTX fails to work.

Question 13 also has a figure I want to copy.

Azathioprine and mycophenolate inhibit nucleotide synthesis. This prevents B cells and T cells from proliferating. These are immunosuppresants. Azathioprine-> 6 mercaptopurine-> 6 Thioguanine active metabolites; the Thioguauanine metabolites inhibit purine synthesis. If you can't replicate your DNA/RNA, you can't reproduce, so azathioprine prevents B and T cells from proliferating. Activated T lymphs make IL-2, so less IL-2 will be made as well. Immunoglobulins come from plasma cells, which form from B cells. So azathioprine also reduces immunoglobulins (because azathioprine prevents the T cells from proliferating and you need T cells to activate B cells with the costimulatory response).

I got a question right because I remembered from watching an OnlineMedEd video yesterday that MHC Class I receptor is edited in the endoplasmic reticulum. Part of MHC Class I receptor is beta 2 microglobulin. Cells that are infected break up the pathogen in their cytoplasm and then send pieces of the pathogen (antigens) into the endoplasmic reticulum via the TAP receptor. Inside the ER, antigen is added to MHC Class I, then the MHC Class I-Antigen complex is sent to the cell membrane. TAP = Transporter Associated with Antigen Processing. Mutations in the TAP1 gene, which codes for TAP, lead to inability to bring antigen into the ER. So the pt gets granulomatous skin ulcers and respiratory infections even though lymphocyte and immunoglobulin levels are normal.

Pneumococcal conjugate vaccine (PCV13) induces a more robust immune response than the pneumococcal polysaccharide vaccine (PPSV23) because the conjugate vaccine causes B and T cell recruitment-> memory. The polysaccharide vaccine (PPSV23) doesn't create memory cells. PCV13 has a conjugated protein whereas PPSV23 doesn't. Pneumovax = PPSV23; Prevnar = PCV13.

In the blood vessels, bradykinin relaxes smooth muscle, causing vasodilation. But in smooth muscle that is not in the vasculature, bradykinin actually causes contraction of that non-vascular smooth muscle. So, bradykinin dilates blood vessels but constricts smooth muscle that is not in the blood vessels. That’s why it causes cough–it causes constriction of smooth muscle in the bronchi. Since bradykinin is degraded by ACE, when you inhibit ACE with ACEIs such as lisinopril, you stop breakdown of bradykinin–> increased vasodilation and bronchoconstriction. That’s why ACEIs can cause angioedema and cough.

Bradykinin vasodilates-> angioedema (fluid leaves blood vessels).

Hereditary angioedema is AD; can also be due to ACEIs. In hereditary angioedema, pts lack C1 esterase inhibitor, which is normally involved in break down of bradykinin. So no C1 esterase inhibitor-> increased bradykinin-> angioedema. Dx hereditary angioedema with low serum C1 esterase inhibitor and C4 levels. C1 esterase inhibitor suppresses C1-> no classic complement pathway. Kininogen is converted to bradykinin by kallikrein. C1 esterase inhibitor inhibits kallikrein-> decreased bradykinin. So of course without C1 esterase inhibitor, you have increased kallikrein-> more bradykinin.

In germinal centers in lymph nodes, B cells undergo somatic hypermutation, which is what allows the B cells that can respond to a particular antigen to proliferate. Somatic hypermutation = immunoglobulin mutation.

Serum sickness = type III hypersensitivity reaction (antigen-antibody complexes in tissues); occurs 1 to 2 weeks after being exposed to non-human proteins. Pts present with vasculitis, arthralgia, fever, rash, low C3 and C4. Histologically, you see fibrinoid necrosis and infiltrating neutrophils. Low complement occurs because complement-fixing IgM and IgG are in the immune complexes.

Hyper IgM syndrome = X-linked recessive deficiency of CD40L (CD40 Ligand located in T cells and necessary to interact with CD40R on B cells); causes recurrent pulmonary and sinus infections, GI infection, infection with opportunistic bugs (e.g., cryptosporidium), failure to thrive. Pts have lots of IgM, but little IgG, IgA, and IgE. B cells have trouble class switching (because the CD40L-CD40R interaction is necessary to create the costimulatory signal that causes B cell class switching and proliferation). Class switching occurs when heavy chain constant region genes are spliced out so the B cell can create the isotype of immunoglobulin it needs to make. That doesn't happen in Hyper-IgM syndrome because the CD40R-CD40L initeraction necessary to cause that can't happen when there's deficient DC40L. CD40 deficiency is autosomal recessive form of this disease. If B cells don't class switch, they stay as IgM-secreting cells.

Severe Combined Immunodeficiency (SCID) = autosomal recessive adenosine deaminase (ADA) deficiency. Adenosine deaminase deficiency leads to accumulation of adenosine in T cells and B cells (lymphocytes)-> cellular and humoral immunodeficiency. Tx: gene therapy; hematopoietic stem cell transplant. X-linked SCID is more commone than ADA deficiency. No lymphocytes-> bacterial, viral, and fungal infections.

Henoch-Schonlein Purpura (HSP) = small vessel leukocytoclastic angiitis + deposition of IgA-C3 complexes in skin and GI tract. It's a hypersensitivity reaction related to recent infection. Pts have a purpuric rash, arthralgia, abdominal pain. Can lead to acute glomerulonephritis. Occurs in kids.

#immunology #anaphylaxis #IGRA #interferon gamma #chediak higashi #chediak higashi syndrome #allergic reaction #TNF alpha #etanercept #PPSV23 #PCV13 #pneumococcal vaccine #serum sickness #hyper IgM syndrome #SCID #Henoch Schonlein pupura #HSP #Henoch Schonlein

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tinyshe · 3 years

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Story at-a-glance

Critical care physician Dr. Paul Marik speaks with Dr. Mobeen Syed about trends in the management of COVID-19, including what he believes could have wiped out the virus early on

The continued recommendation that people stay home and isolate while doing nothing until they’re cyanotic, or turning blue from a lack of oxygen, is a disgrace, because early treatment options are available

The Front Line COVID-19 Critical Care Working Group I-MASK+ protocol can be downloaded in full, giving you step-by-step instructions on how to prevent and treat the early symptoms of COVID-19

According to Marik, a mass distribution program of ivermectin together with melatonin, vitamin D and aspirin could end the COVID-19 pandemic in one month

Dr. Paul Marik, a critical care doctor at Sentara Norfolk General Hospital in East Virginia, is renowned for his work in creating the “Marik Cocktail,” which significantly reduces death rates from sepsis using inexpensive, safe, generic medications.1 In the video above, he speaks with Dr. Mobeen Syed about trends in the management of COVID-19, including what he believes could have wiped out the virus early on.2

According to Marik, the treatment of COVID-19 patients in the early stages of the disease was botched in the U.S. and worldwide, and the continued recommendation that people stay home and isolate while doing nothing until they’re cyanotic, or basically turning blue from a lack of oxygen, is a disgrace, because early treatment options are available.

“There is a scientific vacuum and this starts back to March of last year,” Marik said. “There's been a complete failure of the major medical institutions across the world. Every major society has failed to provide honest useful scientific information.”3

While the World Health Organization, Centers for Disease Control and Prevention and the National Institutes of Health have stated there’s no treatment for COVID-19, only supportive care to treat the fever or provide fluids, Marik describes this as an outrage:4

“While we may not have the best answers, we do have some answers and to tell people to stay at home and isolate so they go blue is an absurdity that's actually causing lots of damage because we are now waiting for the virus to, in some people, cause the cytokine storm. And when they arrive with that state it is very difficult to reverse it and stop it and bring them back.”

FLCC’s COVID-19 Treatment Protocol

Marik and four other critical care physicians formed the Front Line COVID-19 Critical Care Working Group (FLCCC) early on in the pandemic. Not content to offer COVID-19 patients “supportive care,” Marik recruited some of the most knowledgeable pulmonary critical care specialists to solve the COVID-19 treatment puzzle, honing in on stopping the hyper-immune response — including multi-organ inflammation and clotting — which is what typically drives death in fatal COVID-19 cases.5

Marik told Mountain Home magazine, “As pulmonary critical care doctors we know how to treat inflammation and clotting, with corticosteroids and anticoagulants. It’s first-grade science.”6 Yet, when the pandemic began, press briefings neglected to include clinicians who were actually treating COVID-19 patients to state “these are the symptoms and this is what you have to do.”7

FLCCC released their MATH+ protocol for hospitalized COVID-19 patients in March 2020. It gets its name from:

Intravenous Methylprednisolone

High-dose intravenous Ascorbic acid (vitamin C)

Plus optional treatments Thiamine, zinc and vitamin D

Full dose low molecular weight Heparin

The MATH+ protocol led to high survival rates. Out of more than 100 hospitalized COVID-19 patients treated with the MATH+ protocol as of mid-April 2020, only two died. Both were in their 80s and had advanced chronic medical conditions.8 FLCCC also created I-MASK+, which is their mass distribution protocol for prevention and outpatient treatment of COVID-19.

Step-by-Step Guide to COVID Prevention and Early Treatment

FLCCC’s I-MASK+ protocol can be downloaded in full,9 giving you step-by-step instructions on how to prevent and treat the early symptoms of COVID-19. The prevention protocol is for those who are at high risk of COVID-19 or know they’ve been exposed, and includes:

Ivermectin

Vitamin D3

Vitamin C

Quercetin

Zinc

Melatonin

The early outpatient protocol, for those with early symptoms, includes all of the above, plus aspirin and nasopharyngeal sanitation, such as steamed essential oil inhalation three times a day along with chlorhexidine mouthwash gargles and betadine nasal spray. Fluvoxamine is also recommended in certain cases and monitoring of oxygen saturation levels with a pulse oximeter is recommended.

FLCCC also has protocols for at-home prevention and early treatment, called I-MASS, which involves ivermectin, vitamin D3, a multivitamin and a digital thermometer to watch your body temperature in the prevention phase and ivermectin, melatonin, aspirin and antiseptic mouthwash for early at-home treatment. Household or close contacts of COVID-19 patients may take ivermectin (18 milligrams, then repeat the dose in 48 hours) for post-exposure prevention.10

Marik’s original COVID Protocol, released in March 2020, recommended hydroxychloroquine (HCQ), a zinc ionophore, to decrease the duration of viral shedding, particularly in elderly patients with comorbidities.11 However, their latest I-MASK+ protocol, updated June 30, 2021,12 recommends quercetin instead. Quercetin, also a zinc ionophore, is an over-the-counter alternative to HCQ and works much like HCQ does. According to Marik:13

“Experimental and early clinical data (published in high impact journals) suggests that this compound has broad antiviral properties (including against coronavirus) and acting at various steps in the viral life cycle. It also appears to be a potent inhibitor of heat shock proteins (HSP 40 and 70) which are required for viral assembly.”

Censorship Is Keeping This Information Quiet

If you’re surprised to hear that an established protocol for COVID-19 prevention and treatment exists, it’s likely because you’ve heard nothing about it on mainstream media. This is intentional and exemplifies the censorship that has been occurring throughout the pandemic. “What we're going through now is unprecedented in the history of science,” Marik said.14

“I mean this goes back to witchcraft and really prehistoric behaviors. Science is based on exchange of information and that has been censored. So, I think history is going to look back very unfavorably on this period.

I think this is a very dark period in the history of humanity, the history of science, the history of the press, you know the history of freedom of speech, just because of the complete lack of information, misinformation, disinformation and censorship. I mean it's absurd … what we're saying is being censored and labeled as scientific misinformation.”

Ivermectin is a glaring example, which continues to be ignored even though it has shown remarkable success in preventing and treating COVID-19. It was December 2020 when FLCCC called for widespread adoption of ivermectin, both as a prophylactic and for the treatment of all phases of COVID-19.15,16

In one trial,17 58 volunteers took 12 milligrams of ivermectin once per month for four months. Only four (6.96%) came down with mild COVID-19 symptoms during the May through August 2020 trial period. In comparison, 44 of 60 health care workers (73.3%) who had declined the medication were diagnosed with COVID-19. Ivermectin is safe, inexpensive and widely available, with antiviral and anti-inflammatory properties, leading Marik to describe it as the perfect drug to treat COVID-19.18

While an increasing number of doctors and countries have adopted ivermectin’s use for COVID-19, many more refuse it, even going so far as to prohibit its use for patients. Legal fights have ensued, with family members enlisting lawyers to battle hospital boards in order to give their dying loved ones the lifesaving pills — even when all other treatment options have been exhausted.19 Urgent change is needed, Marik said, because profits are being put ahead of lives:20

“Making money and profiteering is what is driving this — not saving lives — and what they're most interested in is preserving that single organ, which may be damaged the most, which is the back pocket. They’re terrified of the back pocket being damaged. The heart, the brain, the lung, they don't care. It's the back pocket that's driving this.”

‘The Most Dangerous Vaccines We’ve Ever Used’

Knowing that treatment options exist may change people’s decisions about COVID-19 vaccines, which Marik describes as “categorically and without question … the most dangerous vaccines that we've ever used.”21 In full disclosure, Marik himself is vaccinated, having received the Pfizer mRNA COVID-19 vaccine, which he said he received since he’s over 60, putting him in a higher risk category.

If he were 24 years old, however, Marik said he wouldn’t get vaccinated, and he doesn’t recommend it for younger children either, as he believes for people under 30 with no risk factors, the risks of the vaccine outweigh those of COVID-19:22

“I think that the risk of a bad outcome from COVID in a 12- to 17-year-old is very low and the risk of an adverse effect to the vaccine is probably much higher. So, it's just not commonsense that you would force vaccination in such kids.

I think it's a risk-benefit ratio. If they were a Type 1 diabetic, if they were immunocompromised, if they were severely obese, you may want to reconsider, but a healthy 12- to 17-year-old, in my opinion and obviously it's my opinion, I would be hesitant in vaccinating these kids.”

While Marik believes the vaccines may be “somewhat effective” in decreasing cases of COVID-19 hospitalization and death, he stresses that they come with sizeable risks. “The number of side effects and deaths from these vaccines — and this is based on reportable data from the WHO and the VAERS network — the number of deaths and adverse events are an order of 10- to 100-fold magnitude than any other vaccine.”23

He refers to the mass COVID vaccination campaign as the biggest experiment done in the history of mankind, and points out that we don’t know what the long-term effects will be. “And to make it even worse,” Marik says, “the vaccine companies know a lot about these vaccines but they haven't given us this information. It's hidden.”

“For example, when you get the mRNA vaccine, people assume it stays in the arm but that's not true. The spikes tend to spread throughout the body. Now the vaccine companies know about this but they don't want to tell us about it. We have to figure this out ourselves.

… we need to respect [people’s] autonomy. We need to respect their informed consent. They should be able to decide for themselves. We should not be forcing this upon people and this mandate that colleges and some hospitals have, I think it goes against the foundation of freedom of choice, freedom to do to your own body as you respect and freedom of consent.”24

Symptoms of Long COVID ‘Identical’ to Vaccination Syndrome

FLCCC also has a management protocol — I-RECOVER25 — for long-haul COVID-19 syndrome, which includes a range of symptoms such as malaise, headaches, painful joints, chest pain and cognitive dysfunction.

The protocol is still evolving as more is learned about the condition, but of note is that it’s been successfully used to treat post-vaccine inflammatory syndromes as well. As noted by Marik, long COVID and post-vaccine inflammatory syndromes share many similarities, but the latter is taboo to talk about:26

“Post-vaccination adverse events are much more common in younger people. That's our impression. There's not a lot of data and if you talk to the experts about a post-vaccination syndrome they have no idea what you're talking about because … it's politically not correct to talk about it. They don't want to hear about it.

So as far as I know, there are not any peer-reviewed publications on post-vaccination syndrome but we know from patients that they develop symptoms almost identical to the long hauler.

They develop severe symptoms very much similar to the post-COVID syndrome. So, you know people say, ‘Oh it's in their head. They're making this up. It's a psychiatric disease. They're trying to gain some something out of this.’ I think it's a real disease … and these people truly have monocyte activation production of cytokines much like the post-COVID syndrome.”

This Could End the Pandemic in One Month

Syed asked Marik what he would do if given the opportunity to end the pandemic next month. His response was remarkably simple: a mass distribution program of ivermectin together with melatonin, vitamin D and aspirin. By assuming everyone is infected and treating with this safe combination of inexpensive compounds, Marik says, “We’ll eliminate SARS-CoV-2. It will be gone.”

This isn’t likely to happen, though, due to “economic and political factors that benefit from the ongoing pandemic.”27 Marik also weighed in on the lab leak theory that SARS-CoV-2 came from a laboratory in Wuhan, China:28

“I think the preponderance of evidence highly suggests this was a manipulated virus that whether it leaked on accident or by design leaked from the Wuhan laboratory … the molecular structure of the spike protein would suggest that this was a manipulated the protein was specifically manipulated and enhanced …

The diversity of the symptoms, the systems it involves, the depth of damage it does and the durability of the damage — that first it causes the acute and then it becomes long COVID and then it just keeps sitting with us — I have not seen any other virus in my lifetime, which does this kind of destruction.”

Moving forward, Marik states that health officials must learn from the enormous mistakes made during the pandemic, which highlighted a global lack of collaboration among health care providers along with a lack of honesty and openness.

“This pandemic has been an example of what not to do. I think everything that could have gone wrong went wrong,” he said. Once COVID is under control, Marik hopes to refocus his efforts on sepsis, which remains a leading cause of deaths overall and is also an important contributor to the death of COVID-19 patients.

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juniperpublisherscellscienc-blog · 5 years

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Impact of Heat Shock Proteins in Hepatocellular Carcinoma- Juniper Publishers

https://juniperpublishers.com/ijcsmb/IJCSMB.MS.ID.555663.php

Abstract

Heat shock proteins are highly conserved proteins, expressed at low levels under normal conditions. Heat shock proteins significantly induced in response to cellular stresses and lead to heat shock response, which could help cancer cells to adapt to stress conditions. As molecular chaperones, Heat shock proteins play critical roles in protein homeostasis, apoptosis, invasion and cellular signaling transduction. A heat shock protein over expression is widely reported in many human cancers due to constant stress condition in tumor microenvironment. Heat shock proteins often associated with poor prognosis in many types of human cancers. Up regulation of Heat shock proteins may serve as diagnostic and prognostic markers in hepatocellular carcinoma. Targeting Heat shock proteins with specific inhibitor alone or in combination with chemotherapy regimens holds promise for the improvement of outcomes for hepatocellular carcinoma patients. In addition, our study suggests progression and challenges in targeting these Heat shock proteins as novel therapeutic strategies in hepatocellular carcinoma.

Keywords: Heat shock proteins; Hepatocellular carcinoma; Heat shock response

Abbrevations: HSPs: Heat Shock Proteins; HCC: Hepatocellular Carcinoma; HSF1: Heat Shock Factor

Introduction

Heat shock proteins (HSPs) are ubiquitous proteins found in the cells of all studied organisms, which are expressed at low levels under normal conditions. Many types of stress, including heat, induce expression of a family of genes known as the heat shock protein genes. Heat shock proteins originally were discovered when it was observed that heat shock produced chromosomal puffs in the salivary glands of fruit flies (Drosophilia) [1–2]. The DNA sequence that makes up this family of genes is highly conserved across species. This family of genes originally was named because of their expression after exposure to heat. However, the genes are now known to be induced by a wide variety of environmental or metabolic stresses that include the following: anoxia (hypoxia), ischemia, heavy metal ions, ethanol, nicotine, surgical stress, viral agents, genotoxic agents, nutrient starvation and overexpression of oncoproteins [3].

Thus, the term “heat shock protein” is a misnomer because many agents other than heat induce the expression of the heat shock protein gene. Consequently, “stress protein” is the preferred term. Stress proteins are critically important because they appear to be necessary in the critical step of three-dimensional folding of some newly formed proteins within the cell. In fact, they ensure that newly formed polypeptides proceed correctly through folding and unfolding to eventually achieve a functional shape (Figure 1). Stress proteins also assist in the repair of denatured proteins or promote their degradation after stress or injury. They have been referred to as “molecular chaperones” because of this function [1,4].

Upregulation of HSPs is a critical part of heat shock response, which could help cells to cope with the stress condition. Many members of HSPs perform their functions as molecular chaperons by stabilizing proteins to ensure their correct folding, inhibiting stress-induced protein aggregation or regulating cellular signalling and transcriptional networks. The increased expression of HSPs under stress condition is often transcriptionally regulated by heat shock factor 1 (HSF1). In response to stress conditions, HSF1 is phosphorylated and forms homotrimers, then binds to heat shock elements (HSEs) located upstream of HSPs genes and activates the transcription of heat shock genes [5–6]. Stress proteins belong to a multigene family and often named according to their molecular weight from 8 to 150kd. In this review, we will discuss three major members of the HSP family, which are closely related to human malignancies, namely HSP27, HSP70 and HSP90. It is thought that stress proteins are produced in response to nonlethal stress to protect organisms from subsequent severe stress that would otherwise be lethal. In the case of exposure to heat, this phenomenon has been called “thermotolerance” and has launched many experiments in which an association has been found between the heat shock response and protection against other stresses, such as hypoxia or ischemia. The addition of one type of stress may provide protection against other types of insults, which results in cross-tolerance. As examples, stress protein induction by hyperthermia may provide protection during a subsequent arterial injury or exposure to a heavy metal may provide subsequent protection against heat or ischemic injury. This thermotolerance treatment strategy has proved successful in experimental models of cardiac ischemia, arterial injury, endotoxic shock, renal and hepatic ischemia, ethanol-induced gastric ulcerations, and skeletal muscle ischemia-reperfusion [7]. HSP27 overexpression is reported in a wide range of human cancers. Report shows that HSP27 performs crucial roles in cell cycle modulation, apoptosis inhibition, cytoskeleton organization, regulation of translation initiation, DNA repair, RNA splicing and degradation of oxidized proteins via the ubiquitin-proteasome pathway.

Stress proteins play a critical role in the maintenance of normal cellular homeostasis. These proteins almost certainly have a pivotal role in cell cycle progression and cell death (apoptosis) and are involved in many disease processes, including cardiovascular disease. Currently, the manipulation of stress proteins remains cumbersome because hyperthermia and pharmacologic manipulations are relatively nonspecific. Eventually, as we gain more insight into the exact role and function of these fascinating molecules, the clinical manipulation of the stress proteins will almost certainly prove beneficial [8]. Liver cancer is one of the most frequent malignancies worldwide [9]. An estimated 782,500 new liver cancer cases and 745,500 deaths occurred worldwide during 2012 [10]. About half of the new cases and related deaths of liver cancer occurred in China. Hepatocellular carcinoma (HCC) accounts for more than 80% of primary liver cancers. Although treatment techniques for HCC have experienced great progress, prognosis is still poor for HCC patients. Only 30–40% of HCC patients are suitable for curative treatment at the time of diagnosis. Long-term survival following radical surgical resection remains unsatisfactory because of high rates of recurrence and metastasis [11]. A better understanding of molecular mechanisms involved in tumorigenesis and metastasis of HCC will provide novel and potential therapeutic implications in HCC treatment. HSPs have become attractive therapeutic targets in HCC. Novel therapeutic strategies that target HSPs alone or combined with other anticancer agents are widely investigated [12].

Conclusion and Future Directions

As stress induction of HSPs plays a crucial role in tumorigenesis, metastasis and therapeutic resistance, the clinical efficacies of HSPs as biomarkers for the diagnosis and prognosis of HCC patients warrant further testing in clinical settings. Targeting HSPs with their specific inhibitors holds attractive therapeutic promise for the improvement of outcomes for HCC patients. Despite promising preclinical data, there are still some challenges to target HSPs in HCC. First, little is known about the therapeutic responses of HSPs inhibitors in HCC patients. Therefore, more clinical trials about the antitumor activity of HSPs inhibitors in HCC patients are urgently required. Second, the future of HSPs inhibitors in the treatment of cancer individuals may lie in combining them with cytotoxic chemotherapy or other targeted therapies. Although some preliminary studies have shown enhanced efficacy of HSPs inhibition combined with targeted drugs such as rapamycin and sorafenib, the best strategy for combination treatment still needs to be validated in further studies. Third, we can focus our attention on HSPs inhibitors directly. Intrinsic or acquired resistance often limits the efficiencies of HSPs inhibitors CRISPR/Cas9- or shRNAbased loss-of-function genetic screens can help us to identify mechanisms of the resistance and find potential combined drug targets whose inactivation is effective to improve efficiencies of HSPs inhibitors.123–125 Fourth, HSPs constitute 1–2% of total proteins in most celltypes.126 HSPs are essential for both cancer and normal cells, and play important roles in a wide range of cellular processes such as maintaining protein homeostasis, intracellular trafficking, signal transduction and regulating innate immune responses. HSPs targeting may have unacceptable deleterious effects on non-malignant cells and normal organs in clinical trials. As a consequence, novel HSPs inhibitors with high selectivity and potency for tumor cells are eagerly to be developed. Finally, molecular mechanisms of HSPs in cytoprotective effects and tumor metastasis are still not fully understood. Answers to key issues of these basic mechanisms will significantly accelerate the applications of HSPs inhibitors in HCC treatment.

https://juniperpublishers.com/ijcsmb/IJCSMB.MS.ID.555663.php

#Cell Science #Molecular biology #Stem cells #Open access journals #Juniper Publishers

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biotechtimes · 5 years

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New combination strategy may kill cancer cells better: study

New Post has been published on https://biotechtimes.org/2019/09/12/new-combination-strategy-may-kill-cancer-cells-better-study/

New combination strategy may kill cancer cells better: study

By Susheela Srinivas

Bengaluru, September 12: In their bid to tackle cancer, scientists have been trying out newer and innovative strategies. In a preliminary study, Indian scientists have explored the possibility of reaching out to cancer cells and triggering their natural programmed death.

This approach uses the combined effect of targeting and inducing a ‘stress’ inside the cell structures called Endoplasmic Reticulum of tumour cells, along with administering a small amount of a drug. Laboratory tests on cervical cancer cell lines have found that the combination treatment increases death of cancer cells due to apoptosis or natural cell disintegration.

Endoplasmic Reticulum is a network of folded membrane spreading across the cell. It is the protein and lipid factory of the cell, responsible for manufacturing, packaging and dispersing of various functional proteins for the body.

The production process sometimes yields unwanted proteins, which are immediately scavenged away by another resident protein called Hsp 90. When Hsp 90 stops functioning many waste proteins build up inside the cell, creating stress, which eventually kills the cell.

The present study focuses on inhibiting Hsp 90 in cancer cells, thereby initiating their death.

“The key aspect of our research is to navigate inside cancer cells, reach the protein synthesis organelle and trigger stress into it for therapy. For this, we have engineered a nanoparticle which can do that as well as show us how it reaches its target, in this case, endoplasmic reticulum, inside the cancer cells,” explained Dr Sudipta Basu, the lead researcher of the study at the Indian Institute of Technology, Gandhinagar.

To target the endoplasmic reticulum, the team synthesised a lipid modified molecule and attached a chemical entity called sulfoxide to its structure such that it would be recognised by the external receptor structure of endoplasmic reticulum. A fluorescent chemical acted as a tracking system tag which traced the path and ascertained the destination of the nanoparticle.

Then, an Hsp 90 inhibiting drug called 17AAG was encapsulated in the lipid nanoparticle to form a nano-package which would quickly disperse in water, which is the chief constituent of cells. The size of the nano packages was so designed to easily enter through pores of cancerous cells and at the same time, be blocked by small healthy cells. By doing so, the team hypothesised that the nano packages target tumour cells explicitly with minimal effect on healthy cells.

When tracked by a confocal microscope, it was confirmed that nano packages reached and permeated into the endoplasmic reticulum and dispersed in the cells. A cell enzyme called Esterase broke opened the nano package to release 17AAG, which inhibited the housekeeping protein Hsp 90, leading to the build-up of unwanted proteins in the tumour cells.

Cell and molecular biology techniques revealed that 17AAG activated stress in the ER, which led to a fair amount of cell death due to the nano packages.

However, cancer cells are known to respond in a ‘smart’ way to the endoplasmic reticulum stress by resorting to autophagy. Autophagy is a survival mechanism of the cancer cells where they eat up their unnecessary proteins to stay alive. To overcome this, chloroquine was introduced, which is an antimalarial drug found to have autophagy inhibitor and anticancer potential. The combination treatment resulted in a significant death of cancer cells.

“In direct drug treatment, cancer cells get acclimatized to the drug and develop resistance toward it, while the combined strategy may offer a better scope of treatment down the line. Although our research is in the early stages, our work proves that this strategy has the potential as a safer route for cancer treatment,” said Dr. Basu.

Besides Sudipta Basu, the research team included Chandramouli Ghosh and Aditi Nandi from Indian Institute of Science Education and Research (IISER), Pune. The results were published in journal ACS Applied Biomaterials (India Science Wire)

#Cancer Research #News

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