Showing papers in "Current Molecular Medicine in 2021"

Resveratrol Induces Apoptosis and Attenuates Proliferation of MCF-7 Cells in Combination with Radiation and Hyperthermia.

Abstract: Aim In the current in vitro study, we tried to examine the possible role of resveratrol as a sensitizer in combination with radiotherapy or hyperthermia. Background Breast cancer is the most common malignancy for women and one of the most common worldwide. It has been suggested that using non-invasive radiotherapy alone cannot eliminate cancer cells. Hyperthermia which is an adjuvant modality induces cancer cell death mainly through apoptosis and necrosis. However, cancer cells can also develop resistance to this modality. Objective The objective of this study was to determine possible potentiation of apoptosis when MCF-7 cells treated with resveratrol before hyperthermia or radiotherapy. Method MCF-7 cancer cells were treated with different doses of resveratrol to achieve IC50%. Afterwards, cells treated with the achieved concentration of resveratrol were exposed to radiation or hyperthermia. Proliferation, apoptosis and the expression of pro-apoptotic genes were evaluated using flow cytometry, MTT assay and real-time PCR. Results for each combination therapy were compared to radiotherapy or hyperthermia without resveratrol. Results Both irradiation or hyperthermia could reduce viability of MCF-7 cells. Furthermore, the regulation of Bax and caspase genes increased, while Bcl-2 gene expression reduced. Resveratrol potentiated the effects of radiation and hyperthermia on MCF-7 cells. Conclusion Results of this study suggest that resveratrol is able to induce the regulation of pro-apoptotic genes and attenuate the viability of MCF-7 cells. This may indicate the sensitizing effect of resveratrol in combination with both radiotherapy and hyperthermia.

The Role of the PI3K/AKT/mTOR Signalling Pathway in Male Reproduction

Abstract: Male fertility is closely related to the normal function of the hypothalamic-pituitary-testicular axis. The testis is an important male reproductive organ that secretes androgen and produces sperm through spermatogenesis. Spermatogenesis refers to the process by which spermatogonial stem cells (SSCs) produce highly differentiated spermatozoa and is divided into three stages: mitosis, meiosis and spermiogenesis. Spermatogenesis requires SSCs to strike a proper balance between self-renewal and differentiation and the commitment of spermatocytes to meiosis, which involves many molecules and signalling pathways. Abnormal gene expression or signal transduction in the hypothalamus and pituitary, but particularly in the testis, may lead to spermatogenic disorders and male infertility. The phosphoinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway is involved in many stages of male reproduction, including the regulation of the hypothalamus-pituitary-gonad (HPG) axis during spermatogenesis, the proliferation and differentiation of spermatogonia and somatic cells, and the regulation of sperm autophagy and testicular endocrine function in the presence of environmental pollutants, particularly endocrine-disrupting chemicals (EDCs). In the PI3K/AKT/mTOR signalling pathway, mTOR is considered the central integrator of several signals, regulating metabolism, cell growth and proliferation. In particular, mTOR plays an important role in the maintenance and differentiation of SSCs, as well as in regulating the redox balance and metabolic activity of Sertoli cells, which play an important role in nutritional support during spermatogenesis.

The Functional Role of Long Non-coding RNA UCA1 in Human Multiple Cancers: a Review Study.

Abstract: In various cancers, high-grade tumor and poor survival rate in patients with upregulated lncRNAs UCA1 have been confirmed Urothelial carcinoma associated 1 (UCA1) is an oncogenic non-coding RNA with a length of more than 200 nucleotides The UCA1 regulate critical biological processes that are involved in cancer progression, including cancer cell growth, invasion, migration, metastasis, and angiogenesis So It should not surprise that UCA1 overexpresses in variety of cancers type, including pancreatic cancer, ovarian cancer, gastric cancer, colorectal cancer, breast cancer, prostate cancer, endometrial cancer, cervical cancer, bladder cancer, adrenal cancer, hypopharyngeal cancer, oral cancer, gallbladder cancer, nasopharyngeal cancer, laryngeal cancer, osteosarcoma, esophageal squamous cell carcinoma, renal cell carcinoma, cholangiocarcinoma, leukemia, glioma, thyroid cancer, medulloblastoma, hepatocellular carcinoma and multiple myeloma In this article, we review the biological function and regulatory mechanism of UCA1 in several cancers and also, we will discuss the potential of its as cancer biomarker and cancer treatment

Rapid Determination of Full and Empty Adeno-Associated Virus Capsid Ratio by Capillary Isoelectric Focusing

Abstract: Adeno-associated virus (AAV) is one of the most promising gene transfer vector types featuring long-term gene expression and low toxicity. The lack of pathogenicity and the availability of many serotypes augmented the applicability of AAV virions in gene therapy applications. The recombinant AAV capsid includes the therapeutic protein-coding transgene as well as a promoter to initiate translation and a poly A sequence portion for stabilization. Current AAV manufacturing technologies, however, cannot guarantee the generation of only full capsids, i.e., including the entire required genome. Partially filled and empty capsids are also part of the product, decreasing in this way the efficacy and safety upon clinical translation. Therefore, rapid, accurate and QC friendly analysis of the full and empty capsid ratio is of high importance during AAV vector manufacturing and release testing. In this paper, an automated capillary isoelectric focusing technique is introduced, readily applicable in the biopharmaceutical industry for fast and efficient determination of the full and empty capsid ratio. The method also reveals information about the proportion of partially filled capsids. For higher resolution (<0.1 pI unit), mixtures of wide and narrow range ampholytes were utilized. The isoelectric point and peak area percentage reproducibility (RSD) of the mixed ampholyte assay were as low as 1.67% and 2.45 %, respectively, requiring only 65 nL of sample volume per injection.

Heat Shock Proteins Regulating Toll-like Receptors and the Immune System could be a Novel Therapeutic Target for Melanoma.

Abstract: Melanoma is a serious type of skin cancer, which develops in melanocyte cells. Although it is less common than some other skin cancers, it can be far more dangerous if not treated at an early stage because of its ability to spread rapidly to other organs. Heat shock proteins (HSP) are intracellular molecular chaperones of naive proteins, which are induced in response to stressful conditions. HSP is released into the extracellular milieu and binds to Toll-like receptors (TLRs) to regulate immune responses, such as cytokine and chemokine release. HSPs can release and bind to tumor-specific antigens, with cross-presentation of major histocompatibility complex (MHC) class I antigens. TLRs are innate immune system receptors, involved in the melanoma growth pathway through HSP activation. Melanocytes express TLR4 and TLR9 to modulate immune responses. Many TLR ligands are considered as proper adjuvant candidates, as they can activate dendritic cells. Targeting some TLRs, such as TLR7 and TLR9, is an available option for treating melanoma. In this review, we aimed to determine the relationship between TLRs and HSP groups in melanoma.

The Roles of mitochondrial dysfunction and Reactive Oxygen Species in Aging and Senescence

Abstract: The aging process deteriorates organs' function at different levels, causing its progressive decline to resist stress, damage, and disease. In addition to alterations in metabolic control and gene expression, the rate of aging has been connected with the generation of high amounts of Reactive Oxygen Species (ROS). The essential perspective in free radical biology is that reactive oxygen species (ROS) and free radicals are toxic, mostly cause direct biological damage to targets, and are thus a major cause of oxidative stress. Different enzymatic and non-enzymatic compounds in the cells have roles in neutralizing this toxicity. Oxidative damage in aging is mostly high in particular molecular targets, such as mitochondrial DNA and aconitase, and oxidative stress in mitochondria can cause tissue aging across intrinsic apoptosis. Mitochondria's function and morphology are impaired through aging, following a decrease in the membrane potential by an increase in peroxide generation and size of the organelles. Telomeres may be the significant trigger of replicative senescence. Oxidative stress accelerates telomere loss, whereas antioxidants slow it down. Oxidative stress is a crucial modulator of telomere shortening, and that telomere-driven replicative senescence is mainly a stress response. The age-linked mitochondrial DNA mutation and protein dysfunction aggregate in some organs like the brain and skeletal muscle, thus contributing considerably to these post-mitotic tissues' aging. The aging process is mostly due to accumulated damage done by harmful species in some macromolecules such proteins, DNA, and lipids. The degradation of non-functional, oxidized proteins is a crucial part of the antioxidant defenses of cells, in which the clearance of these proteins occurs through autophagy in the cells, which is known as mitophagy for mitochondria.

Quercetin and its relative therapeutic potential against COVID-19: A retrospective review and prospective overview.

Abstract: COVID-19 is an emerging disease that is a major threat to the global community. The main challenge in this disease is the lack of proper or proven medication. The drugs used to treat this disease are only for symptomatic treatment. Studies of other coronaviruses, such as SARS and MERS, suggest that quercetin has sufficient potential to treat COVID-19. Previous studies have shown that quercetin reduces the entry of the virus into the cell by blocking the ACE2 receptor, as well as reducing the level of interleukin-6 in SARS and MERS patients. Therefore, the aim of this review was to scrutinize the potential of quercetin as a drug in the treatment of COVID-19 from a molecular perspective.

Triazavirin - Potential inhibitor for 2019-nCoV Coronavirus M protease: A DFT study.

Abstract: Triazavirin (2-methylsulfanyl-6-nitro[1,2,4]triazolo[5,1-c][1,2,4]triazin-7(4H)-one, TZV) is an antiviral drug synthesized. TZV is being investigated for potential application against the Coronavirus 2019-nCoV. In order to find candidate drugs for 2019-nCoV, we have carried out a computational study to screen for effective available drug Triazavirin (C5H4N6O3S) which may work as inhibitor for the Mpro of 2019-nCoV. In the present work, first time the molecular structure of title molecule has been investigated using Density Functional Theory (DFT/B3LYP/MidiX) in gas phase. The molecular HOMO-LUMO, excitation energies and oscillator strengths of investigated compound have also been calculated and presented. The interaction of TZV compound with the Coronavirus was performed by molecular docking studies. Therefore, TZV can be used for potential application against the Coronavirus 2019-nCoV.

Targeting Abnormal Nrf2/HO-1 Signaling in Amyotrophic Lateral Sclerosis: Current Insights on Drug Targets and Influences on Neurological Disorders.

Abstract: The nuclear erythroid 2-related-factor (Nrf2) transcription factor/hemoxygenase 1 (HO-1) is a key regulator of an important neuroprotection response by driving the interpretation of various cytoprotective gene to encode for anti-inflammatory, antioxidant, and detoxifying proteins. Various studies investigated that the upregulation of Nrf2/HO-1 has become the potential therapeutic approach in amyotrophic lateral sclerosis (ALS). Amyotrophic lateral sclerosis is a motor neuron disease in which there is a progressive loss of upper motor neuron and lower motor neurons of the motor cortex, brain stem, and corticospinal tract. A result of this upregulation of Nrf2/HO-1 indicates that in the brain, anti-oxidant capacity is reinforced. Further, this shows a cytoprotective effect against oxidative stress in amyotrophic lateral sclerosis. A study reported functions associated with the Nrf2/HO-1 in the neuronal cell, oligodendrocytes, microglia, and astrocytes. Although ALS's pathogenesis is not yet clear, but it is compelling. The evidence shows any dysfunction in the brain such as mitochondrial dysfunction, protein aggregation, glial cell activation, excitotoxicity, and apoptosis which gives ALS-like symptoms. In this review, we have mainly focused on detailing the downregulation of Nrf2/HO-1, which may be the prime reason and may further serve as a pathological hallmark for ALS development. As surveyed, there are limited targetbased interventions that only provide symptomatic relief but do not cure the disease completely. Dysregulation of the Nrf2/HO-1 signaling pathway leads to many physiological changes contributing to neurological conditions, including ALS. Based on the above view, we summarized the combined role of Nrf2/HO-1 signaling in ALS and explored potential therapeutic strategies for disease improvement through pathway modulators.

The Role of Retinoblastoma Protein in Cell Cycle Regulation: An Updated Review.

Abstract: Selected transcription factors have critical roles to play in organism survival by regulating the expression of genes that control the adaptations needed to handle stress conditions. The retinoblastoma (Rb) protein coupled with the E2F transcription factor family was demonstrated to have roles in controlling the cell cycle during freezing and associated environmental stresses (anoxia, dehydration). Rb phosphorylation or acetylation at different sites provides a mechanism for repressing cell proliferation that is under the control of E2F transcription factors in animals facing stresses that disrupt cellular energetics or cell volume controls. Other central regulators of the cell cycle including Cyclins, Cyclin-dependent kinases (Cdks), and checkpoint proteins detect DNA damage or any improper replication, blocking further progression of cell cycle and interrupting cell proliferation. This review provides an insight into the molecular regulatory mechanisms of cell cycle control, focusing on Rb-E2F along with Cyclin-Cdk complexes typically involved in development and differentiation that need to be regulated in order to survive extreme cellular stress.

Obesity and Insulin Resistance: A Review of Molecular Interactions.

Abstract: The prevalence of insulin resistance and diabetes mellitus is rising globally in epidemic proportions. Diabetes and its complications contribute to significant morbidity and mortality. An increase in sedentary lifestyle and consumption of a more energydense diet increased the incidence of obesity which is a significant risk factor for type 2 diabetes. Obesity acts as a potent upstream event that promotes molecular mechanisms involved in insulin resistance and diabetes mellitus. However, the exact molecular mechanisms between obesity and diabetes are not clearly understood. In the current study, we have reviewed the molecular interactions between obesity and type 2 diabetes.

Role of Oxidative Stress and Antioxidant Supplementation in Male Fertility.

Abstract: Nearly 15% of couples involve in infertility as a universal health issue. About 50% of infertility cases have been known to be associated with the male parameters. Oxidative stress (OS) represents an imbalance in the level of reactive ox-ygen species (ROS) and anti-oxidant. In fact, OS has been considered as one of the popular pathologies reported in about 50% of all infertile male. Therefore, the increased level of ROS may result in infertility via DNA damages or lipid peroxida-tion (LPO) as well as the enzymes inactivation and proteins oxidation in spermatozoa. Basically, OS results from the life-style variables. As the absence of antioxidant and the respective deficiencies in the semen cause OS, variations in the life-style and anti-oxidant regimes may be advantageous to treatment strategies for resolving such an issue. Actually, anti-oxidants like vitamins E and C, glutathione, coenzyme-Q10, carnitines, selenium, N-acetylcysteine, carotenoids, zinc, and pentoxifylline decline the OS-induced sperm damages.Therefore, the present review overviews the oxidative bio-chemistry associated with the sperm health and identifies which men would be most at risk of the oxidative infertility. Hence, the re-view would show the techniques provided to diagnose OS and diverse therapeutic options.

Proteomics Profiling of Plasma Exosomes in VKH Patients

Abstract: Objectives Vogt-Koyanagi-Harada syndrome is a common autoimmune uveitis that can cause blindness. Recent studies have shown that plasma exosomes carry disease-related proteins that may serve as biomarkers. Here, we aimed to find candidate biomarkers of Vogt-Koyanagi-Harada disease using proteomic analysis of plasma exosomes. Methods Exosomes were isolated from the plasma of normal controls and Vogt-Koyanagi-Harada patients in the following groups: a) initial inflammatory attack (active stage), b) remission after one month of treatment (unstable stage), and c) stationary phase after three months of treatment (stable stage). Groups were analyzed by mass spectrometry using isobaric tags for relative and absolute quantitation. After functional analysis, proteins of interest were verified by ELISA. Results 463 proteins were identified in the exosomes. Forty-three were upregulated at the active inflammation stage, including inflammation-associated proteins. Thirty-one were downregulated. Gene ontology and pathway analyses revealed differential proteins related to cell adhesion, cell phagocytosis, cytoskeleton movement, leukocyte migration across endothelial cells, and platelet activation. By ELISA, Carbonic anhydrase 2 and Ras-related protein Rap-1b were verified as more plentiful at the active stage compared to the normal control and stationary phase in exosomes, but not, however, in microvesicles or plasma. Conclusion Plasma exosomes of Vogt-Koyanagi-Harada patients contain many proteins related to the degree of inflammation. The levels of Carbonic anhydrase 2 and Ras-related protein Rap-1b in exosomes can be used as biomarkers for active inflammation in Vogt-Koyanagi-Harada disease. Further investigation could help study the pathogenesis of Vogt-KoyanagiHarada disease and identify therapeutic targets.

The Role of Pro-fibrotic Myofibroblasts in Systemic Sclerosis: from Origin to Therapeutic Targeting.

Abstract: Systemic sclerosis (SSc, scleroderma) is a complex connective tissue disorder characterized by multisystem clinical manifestations resulting from immune dysregulation/autoimmunity, vasculopathy and, most notably, progressive fibrosis of the skin and internal organs In recent years, it has emerged that the main drivers of SSc-related tissue fibrosis are myofibroblasts, a type of mesenchymal cells with both the extracellular matrix-synthesizing features of fibroblasts and the cytoskeletal characteristics of contractile smooth muscle cells The accumulation and persistent activation of pro-fibrotic myofibroblasts during SSc development and progression result into elevated mechanical stress and reduced matrix plasticity within the affected tissues and may be ascribed to a reduced susceptibility of these cells to pro-apoptotic stimuli, as well as their increased formation from tissue-resident fibroblasts or transition from different cell types Given the crucial role of myofibroblasts in SSc pathogenesis, finding the way to inhibit myofibroblast differentiation and accumulation by targeting their formation, function and survival may represent an effective approach to hamper the fibrotic process or even halt or reverse established fibrosis In this review, we discuss the role of myofibroblasts in SSc-related fibrosis, with a special focus on their cellular origin and the signaling pathways implicated in their formation and persistent activation Furthermore, we provide an overview of potential therapeutic strategies targeting myofibroblasts that may be able to counteract fibrosis in this pathological condition

Molecular characterization of SARS-CoV-2.

Abstract: The coronavirus disease 2019 (COVID-19) is currently a new public health crisis threatening the world. This pandemic disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus has been reported to be originated in bats, and by yet unknown intermediary animals were transmitted to humans in China 2019. The SARS-CoV-2 spreads faster than its two ancestors, the SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) but has reduced fatality. At present, the SARS-CoV-2 has caused about 1.16 million deaths with more than 43.4 million confirmed cases worldwide, resulting in a serious threat to public health globally with yet uncertain impact. The disease is transmitted by inhalation or direct contact with an infected person. The incubation period ranges from 1 to 14 days. COVID-19 is accompanied by various symptoms, including cough and fatigue. In most people, the disease is mild, but in some other people, such as in the elderly and people with chronic diseases, it may progress from pneumonia to a multi-organ dysfunction. Many people are reported asymptomatic. The virus genome is sequenced, but new variants are reported. Numerous biochemical aspects of its structure and function are revealed. To date, no clinically approved vaccines and/or specific therapeutic drugs are available to prevent or treat COVID-19. However, there are reported intensive researches on the SARS-CoV-2 to potentially identify vaccines and/or drug targets, which may help to overcome the disease. In this review, we discuss recent advances in understanding the molecular structure of SARS-CoV-2 and its biochemical characteristics.

Exosomes Harnessed as Nanocarriers for Cancer Therapy - Current Status and Potential for Future Clinical Applications.

Abstract: Exosomes are nano structured (50-90 nm) vesicles that originate from endosomal compartment of eukaryotic cells and are secreted into extracellular matrix. In recent years there has been increased interest in exploring exosomes for diagnostic and therapeutic applications. Like many other diseases e.g. neurodegenerative disorders, autoimmune diseases exosomes have large significance in cancer too. Exosomes are known to prevail in large numbers and carry unique cargos in different types of cancers and thus are proving as versatile entities in understanding their biology of cancers and utilized as efficient diagnostic biomarkers in identification of cancer type. In addition to diagnostic applications there has been an increased interest in recent years to exploit exosomes as carriers for delivery of therapeutic agents to target sites as well. This is indebted to their exceptional non-immunogenic and biomimetic properties that prompted researchers to use exosomes as carriers for delivery of therapeutic agents e.g. drugs, genes and peptides. Exosomes also circumvent many drawbacks associated with other lipid or polymeric nanocarriers e.g. low circulation time, lipid toxicities, long term stability etc. However, in spite of many favorable aspects for exosome based therapy there have been a number of challenges too. This review will focus on the current status of the exosome based drug therapy for cancer, the challenges faced and its potential for future clinical use.

Targeting Tumor-derived Exosomes Expressing CD73: New Opportunities in the Pathogenesis and Treatment of Cancer.

Abstract: Tumor-derived exosomes contain biological contents such as proteins, lipids, RNA (miRNAs, mRNAs, lncRNA), and DNA for intracellular communication. Meanwhile, studies have shown the role of exosomes in cancer progression, metastasis, and therapeutic resistance. Furthermore, tumor exosomes have received growing attention due to their potential as novel therapeutic protocols for the treatment of cancers. Adenosine nucleoside, which is a derivative of ATP, is highly elevated in the tumor microenvironment by CD39 and CD73 enzymatic activity. Recently, it is distinguished that cancer cell-derived exosomes carry CD39 and CD73 on their surface and may contribute to rising adenosine levels in the tumor microenvironment. In this review, we summarize the evidence of CD39/CD73-bearing exosomes and their role in cancer development, progression, invasion, angiogenesis, metastasis and their application in the selection of the appropriate strategy to treat different types of cancer.

JAK2-mediated Intracellular Signaling.

Abstract: Janus kinase-2 (JAK2) is a non-receptor tyrosine kinase that serves key roles as the intracellular signaling effector of the cytokine receptor, such as mediating effects of leptin, erythropoietin, interferon, and growth hormone. A lot of molecular underlying mechanisms of JAK2 participation are known, however, additional signaling mechanisms of its activation, regulation, and pleiotropic signaling roles are still being explored. Here, we review the current knowledge of JAK2-mediated cellular signaling at the molecular level. In the beginning, we will focus on the recent advances in JAK2 activation and regulation. A part of our review focuses on the JAK2 involvement in various diseases/conditions. Recent advances highlight the molecular regulatory mechanisms utilized by the JAK2 signaling, thus, enabling to consider alternative therapeutic strategies to treat various diseases/conditions mediated by JAK2 by using it as a therapeutic target.

The Role of Skin and Gut Microbiome and Epigenetic Modifications in Skin-Autoimmune Disorders.

Abstract: Human microbiota and immune system are strictly connected to each other. Several studies demonstrated that normal skin and/or gut floral alterations may have negative consequences upon disease pathogenesis. Indeed, a strong association between skin and gut microbiota alterations and autoimmune diseases was found. Moreover, a significant interplay between microbiome and miRNAs expression was noticed among several conditions. The aim of this review article is to shed new light on some of the commonest skin disorders such as psoriasis, atopic dermatitis, allergic contact dermatitis, with special regards to epigenetic pathogenetic mechanisms such as miRNAs expression and skin and gut microbiome alterations. Indeed, evidence is still lacking regarding these two factors and their possible interactions. We believe their implications may be crucial for screening, early diagnosis and also therapeutic strategies, therefore this field could represent a promising challenge for further studies.

Recent Advances in the Analysis Full/Empty Capsid Ratio and Genome Integrity of Adeno-associated Virus (AAV) Gene Delivery Vectors.

Abstract: Adeno-associated virus (AAV) is one of the most promising viral gene delivery vectors with long-term gene expression and disease correction, featuring high efficiency and excellent safety in human clinical trials. During the production of AAV vectors, there are several quality control (QC) parameters that should be rigorously monitored to comply with clinical safety and efficacy. This review gives a short summary of the most frequently used AVV production and purification methods, focusing on the analytical techniques applied to determine the full/empty capsid ratio and the integrity of the encapsidated therapeutic DNA of the products.

The regulatory role of pivotal microRNAs in the AKT signaling pathway in breast cancer.

Abstract: Breast cancer is the most prevalent type of cancer among women, and it remains the main challenge despite improved treatments. MicroRNAs (miRNAs) are a small non-coding family of RNAs that play an indispensable role in regulating major physiological processes, including differentiation, proliferation, invasion, migration, cell cycle regulation, stem cell maintenance, apoptosis, and organ development. The dysregulation of these tiny molecules is associated with various human malignancies. More than 50% of these non-coding RNA sequences estimated have been placed on genomic regions or fragile sites linked to cancer. Following the discovery of the first signatures of specific miRNA in breast cancer, numerous researches focused on involving these tiny RNAs in breast cancer physiopathology as a new therapeutic approach or as reliable prognostic biomarkers. In the current review, we focus on recent findings related to the involvement of miRNAs in breast cancer via the AKT signaling pathway and the related clinical implications.

The Antitumor Effects of Icaritin Against Breast Cancer is Related to Estrogen Receptors.

Abstract: Objective We aim to investigate the anticancer effects and mechanisms of icaritin against breast cancer. Materials and methods Both estrogen receptor (ER) positive breast cancer cells MCF- 7 and ER-negative MDA-MB-231 cells were employed. We examined the effects of icaritin on the proliferation and migration by wound healing assay and transwell assay. Cell apoptosis and cell cycle of MCF-7 and MDA-MB-231 cells were analyzed using Flow cytometry. Cell autophagy of MCF-7 and MDA-MB-231 cells was assessed by western blotting, acridine orange staining and confocal microscopy. We also detected the expression of apoptosis-related genes by western blotting. In addition, an autophagy inhibitor was used to investigate whether cytoprotective autophagy was induced. Meanwhile, an ER inhibitor was utilized to explore whether ER was involved in autophagy. Results Icaritin inhibited the proliferation and migration, and induced cell cycle arrest of both MDA-MB-231 and MCF-7 cells. Icaritin significantly induced apoptosis of MDA-MB- 231 cells by activating caspase-3. And icaritin stimulated autophagy in MCF-7 cells, as evidenced by increased LC3II/LC3I, enhanced p62 degradation, the accumulation of endogenous LC3 puncta formation, and the increased autophagy flux. Icaritin induced autophagy through upregulating the phosphorylation of AMPK and ULK1. Chloroquine, an autophagy inhibitor, increased icaritin-induced apoptosis and proliferation inhibition of MCF-7 cells. Meanwhile, tamoxifen, an ER inhibitor, reversed icaritin-induced autophagy and proliferation inhibition of MCF-7 cells. Conclusion Our study demonstrated that the antitumor effects of icaritin against breast cancer are related to ER, which suggested that the status of ER should be considered in the clinical application of icaritin.

NPC1 as a Modulator of Disease Severity and Viral Entry of SARSCoV- 2.

Abstract: The COVID-19 plague is hitting mankind. Several viruses, including SARS-CoV-1, MERS-CoV, EBOV, and SARS-CoV-2, use the endocytic machinery to enter the cell. Genomic variants in NPC1, which encodes for the endo-lysosomal Niemann-Pick type C1 protein, restricts the host-range of viruses in bats and susceptibility to infections in humans. Lack of NPC1 and its pharmacological suppression inhibits many viral infections including SARS-CoV-1 and Type I Feline Coronavirus Infection. Antiviral effects of NPC1-inhibiting drugs for COVID-19 treatment should be explored.

OSI-027 alleviates oxaliplatin chemoresistance in gastric cancer cells by suppressing P-gp induction.

Abstract: Gastric cancer is one of the most common malignancies worldwide and the third leading cause of cancer-related death. In the present study, we investigated the potential activity of OSI-027, a potent and selective mammalian target of rapamycin complex 1/2 (mTOR1/2) dual inhibitor, alone or in combination with oxaliplatin against gastric cancer cells in vitro. Cell counting kit-8 assays and EdU staining were performed to examine the proliferation of cancer cells. Cell cycle and apoptosis were detected by flow cytometry. Western blot was used to detect the elements of the mTOR pathway and Pgp in gastric cancer cell lines. OSI-027 inhibited the proliferation of MKN-45 and AGS cells by arresting the cell cycle in the G0/G1 phase. At the molecular level, OSI-027 simultaneously blocked mTORC1 and mTORC2 activation, and resulted in the downregulation of phosphor-Akt, phpspho-p70S6k, phosphor-4EBP1, cyclin D1, and cyclin-dependent kinase4 (CDK4). Additionally, OSI-027 also downregulated P-gp, which enhanced oxaliplatin-induced apoptosis and suppressed multidrug resistance. Moreover, OSI-027 exhibited synergistic cytotoxic effects with oxaliplatin in vitro, while a P-gp siRNA knockdown significantly inhibited the synergistic effect. In summary, our results suggest that dual mTORC1/mTORC2 inhibitors (e.g., OSI-027) should be further investigated as a potential valuable treatment for gastric cancer.

The Ineluctable Role of ACE-2 Receptors in SARS COV-2 Infection and Drug Repurposing as a Plausible SARS COV-2 Therapy : A Concise Treatise.

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent for the COVID-19 infectious disease that spreads via the respiratory route and has reached a drastic level of a global pandemic Symptoms of COVID-19 may vary from mild (fever, dry cough, shortness of breath) to severe pneumonia-like respiratory symptoms as exacerbation of disease occurs Unlike SARS-CoV, the SARS-CoV-2 has a higher binding affinity to ACE-2 receptors which signify its higher transmission rate from person to person Even though ACE-2 is significant in the renin-angiotensin-aldosterone system (RAAS) regulation that exhibits protection to various organs, they play a significant role in COVID-19 disease pathogenesis Viral interferences with the ACE-2 peptidase activity are found in SARS-CoV-2 infected patients leading to pro-inflammatory responses, hypertension and multi-organ damage Angiotensin-converting enzyme-2 is constrained to a variety of organ systems but surface ACE-2 receptors on lung epithelia are largely affected, that lead to pathological alterations in lung histology which may progress to respiratory failure The viral tropism mainly occurs by the attachment to the angiotensin-converting enzymes-2 receptors in the host cell, thus drugs targeting ACE-2 expressions may arise as the future therapeutic strategy to combat COVID-19 infectionsThe innovative approach of repurposing of drugs has shown temporary effectiveness to the rising pandemic This article mainly focuses on the prominence of ACE-2 receptors which are expressed during the COVID infections and repurposing strategy of available drug therapies

Critical Role of NFκB in the Pathogenesis of Non-alcoholic Fatty Liver Disease: A Widespread Key Regulator.

Abstract: Non-alcoholic fatty liver disease is a chronic metabolic disorder representing the most common cause of chronic liver disease in western civilization and one of the main causes of cirrhosis with a significant impact on all-cause mortality in the most advanced phases. It is characterized by hepatic fat accumulation in the absence of significant ethanol consumption, virus infection or other specific causes of liver disease. Accumulation of fat in liver tissue occurs as a consequence of the imbalance between overconsumption of high-fat diet and increased de novo lipogenesis and decreased lipid disposal. Novel dietary and pharmacological therapies for the prevention of fatty liver disease and the progression to cirrhosis are an actual field of study but still poorly understood. In this perspective, the current review aims to summarise and clarify the transcription factor NFκB effects, which may exert among non-alcoholic fatty liver diseases and their progression. Through extensive previous research, it has become clear that several signaling pathways are involved: metabolic dysregulation (such as free fatty acids increase, adipokine alteration, insulin resistance), oxidative stress and inflammation contribute together in a "vicious circle" to the pathogenesis of non-alcoholic fatty liver diseases. Within this, NFκB signaling is a primary factor in inflammatory reactions and diseases, with important molecular connections between metabolic, oxidative, immune and inflammation systems.

The Key Role of Akt Protein Kinase in Metabolic-Inflammatory Pathways Cross-Talk: TNF-α Down-Regulation and Improving of Insulin Resistance in HepG2 Cell Line.

Abstract: Background: Elevation of plasma free fatty acids as a principal aspect of type 2 diabetes maintains etiologically insulin insensitivity in target cells. TNF-α inhibitory effects on key insulin signaling pathway elements remain to be verified in insulin-resistant hepatic cells. Thus, TNF-α knockdown effects on the key elements of insulin signaling were investigated in the palmitate-induced insulin-resistant hepatocytes. The Akt serine kinase, a key protein of the insulin signaling pathway, phosphorylation was monitored to understand the TNF-α effect on probable enhancing of insulin resistance. Methods: Insulin-resistant HepG2 cells were produced using 0.5 mM palmitate treatment and shRNA-mediated TNF-α gene knockdown and its down-regulation confirmed using ELISA technique. Western blotting analysis was used to assess the Akt protein phosphorylation status. Results: Palmitate-induced insulin resistance caused TNF-α protein overexpression 1.2-, 2.78, and 2.25-fold as compared to the control cells at post-treatment times of 8 h, 16 h, and 24 h, respectively. In the presence of palmitate, TNF-α expression showed around 30 reduction in TNF-α knockdown cells as compared to normal cells. In the TNF-α down-regulated cell, Akt phosphorylation was approximately 62 more than control cells after treatment with 100 nM insulin in conjugation with 0.5 mM palmitate. Conclusions: The obtained data demonstrated that TNF-α protein expression reduction improved insulin-stimulated Akt phosphorylation in the HepG2 cells and decreased lipid-induced insulin resistance of the diabetic hepatocytes. © 2021 Bentham Science Publishers.

The Therapeutic Effect of Stem Cells on Chemotherapy-Induced Premature Ovarian Failure.

Abstract: Premature ovarian failure (POF) refers to ovarian dysfunction in women under 40 years old. It is characterized by low estrogen, high gonadotropin, amenorrhea, and infertility, which seriously affect women's physical and mental health of women. The pathogenic factors of POF include iatrogenic factors, autoimmune factors, genetic factors, oxidative stress, infection, thyroid dysfunction, and adrenal diseases. Chemotherapy is a common cause of POF and is attracting increasing attention. With the development of modern medicine and advances in understanding cancer, women's cancer survival rates have significantly increased. Currently, the main treatment options for POF are hormone supplement and in vitro activation (IVA), but there is still no specific treatment for POF. Stem cells, known as undifferentiated cells of multicellular organisms, exhibit characteristics of self-renewal, directional differentiation into different cells, and low immunogenicity. Thus, they have potential in regenerative medicine and provide a promising direction for POF treatment. In this review, we summarize the latest research progress of various stem cells in chemotherapy-induced POF models to provide a theoretical basis for further research and treatment.

N-glycomic Analysis of Z(IgA1) Partitioned Serum and Salivary Immunoglobulin A by Capillary Electrophoresis

Abstract: AIMS Application of capillary electrophoresis with laser induced fluorescence detection (CE-LIF) to identify the N-glycosylation structures of serum and saliva IgA from healthy controls and patients with malignant hematological diseases having cytostatic treatment induced mild oral mucosal lesions. BACKGROUND Altered N-glycosylation of body fluid glycoproteins can be an effective indicator of most inflammatory processes. Immunoglobulin A (IgA) is the second highest abundant immunoglobulin and has a major role in the immune-defense against potential pathogen attacks. While IgA is abundant in serum, secretory immunoglobulin A (sIgA) is one of the most prevalent proteins in mucosal surfaces, such as in saliva. OBJECTIVE Our aim was to investigate the changes of IgA glycosylation in serum and saliva as a response to an administered cytostatic treatment in patients with malignant hematological disorders. METHODS Capillary electrophoresis with laser induced fluorescent detection (CE-LIF) was used to analyze the N-glycosylation profiles of Z(IgA1) partitioned immunoglobulin A in pooled serum and saliva of 10 control subjects and 8 patients with malignant hematological diseases having cytostatic treatment induced mild oral mucosal lesions. RESULTS Eight of 31 and four of 38 N-glycans in serum and saliva, respectively, showed significant (p<0.05) differences upon comparison to the control group. Thirteen glycans were present in the saliva but not in the serum, on the other hand, six structures were found in the serum samples not present in the saliva. CONCLUSION The developed Z(IgA1) partitioning and the high resolution CE-LIF based glyocoanalytical methods provided an efficient and sensitive workflow to detect and monitor IgA glycosylation alterations in serum and saliva with the scope for widespread molecular medicinal use.

Correlation Between Dexamethasone and miRNAs in the Regulation of Apoptosis, Drug-resistance, and Metastasis of Cancer Cell.

Abstract: Dexamethasone (Dex) is a synthetic corticosteroid hormone derived from the steroid chemical group and is applicable in treating several pathological conditions like inflammation, autoimmune disease, and malignancies. Recent investigations on the mechanism of action of Dex and its possible interactions with other cellular regulatory networks may help explanation of the inconsistent effects of Dex in cancer treatment. Fine-tuning regulation of essential post-transcriptional regulators such as microRNA (miRNAs) has indispensable impacts on modulating fundamental cellular processes including gene expression, cell proliferation, cell cycling, and apoptosis. Dex appears to act as a double-edged sword on cancer cell progression and metastasis through regulating miRNA networks. As a proof of concept, recent investigations have proved Dex to be effective in cancer-treating either individually or in combination with other therapeutical compounds while several evidences have point to the controversial effects of Dex in the promotion of cancer cell survival, drug-resistance, and metastasis. In addition, it has been proved that other non-coding RNAs (ncRNAs) can also be directly or indirectly affected by Dex. In this review, we aimed to investigate the controversial effect of Dex on the cancer-related miRNAs.