Combination of miR-99b-5p and Enzalutamide or Abiraterone Synergizes the Suppression of EMT-Mediated Metastasis in Prostate Cancer.

Prostate cancer (PCa) is the most frequently diagnosed cancer and second leading cause of cancer deaths among American men. Androgen deprivation therapy (ADT) has been systemically applied as a first-line therapy for PCa patients. Despite the initial responses, the majority of patients under ADT eventually experienced tumor progression to castration-resistant prostate cancer (CRPC), further leading to tumor metastasis to distant organs. Therefore, identifying the key molecular mechanisms underlying PCa progression remains crucial for the development of novel therapies for metastatic PCa. Previously, we identified that tumor-suppressive miR-99b-5p is frequently downregulated in aggressive African American (AA) PCa and European American (EA) CRPC, leading to upregulation of mTOR, androgen receptor (AR), and HIF-1α signaling. Given the fact that mTOR and HIF-1α signaling are critical upstream pathways that trigger the activation of epithelial-mesenchymal transition (EMT), we hypothesized that miR-99b-5p may play a critical functional role in regulating EMT-mediated PCa metastasis. To test this hypothesis, a series of cell biology, biochemical, and in vitro functional assays (wound healing, transwell migration, cell/ECM adhesion, and capillary-like tube formation assays) were performed to examine the effects of miR-99b-5p mimic on regulating EMT-mediated PCa metastasis processes. Our results have demonstrated that miR-99b-5p simultaneously targets MTOR and AR signaling, leading to upregulation of E-cadherin, downregulation of Snail/N-cadherin/Vimentin, and suppression of EMT-mediated PCa metastasis. MiR-99b-5p alone and in combination with enzalutamide or abiraterone significantly inhibits the EMT-mediated metastasis of AA PCa and EA CRPC.

Organoids: An Emerging Precision Medicine Model for Prostate Cancer Research.

Prostate cancer (PCa) has been known as the most prevalent cancer disease and the second leading cause of cancer mortality in men almost all over the globe. There is an urgent need for establishment of PCa models that can recapitulate the progress of genomic landscapes and molecular alterations during development and progression of this disease. Notably, several organoid models have been developed for assessing the complex interaction between PCa and its surrounding microenvironment. In recent years, PCa organoids have been emerged as powerful in vitro 3D model systems that recapitulate the molecular features (such as genomic/epigenomic changes and tumor microenvironment) of PCa metastatic tumors. In addition, application of organoid technology in mechanistic studies (i.e., for understanding cellular/subcellular and molecular alterations) and translational medicine has been recognized as a promising approach for facilitating the development of potential biomarkers and novel therapeutic strategies. In this review, we summarize the application of PCa organoids in the high-throughput screening and establishment of relevant xenografts for developing novel therapeutics for metastatic, castration resistant, and neuroendocrine PCa. These organoid-based studies are expected to expand our knowledge from basic research to clinical applications for PCa diseases. Furthermore, we also highlight the optimization of PCa cultures and establishment of promising 3D organoid models for in vitro and in vivo investigations, ultimately facilitating mechanistic studies and development of novel clinical diagnosis/prognosis and therapies for PCa.

Tumor suppressive miR-99b-5p as an epigenomic regulator mediating mTOR/AR/SMARCD1 signaling axis in aggressive prostate cancer.

Introduction: African American (AA) men exhibited 2.3-fold higher PCa incidence and 1.7-fold higher PCa mortality rates when compared to the European American (EA) men. Besides the socioeconomic factors, emerging evidence has highlighted that biological risk factors may play critical roles in the AA PCa disparities. Previously, we have shown that downregulated miR-99b-5p and upregulated mTOR cooperatively promotes the AA PCa aggressiveness and drug resistance. Methods: In this study, we aimed to explore the miR-99b-5p/mTOR/AR/SMARCD1 signaling axis in AA PCa aggressiveness. The analyses used in the study included immunofluorescence, western blot, in-vitro functional assays (TUNEL, colony forming, and MTT), and chromatin immunoprecipitation (ChIP)-qPCR assays in 2D and/or 3D culture model of EA PCa and AA PCa cell lines. Results: Specifically, the immunofluorescence staining, and western blot analysis has revealed that nuclear mTOR, AR, and SMARCD1 were highly expressed in AA PCa (MDA PCa 2b) compared to EA PCa (LNCaP) cell line. Western blot analysis further revealed that miR-99b-5p inhibited protein levels of mTOR, AR/AR-V7 and SMARCD1 in cytoplasm and nuclei of EA and AA PCa. The in-vitro functional (MTT, TUNEL, and clonogenic) assays have demonstrated that miR-99b-5p effectively inhibited cell proliferation/survival and induced cell apoptosis in EA and AA PCa cells. Moreover, combination of miR-99b-5p and enzalutamide (Enz) synergistically enhances the cytotoxicity against aggressive AA PCa and castration-resistant prostate cancer (CRPC). mTOR ChIP-qPCR assays further demonstrated that miR-99b-5p or miR-99b-5p/Enz significantly reduces the recruitment of mTOR to the genes involved in the metabolic reprogramming in CRPC. Discussion: Taken together, miR-99b-5p may function as an epigenomic driver to modulate the mTOR/AR/SMARCD1 signaling axis in AA PCa and resistant CRPC.

PM2.5-Induced Cardiac Structural Modifications and Declined Pro-Survival Signalling Pathways Are Responsible for the Inefficiency of GSK-3ß Inhibitor in Attenuating Myocardial Ischemia-Reperfusion Injury in Rats.

Circulatory GSK3ß is recognized as a biomarker and therapeutic target for diseases, including myocardial diseases. However, its potential as a target for myocardial ischemia-reperfusion injury (IR) in the presence of PM2.5 exposure is unclear. Wistar rats underwent IR following either a 21-day or single exposure to PM2.5 at a concentration of 250 µg/m3. The effects of GSK3ß inhibitor on cardiac physiology, tissue injury, mitochondrial function, and the PI3K/AKT/GSK3ß signalling axis were examined. The inhibitor was not effective in improving hemodynamics or reducing IR-induced infarction in the myocardium exposed to PM2.5 for 21 days. However, for a single-day exposure, the inhibitor showed potential in mitigating cardiac injury. In normal hearts undergoing IR, the inhibitor activated the PI3K/AKT signalling pathway, improved mitochondrial function, and reduced oxidative stress. These positive effects were not observed in PM2.5-exposed rats. Furthermore, the inhibitor stimulated autophagy in hearts exposed to PM2.5 for 21 days and subjected to IR, resulting in increased mTOR expression and decreased AMPK expression. In normal hearts and those exposed to a single dose of PM2.5, the inhibitor effectively activated the PI3K/Akt/AMPK axis. These findings suggest that GSK3ß may not be a reliable therapeutic target for IR in the presence of chronic PM2.5 exposure.

An In Silico Investigation of Pharmacological Modulators and Inflammasomes in Glioblastoma Multiforme.

For the past decades, inflammatory signals have been considered a possible key for pharmacological interventions. There are several compounds and/or molecules that have been known as most promising medication against inflammation and its mediated chronic disorders. Inflammasomes could be recognized as a trigger by detrimental stimuli as pathogenic attack and endogenous signals mediated injury inside the cells. In addition, there has been an inflammatory key mechanism involved in cancers including glioblastoma multiforme (GBM). GBM has been considered the foremost aggressive primary brain tumors in adult stage. There is a scattered beam of light on both cellular and molecular links in inflammation and GBM. However, the immune response of GBM has been characterized extensively by macrophages and lymphocytes related to tumors, and some recent investigations have pinpointed the focus of inflammasomes on the progression of GBM. Nevertheless, risk factors linked with GBM are still debatable. In our study, the most considerable compounds and their bonded and/or targeted proteins have depicted the most promising highlights under in silico condition. Our in silico investigations have revealed a powerful pharmacological agents/compound against inflammasome-mediated GBM.

CABG Patients Develop Global DNA Hypermethylation, That Negatively Affect the Mitochondrial Function and Promote Post-Surgical Cognitive Decline: A Proof of Concept in Small Cohort.

Global DNA hypermethylation and mitochondrial dysfunction are reported to be associated with the development of mild cognitive decline (MCI). The present study aims to generate preliminary data that connect the above association with post-surgical coronary artery bypass grafting (CABG) cognitive decline in patients. Data were collected from 70 CABG patients and 25 age-matched controls. Cognitive function was assessed using the Montreal Cognitive Assessment (MOCA) test on day 1 (before surgery) and on the day of discharge. Similarly, blood was collected before and one day after the CABG procedure for mitochondrial functional analysis and expression of DNA methylation genes. Test analysis score suggested 31 (44%) patients had MCI before discharge. These patients showed a significant decrease in complex I activity and an increase in malondialdehyde levels (p < 0.001) from the control blood samples. Post-surgical samples showed a significant reduction in blood MT-ND1 mRNA expression from control and from pre-surgical samples (p < 0.005), along with elevated DNMT1 gene expression (p < 0.047), with an insignificant increase in TET1 and TET3 gene expression. Correlation analysis showed a significant positive relation between cognitive decline and elevated blood DNMT1 and declined blood complex I activity, signifying that cognitive decline experienced by post-surgical CABG patients is associated with increased DNMT1 expression and declined complex I activity. Based on the data, we conclude that both DNA hypermethylation and mitochondrial dysfunction are associated with post-CABG MCI, where the former is negatively correlated, and the latter is positively correlated with post-surgical MCI in CABG cases. Additionally, a multimarker approach that comprises MOCA, DNA methylation, DNMT, and NQR activities can be utilized to stratify the population that is sensitive to developing post-CABG MCI.

Promising Strategy of mPTP Modulation in Cancer Therapy: An Emerging Progress and Future Insight.

Cancer has been progressively a major global health concern. With this developing global concern, cancer determent is one of the most significant public health challenges of this era. To date, the scientific community undoubtedly highlights mitochondrial dysfunction as a hallmark of cancer cells. Permeabilization of the mitochondrial membranes has been implicated as the most considerable footprint in apoptosis-mediated cancer cell death. Under the condition of mitochondrial calcium overload, exclusively mediated by oxidative stress, an opening of a nonspecific channel with a well-defined diameter in mitochondrial membrane allows free exchange between the mitochondrial matrix and the extra mitochondrial cytosol of solutes and proteins up to 1.5 kDa. Such a channel/nonspecific pore is recognized as the mitochondrial permeability transition pore (mPTP). mPTP has been established for regulating apoptosis-mediated cancer cell death. It has been evident that mPTP is critically linked with the glycolytic enzyme hexokinase II to defend cellular death and reduce cytochrome c release. However, elevated mitochondrial Ca2+ loading, oxidative stress, and mitochondrial depolarization are critical factors leading to mPTP opening/activation. Although the exact mechanism underlying mPTP-mediated cell death remains elusive, mPTP-mediated apoptosis machinery has been considered as an important clamp and plays a critical role in the pathogenesis of several types of cancers. In this review, we focus on structure and regulation of the mPTP complex-mediated apoptosis mechanisms and follow with a comprehensive discussion addressing the development of novel mPTP-targeting drugs/molecules in cancer treatment.

Promising Action of Cannabinoids on ER Stress-Mediated Neurodegeneration: An In Silico Investigation.

Neurodegeneration has been recognized as a clinical episode characterized by neuronal death, including dementia, cognitive impairment and movement disorder. Most of the neurodegenerative deficits, via clinical symptoms, includes common pathogenic features as protein misfolding and aggregation. Therefore, the focus highlights the cellular organelle endoplasmic reticulum (ER) critically linked with the quality control and protein homeostasis. Unfolded protein response (UPR) or ER stress have also been considered as hallmarks for neurodegenerative disorders. It has been implicated that the levels of endocannabinoids (ECB) could rise at the platform of neurodegeneration. In addition, phytocannabinoids (PCB) including cannabidiol (CBD) could also initiate the IRE1, PERK, XBP-1, and ATF6, pathways that could lead to the degradation of the misfolded proteins and termination of protein translation. Thus, our aim was to determine if cannabinoids bind to these ER arm proteins involved in UPR by molecular docking and therefore determine its drug resemblance through ADME analysis. In our study, three cannabinoid receptors (CB1, CB2, and CB3) were considered to demonstrate their neuroprotective actions. The chosen ligands were screened as PCB (Δ9-tetrahydrocannabinol or THC), CBD, and two ECB, anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The current findings have advocated that the cannabinoids and their molecular targets have shown considerable binding and their ADME properties also reveals that they possess moderate drug-like properties making it as a valuable option for the treatment and management of neurodegenerative diseases.

Downregulation of miR-99b-5p and Upregulation of Nuclear mTOR Cooperatively Promotes the Tumor Aggressiveness and Drug Resistance in African American Prostate Cancer.

Mammalian target of rapamycin (mTOR) regulates various fundamental cellular events including cell proliferation, protein synthesis, metabolism, apoptosis, and autophagy. Tumor suppressive miR-99b-5p has been implicated in regulating PI3K/AKT/mTOR signaling in a variety of types of cancer. Our previous study suggested the reciprocal miR-99b-5p/MTOR (downregulated/upregulated) pairing as a key microRNA-mRNA regulatory component involved in the prostate cancer (PCa) disparities. In this study, we further validated the expression profiles of mTOR and miR-99b-5p in the PCa, colon, breast, and lung cancer specimens and cell lines. The immunohistochemistry (IHC), immunofluorescence, Western blot, and RT-qPCR assays have confirmed that mTOR is upregulated while miR-99b-5p is downregulated in different patient cohorts and a panel of cancer cell lines. Intriguingly, elevated nuclear mTOR expression was observed in African American PCa and other advanced cancers. Transfection of the miR-99b-5p mimic resulted in a significant reduction in nuclear mTOR and androgen receptor (AR), while a slight/moderate to no decrease in cytoplasmic mTOR and AR in PCa and other cancer cells, suggesting that miR-99b-5p inhibits mTOR and AR expression and their nuclear translocation. Moreover, overexpression of miR-99b-5p targets/inhibits AR-mTOR axis, subsequently initiating cell apoptosis and sensitizing docetaxel-induced cytotoxicity in various cancers. In conclusion, our data suggest that reciprocal miR-99b-5p/nuclear mTOR pairing may be a more precise diagnostic/prognostic biomarker for aggressive PCa, than miR-99b-5p/MTOR pairing or mTOR alone. Targeting the AR-mTOR axis using miR-99b-5p has also been suggested as a novel therapeutic strategy to induce apoptosis and overcome chemoresistance in aggressive PCa.

Cellular and Molecular Machinery of Neuropathic Pain: an Emerging Insight.

Purpose of Review: Neuropathic pain (NP) has been ubiquitously characterized by lesion and its linked somatosensory system either the central nervous system (CNS) or peripheral nervous system (PNS) This PNS episode is the most prevalent site of NP origin and is found to be associated with afferent nerve fibers carrying pain signals from injured/trauma site to the CNS including the brain. Several kinds of pharmacotherapeutic drugs shuch as analgesics, anti-convulsants, and anti-depressants are being employed for the its possible interventions. The NP has been a great interest to follow different pathophysiological mechanisms which are often considered to correlate with the metabolic pathways and its mediated disease. There is paucity of knowledge to make such mechanism via NP. Recent Finding: Most notably, recent pandemic outbreak of COVID-19 has also been reported in chronic pain mediated diabetes, inflammatory disorders, and cancers. There is an increasing incidence of NP and its complex mechanism has now led to identify the possible investigations of responsible genes and proteins via bioinformatics tools. The analysis might be more instrumental as collecting the genes from pain genetic database, analyzing the variants through differential gene expression (DEG) and constructing the protein-protein interaction (PPI) networks and thereby determining their upregulating and downregulating pathways. Summary: This review sheds a bright light towards several mechanisms at both cellular and molecular level, correlation of NP-mediated disease mechanism and possible cell surface biomarkers (receptors), and identified genes could be more promising for their pharmacological targets.

Lipidomics: An excellent tool for chronic disease detection.

It has been known as almost all the cells consists a lipid molecule which has a considerable impact in various biological processes. Lipids have been investigated with a potential role for the formation of cellular membrane and thereby maintaining the structural integrity. Omics has placed as a combined technologies utilized for an exploaration of mechanistic actions in several kinds of molecules that make up the cells of an organism. Lipidomics has been recognized as a newly emerged branch of omics technology. This technology has the captivating factors to classify and characterize almost all the cellular lipids with the help of various analytical techniques and computational biological plateform. In lipidomics studies, structural display of several lipid biomarkers could also be analyzed and considered for actual disease diagnosis procedures. This could also replace certain traditional diagnostics method at all over the globe. Our review focuses how important this lipidomics particularly in disease diagnosis and also covers various analytical techniques and computational methods or bioinformatics tools in for the diagnosis of disease. In addtion, we also pinponted the possible role of lipids in several kinds of cellular disorders including cancer, neurodegenerative diseases, cardiovascular diseases, diabetes and obesity in human population. .

Mechanistic Episodes on SARS-CoV-2-Mediated Neurological Manifestations and Their Possible Therapeutic Interventions.

Recently, the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been critically recognized and spread rapidly on this planet. Considerable recognition of SARS-CoV-2 has been known with a range of viruses that are more capable to cause diseases in avian and mammals including humans. The virus was found as a main culprit for major defects in respiratory system and thereby caused severe acute respiratory syndrome disease. This has led to depict the mortality in human population. Nevertheless, compromised reports on SARS-CoV-2 has also shown neurological complications in both central nervous system (CNS) and peripheral nervous system (PNS). This virus has notified with neurological defects as stroke, encephalopathy, cerebral edema, erythema, seizures, meningitis, ischemic, ageusia, loss of smell, myalgia and Guillain Barre Syndrome. In this review, we focused on COVID-19 mediated neurodegeneration and its mechanistic episodes on affected patients. We also discuss the possible available therapeutic interventions with clinically investigated drugs against COVID-19 mediated neurological impairment in patients and experimental in vitro and in vivo research models required for the development of drugs and/or vaccines against COVID-19 mediated neurological complications.

Identification of miRNAs and related hub genes associated with the triple negative breast cancer using integrated bioinformatics analysis and in vitro approach.

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype generally associated with younger women. Due to the lack of suitable drugable targets in TNBC, the microRNAs are considered as a better hope as therapeutic agents for the management of the disease. In this study, we identified differentially expressed miRNAs (DEMs) and associated hub genes in TNBC microarray data (GSE38167, GSE60714, and GSE10833) using bioinformatics tools. The identified miRNAs and genes were validated in the TNBC cell line model (MDA-MB-231) compared with the normal breast cells (MCF-10A) using the qRT-PCR technique. False-positive DEMs were avoided by comparing the DEMs profile of TNBC and triple positive breast cancer (TPBC) cell line model (BT474) compared with the MCF-10A cells data. In addition, we studied the effect of anticancer phytochemicals on the differential expression of miRNAs and genes in MDA-MB-231 cells. Furthermore, target predictions, functional enrichment and KEGG pathway analysis, mutation and copy number alterations, and overall survival analysis of DEMs in TNBC sample was investigated using standard computational tools. The study identifies first time the association of hsa-miR-1250, has-miR-1273, and has-miR-635 with the TNBC. DEMs showed significant association with the Wnt, ErbB, PI3-Akt and cAMP signaling pathways having clinical implications in TNBC tumorigenesis. The DEMs and hub genes (HOXC6 and ACVR2B) showed survival disadvantages in TNBC patients. In summary, the identified miRNAs and hub genes show important implications in TNBC tumorigenesis and patient survival. We recommend further experimental studies on pathophysiological mechanism of the identified miRNAs and hub genes in TNBC.Communicated by Ramaswamy H. Sarma.

Compression neuropathies of the forearm: anatomy, clinical features and management.

The upper limb consists of four major parts: a girdle formed by the clavicle and scapula, the arm, the forearm and the hand. Peripheral nerve lesions of the upper limb are divided into lesions of the brachial plexus or the nerves arising from it. Lesions of the nerves arising from the brachial plexus are further divided into upper (proximal) or lower (distal) lesions based on their location. Peripheral nerves in the forearm can be compressed in various locations and by a wide range of pathologies. A thorough understanding of the anatomy and clinical presentations of these compression neuropathies can lead to prompt diagnosis and management, preventing possible permanent damage. This article discusses the aetiology, anatomy, clinical presentation and surgical management of compressive neuropathies of the upper limb.

AgNPs from Nigella sativa Control Breast Cancer: An In Vitro Study.

In our current study, we synthesized silver nanoparticles (AgNPs) from an aqueous seed extract of Nigella sativa. The seed extract contains phytochemical compounds including phenols, terpenoids, and flavonoids that may act as reducing agents and are able to convert metal ions to metal nanoparticles. The formation of synthesized AgNPs was characterized using UV-visible spectroscopy, Fourier transform infra-red spectroscopy (FT-IR), scanning electron microscopy (SEM) and energy dispersive analysis of X-rays (EDX). The efficacy of N-AgNPs against human breast cancer (MCF-7) cells was tested. The synthesized AgNPs displayed dose-dependent cytotoxicity (1-200 µg/mL) against MCF-7 cells. Morphological alterations of the cells also appeared as bright field images. Treatment of synthesized AgNPs altered the expression of Bax and Bcl-2 (apoptotic proteins) and COX-2 (inflammatory marker) in MCF-7 cells. To our knowledge, this is the first report demonstrating that N-AgNPs from Nigella sativa can induce apoptosis in MCF-7 cells.

Biogenic AgNPs synthesized via endophytic bacteria and its biological applications.

In this present study, the endophytic bacteria were isolated from the drought-tolerant ornamental plant Pennisetum setaceum. The biomass of endophytic bacteria was utilized for the biogenic synthesis of silver nanoparticles (AgNPs). The synthesis of AgNPs was confirmed by UV-Visible and FTIR spectroscopy followed by SEM analysis. The antibacterial studies were performed through MIC, MBC, and biofilm assays. Efficacy of AgNPs against the human breast cancer (MCF-7) cells was also tested, and the IC50 was determined by MTT assay. In our study, we have observed that the synthesized AgNPs exhibited a dose-dependent cytotoxicity (1-100 µg/mL) against MCF-7 cells and morphological alterations of the cells were also visualized and the IC50 was observed at 50 µg/mL. The treatment of synthesized AgNPs altered the expression of apoptotic proteins including Bax, Bcl-2, and inflammatory marker COX-2 in MCF-7 cells. To the best of our knowledge, this is the first report that demonstrates the AgNPs from endophytic bacteria isolated from the plant Pennisetum setaceum can induce apoptosis in human breast cancer MCF-7 cells. Our results suggest that AgNPs used in this study can be utilized to control human pathogens and can also be utilized to induce apoptosis in breast cancer cells.

MicroRNA-183-5p: A New Potential Marker for Prostate Cancer.

The microRNA (miR)-183-5p is expressed at high level in the majority of cancer. The purpose of present study was to investigate the role of oncogenic miR-183-5p in prostate cancer (PCa) as biomarker. We carried out our experiment in 50 prostate cancer patients and 40 patients of benign prostatic hyperplasia (BPH) and 40 adjacent controls tissue. The expression of miR-183-5p was evaluated through reverse transcription qualitative polymerase chain reaction. We found that the expression of miR-183-5p in PCa tissue was significantly up regulated as compared to BPH patients and adjacent normal tissues as control. Additionally, miR-183 expression was correlated with higher prostate-specific antigen, higher Gleason Score and metastatic condition. A receiver operating characteristic curve analysis revealed that miR-183-5p distinguished PCa patients from BPH patients and also from control. In conclusion, our data suggest that oncogenic miR-183-5p may be useful as a new tissue specific diagnostic biomarker in prostate cancer.

Effects of citral on oxidative stress and hepatic key enzymes of glucose metabolism in streptozotocin/high-fat-diet induced diabetic dyslipidemic rats.

OBJECTIVES: Phytochemicals such as polyphenols, alkaloids, and terpenoids, protect against the development of early stages and complications of diabetes mellitus according to various reports. The aim of this study was to measure the anti-dyslipidemic and anti-diabetic effects of Citral on high-fat-diet (HFD) and streptozotocin (STZ) induced diabetic dyslipidemic rats and to see also its effect on carbohydrate metabolic regulatory enzymes in the liver. MATERIALS AND METHODS: Rats were kept on a high-fat diet for 2 weeks, then diabetes was induced by a single dose of STZ (35 mg/kg/BW, intraperitoneally), Citral was administered orally at a dose of 45 mg/kg/BW for 28 days to diabetic rats. Blood glucose, plasma insulin, and lipid profile in blood were studied. Antioxidant activities were assayed in the liver, pancreas, and adipose tissues. Carbohydrate metabolic enzymes of the liver were also studied in diabetic dyslipidemic rats. RESULTS: The results of this study confirmed that administration of Citral significantly (P<0.05) decreased the blood glucose level and increased plasma insulin in diabetic rats. Citral also improved oxidative markers along with anti-oxidative enzymes of the liver, adipose tissue, and pancreas in the HFD/STZ group. Citral also regulated the activity of the glucose-metabolic enzymes in the liver. The results of the present study were compared to Glibenclamide, which is a standard oral drug for lowering the blood sugar. CONCLUSION: Results may show that Citral possesses anti-dyslipidemic activity as well as anti-diabetic activity and also regulates the enzyme activity of glycolytic and gluconeogenic processes in the liver.

Differential expression of Helios, Neuropilin-1 and FoxP3 in head and neck squamous cell carcinoma (HNSCC) patients.

In recent years, studies have begun to explore the immune involvement in head and neck tumors. Advanced stage head and neck squamous cell carcinoma (HNSCC) has a poor prognosis with low survival rates with high level of immune infiltrates. Tregs (regulatory T cells) play a crucial role in constructing an immunosuppressive tumor microenvironment. In the present study, we highlighted specific Treg markers and its factors in HNSCC solid tumors and peripheral blood of cancer patients. By histopathology and immunofluorescence staining, we observed differential expression of CD4, CD25, Foxp3, Helios and Neuropilin-1. Further, we analyzed the expression of Foxp3, Helios, Neuropilin-1 and GARP by qPCR and flow cytometry in whole blood and found to be elevated in HNSCC patients in comparison with healthy donors. Additionally, IFN-γ, TGF-ß, IL-6, IL-2, IL-10 and TNF-α expressions were also found to be relatively increased in the head and neck cancer patients when compared with healthy donors. Our findings emphasize that Tregs may be involved in promoting tumor progression. Helios and Neuropilin-1 could be potent markers in identifying subsets of Tregs. Association of soluble factors could sculpture the activity of Tregs. With further research, Treg markers and its associated soluble factors could be employed to block Tregs trafficking to the tumor, thus enlightening a potential strategy for targeting human cancers.

Ellagic acid mitigates arsenic-trioxide-induced mitochondrial dysfunction and cytotoxicity in SH-SY5Y cells.

In the current study, neuroprotective significance of ellagic acid (EA, a polyohenol) was explored by primarily studying its antioxidant and antiapoptotic potential against arsenic trioxide (As2 O3 )-induced toxicity in SH-SY5Y human neuroblastoma cell lines. The mitigatory effects of EA with particular reference to cell viability and cytotoxicity, the generation of reactive oxygen species, DNA damage, and mitochondrial dynamics were studied. Pretreatment of SH-SY5Y cells with EA (10 and 20 µM) for 60 min followed by exposure to 2 µM As2 O3 protected the SH-SY5Y cells against the harmful effects of the second. Also, EA pre-treated groups expressed improved viability, repaired DNA, reduced free radical generation, and maintained altered mitochondrial membrane potential than those exposed to As2 O3 alone. EA supplementation also inhibited As2 O3 -induced cytochrome c expression that is an important hallmark for determining mitochondrial dynamics. Thus, the current investigations are more convinced for EA as a promising candidate in modulating As2 O3 -induced mitochondria-mediated neuronal toxicity under in vitro system.