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Abstract Brain cancer is regarded as one of the most life-threatening forms of cancer worldwide. Oxidative stress acts to derange normal brain homeostasis, thus is involved in carcinogenesis in brain. The Nrf2/Keap1/ARE pathway is an important signaling cascade responsible for the maintenance of redox homeostasis, and regulation of anti-inflammatory and anticancer activities by multiple downstream pathways. Interestingly, Nrf2 plays a somewhat, contradictory role in cancers, including brain cancer. Nrf2 has traditionally been regarded as a tumor suppressor since its cytoprotective functions are considered to be the principle cellular defense mechanism against exogenous and endogenous insults, such as xenobiotics and oxidative stress. However, hyperactivation of the Nrf2 pathway supports the survival of normal as well as malignant cells, protecting them against oxidative stress, and therapeutic agents. Plants possess a pool of secondary metabolites with potential chemotherapeutic/chemopreventive actions. Modulation of Nrf2/ARE and downstream activities in a Keap1-dependant manner, with the aid of plant-derived secondary metabolites exhibits promise in the management of brain tumors. Current article highlights the effects of Nrf2/Keap1/ARE cascade on brain tumors, and the potential role of secondary metabolites regarding the management of the same.

Abstract The production and release of tumor-derived small extracellular vesicles (TDSEVs) from cancerous cells play a pivotal role in the propagation of cancer, through genetic and biological communication with healthy cells. TDSEVs are known to orchestrate the invasion-metastasis cascade via diverse pathways. Regulation of early metastasis processes, pre-metastatic niche formation, immune system regulation, angiogenesis initiation, extracellular matrix (ECM) remodeling, immune modulation, and epithelial-mesenchymal transition (EMT) are among the pathways regulated by TDSEVs. MicroRNAs (miRs) carried within TDSEVs play a pivotal role as a double-edged sword and can either promote metastasis or inhibit cancer progression. TDSEVs can serve as excellent markers for early detection of tumors, and tumor metastases. From a therapeutic point of view, the risk of cancer metastasis may be reduced by limiting the production of TDSEVs from tumor cells. On the other hand, TDSEVs represent a promising approach for in vivo delivery of therapeutic cargo to tumor cells. The present review article discusses the recent developments and the current views of TDSEVs in the field of cancer research and clinical applications.

Abstract Breast cancer is the second leading cause of death for women worldwide. The heterogeneity of this disease presents a big challenge in its therapeutic management. However, recent advances in molecular biology and immunology enable to develop highly targeted therapies for many forms of breast cancer. The primary objective of targeted therapy is to inhibit a specific target/molecule that supports tumor progression. Ak strain transforming, cyclin-dependent kinases, poly (ADP-ribose) polymerase, and different growth factors have emerged as potential therapeutic targets for specific breast cancer subtypes. Many targeted drugs are currently undergoing clinical trials, and some have already received the FDA approval as monotherapy or in combination with other drugs for the treatment of different forms of breast cancer. However, the targeted drugs have yet to achieve therapeutic promise against triple-negative breast cancer (TNBC). In this aspect, immune therapy has come up as a promising therapeutic approach specifically for TNBC patients. Different immunotherapeutic modalities including immune-checkpoint blockade, vaccination, and adoptive cell transfer have been extensively studied in the clinical setting of breast cancer, especially in TNBC patients. The FDA has already approved some immune-checkpoint blockers in combination with chemotherapeutic drugs to treat TNBC and several trials are ongoing. This review provides an overview of clinical developments and recent advancements in targeted therapies and immunotherapies for breast cancer treatment. The successes, challenges, and prospects were critically discussed to portray their profound prospects.

Cancer is an abnormal state of cells where they undergo uncontrolled proliferation and produce aggressive malignancies that causes millions of deaths every year. With the new understanding of the molecular mechanism(s) of disease progression, our knowledge about the disease is snowballing, leading to the evolution of many new therapeutic regimes and their successive trials. In the past few decades, various combinations of therapies have been proposed and are presently employed in the treatment of diverse cancers. Targeted drug therapy, immunotherapy, and personalized medicines are now largely being employed, which were not common a few years back. The field of cancer discoveries and therapeutics are evolving fast as cancer type-specific biomarkers are progressively being identified and several types of cancers are nowadays undergoing systematic therapies, extending patients' disease-free survival thereafter. Although growing evidence shows that a systematic and targeted approach could be the future of cancer medicine, chemotherapy remains a largely opted therapeutic option despite its known side effects on the patient's physical and psychological health. Chemotherapeutic agents/pharmaceuticals served a great purpose over the past few decades and have remained the frontline choice for advanced-stage malignancies where surgery and/or radiation therapy cannot be prescribed due to specific reasons. The present report succinctly reviews the existing and contemporary advancements in chemotherapy and assesses the status of the enrolled drugs/pharmaceuticals; it also comprehensively discusses the emerging role of specific/targeted therapeutic strategies that are presently being employed to achieve better clinical success/survival rate in cancer patients.

Continuous revision of the histologic and stage-wise classification of lung cancer by the World Health Organization (WHO) provides the foundation for therapeutic advances by promoting molecular targeted and immunotherapies and ensuring accurate diagnosis. Cancer epidemiologic data provide helpful information for cancer prevention, diagnosis, and management, supporting health-care interventions. Global cancer mortality projections from 2016 to 2060 show that cancer will overtake ischemic heart diseases (IHD) as the leading cause of death (18.9 million) immediately after 2030, surpassing non-small cell lung cancer (NSCLC), which accounts for 85 percent of lung cancers. The clinical stage at the diagnosis is the main prognostic factor in NSCLC therapies. Advanced early diagnostic methods are essential as the initial stages of cancer show reduced mortality compared to the advanced stages. Sophisticated approaches to proper histological classification and NSCLC management have improved clinical efficiency. Although immune checkpoint inhibitors (ICIs) and targeted molecular therapies have refined the therapeutic management of late-stage NSCLC, the specificity and sensitivity of cancer biomarkers should be improved by focusing on prospective studies, followed by their use as therapeutic tools. The liquid biopsy candidates such as circulating tumor cells (CTCs), circulating cell-free tumor DNA (cfDNA), tumor educated platelets (TEP), and extracellular vesicles (EVs) possess cancer-derived biomolecules and aid in tracing: driver mutations leading to cancer, acquired resistance caused by various generations of therapeutic agents, refractory disease, prognosis, and surveillance.

Diabetic nephropathy (DN) is a serious microvascular consequence of diabetes mellitus (DM), posing an encumbrance to public health worldwide. Control over the onset and progress of DN depend heavily on early detection and effective treatment. DN is a major contributor to end-stage renal disease, and a complete cure is yet to be achieved with currently available options. Though some therapeutic molecules have exhibited promise in treating DN complications, their poor solubility profile, low bioavailability, poor permeation, high therapeutic dose and associated toxicity, and low patient compliance apprehend their clinical usefulness. Recent research has indicated nano-systems as potential theranostic platforms displaying futuristic promise in the diagnosis and treatment of DN. Early and accurate diagnosis, site-specific delivery and retention by virtue of ligand conjugation, and improved pharmacokinetic profile are amongst the major advantages of nano-platforms, defining their superiority. Thus, the emergence of nanoparticles has offered fresh approaches to the possible diagnostic and therapeutic strategies regarding DN. The present review corroborates an updated overview of different types of nanocarriers regarding potential approaches for the diagnosis and therapy of DN.

Abstract Malignant brain tumors rank among the most challenging type of malignancies to manage. The current treatment protocol commonly entails surgery followed by radiotherapy and/or chemotherapy, however, the median patient survival rate is poor. Recent developments in immunotherapy for a variety of tumor types spark optimism that immunological strategies may help patients with brain cancer. Chimeric antigen receptor (CAR) T cells exploit the tumor-targeting specificity of antibodies or receptor ligands to direct the cytolytic capacity of T cells. Several molecules have been discovered as potential targets for immunotherapy-based targeting, including but not limited to EGFRvIII, IL13Rα2, and HER2. The outstanding clinical responses to CAR T cell-based treatments in patients with hematological malignancies have generated interest in using this approach to treat solid tumors. Research results to date support the astounding clinical response rates of CD19-targeted CAR T cells, early clinical experiences in brain tumors demonstrating safety and evidence for disease-modifying activity, and the promise for further advances to ultimately assist patients clinically. However, several variable factors seem to slow down the progress rate regarding treating brain cancers utilizing CAR T cells. The current study offers a thorough analysis of CAR T cells’ promise in treating brain cancer, including design and delivery considerations, current strides in clinical and preclinical research, issues encountered, and potential solutions.

Abstract Brain cancer is regarded among the deadliest forms of cancer worldwide. The distinct tumor microenvironment and inherent characteristics of brain tumor cells virtually render them resistant to the majority of conventional and advanced therapies. Oxidative stress (OS) is a key disruptor of normal brain homeostasis and is involved in carcinogenesis of different forms of brain cancers. Thus, antioxidants may inhibit tumorigenesis by preventing OS induced by various oncogenic factors. Antioxidants are hypothesized to inhibit cancer initiation by endorsing DNA repair and suppressing cancer progression by creating an energy crisis for preneoplastic cells, resulting in antiproliferative effects. These effects are referred to as chemopreventive effects mediated by an antioxidant mechanism. In addition, antioxidants minimize chemotherapy-induced nonspecific organ toxicity and prolong survival. Antioxidants also support the prooxidant chemistry that demonstrate chemotherapeutic potential, particularly at high or pharmacological doses and trigger OS by promoting free radical production, which is essential for activating cell death pathways. A growing body of evidence also revealed the roles of exogenous antioxidants as adjuvants and their ability to reverse chemoresistance. In this review, we explain the influences of different exogenous and endogenous antioxidants on brain cancers with reference to their chemopreventive and chemotherapeutic roles. The role of antioxidants on metabolic reprogramming and their influence on downstream signaling events induced by tumor suppressor gene mutations are critically discussed. Finally, the review hypothesized that both pro- and antioxidant roles are involved in the anticancer mechanisms of the antioxidant molecules by killing neoplastic cells and inhibiting tumor recurrence followed by conventional cancer treatments. The requirements of pro- and antioxidant effects of exogenous antioxidants in brain tumor treatment under different conditions are critically discussed along with the reasons behind the conflicting outcomes in different reports. Finally, we also mention the influencing factors that regulate the pharmacology of the exogenous antioxidants in brain cancer treatment. In conclusion, to achieve consistent clinical outcomes with antioxidant treatments in brain cancers, rigorous mechanistic studies are required with respect to the types, forms, and stages of brain tumors. The concomitant treatment regimens also need adequate consideration.

An enveloped double-stranded DNA monkeypox virus (MPXV) is a causative agent of the zoonotic viral disease, human monkeypox (HMPX). MPXV belongs to the genus Orthopoxviridae, a family of notorious smallpox viruses, and so it shares similar clinical pathophysiological features. The recent multicountry HMPX outbreak (May 2022 onwards) is recognized as an emerging global public health emergency by the World Health Organization, shunting its endemic status as opined over the past few decades. Re-emergence of HMPX raises concern to reassess the present clinical strategy and therapeutics as its outbreak evolves further. Keeping a check on these developments, here we provide insights into the HMPX epidemiology, pathophysiology, and clinical representation. Weighing on its early prevention, we reviewed the strategies that are being enrolled for HMPX diagnosis. In the line of expanded MPXV prevalence, we further reviewed its clinical management and the diverse employed preventive/therapeutic strategies, including vaccines (JYNNEOS, ACAM2000, VIGIV) and antiviral drugs/inhibitors (Tecovirimat, Cidofovir, Brincidofovir). Taken together, with a revised perspective of HMPX re-emergence, the present report summarizes new knowledge on its prevalence, pathology, and prevention strategies.

Diabetes mellitus (DM) and cardiovascular complications are two unmet medical emergencies that can occur together. The rising incidence of heart failure in diabetic populations, in addition to apparent coronary heart disease, ischemia, and hypertension-related complications, has created a more challenging situation. Diabetes, as a predominant cardio-renal metabolic syndrome, is related to severe vascular risk factors, and it underlies various complex pathophysiological pathways at the metabolic and molecular level that progress and converge toward the development of diabetic cardiomyopathy (DCM). DCM involves several downstream cascades that cause structural and functional alterations of the diabetic heart, such as diastolic dysfunction progressing into systolic dysfunction, cardiomyocyte hypertrophy, myocardial fibrosis, and subsequent heart failure over time. The effects of glucagon-like peptide-1 (GLP-1) analogues and sodium-glucose cotransporter-2 (SGLT-2) inhibitors on cardiovascular (CV) outcomes in diabetes have shown promising results, including improved contractile bioenergetics and significant cardiovascular benefits. The purpose of this article is to highlight the various pathophysiological, metabolic, and molecular pathways that contribute to the development of DCM and its significant effects on cardiac morphology and functioning. Additionally, this article will discuss the potential therapies that may be available in the future.

Chitin is the second most abundant biopolymer consisting of N-acetylglucosamine units and is primarily derived from the shells of marine crustaceans and the cell walls of organisms (such as bacteria, fungi, and algae). Being a biopolymer, its materialistic properties, such as biodegradability, and biocompatibility, make it a suitable choice for biomedical applications. Similarly, its deacetylated derivative, chitosan, exhibits similar biocompatibility and biodegradability properties, making it a suitable support material for biomedical applications. Furthermore, it has intrinsic material properties such as antioxidant, antibacterial, and antitumor. Population studies have projected nearly 12 million cancer patients across the globe, where most will be suffering from solid tumors. One of the shortcomings of potent anticancer drugs is finding a suitable cellular delivery material or system. Therefore, identifying new drug carriers to achieve effective anticancer therapy is becoming essential. This paper focuses on the strategies implemented using chitin and chitosan biopolymers in drug delivery for cancer treatment.

Site-specific delivery of chemotherapeutics specifically to neoplastic hepatocytes without affecting normal hepatocytes should be a focus for potential therapeutic management of hepatocellular carcinoma (HCC). The aptamer TLS 9a with phosphorothioate backbone modifications (L5) has not been explored so far for preferential delivery of therapeutics in neoplastic hepatocytes to induce apoptosis. Thus, the objective of the present investigation was to compare the therapeutic potential of L5-functionalized drug nanocarrier (PTX-NPL5) with those of the other experimental drug nanocarriers functionalized by previously reported HCC cell-targeting aptamers and non-aptamer ligands, such as galactosamine and apotransferrin. A myriad of well-defined investigations such as cell cycle analysis, TUNEL (terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling) assay, and studies related to apoptosis, histopathology, and immunoblotting substantiated that PTX-NPL5 had the highest potency among the different ligand-attached experimental formulations in inducing selective apoptosis in neoplastic hepatocytes via a mitochondrial-dependent apoptotic pathway. PTX-NPL5 did not produce any notable toxic effects in healthy hepatocytes, thus unveiling a new and a safer option in targeted therapy for HCC. Molecular modeling study identified two cell-surface biomarker proteins (tumor-associated glycoprotein 72 [TAG-72] and heat shock protein 70 [HSP70]) responsible for ligand-receptor interaction of L5 and preferential internalization of PTX-NPL5 via clathrin-mediated endocytosis in neoplastic hepatocytes. The potential of PTX-NPL5 has provided enough impetus for its rapid translation from the pre-clinical to clinical domain to establish itself as a targeted therapeutic to significantly prolong survival in HCC.

The Japanese encephalitis virus (JEV) is the most common cause of neurodegenerative disease in Southeast Asia and the Western Pacific region; approximately 1.15 billion people are at risk, and thousands suffer from permanent neurological disorders across Asian countries, with 10–15 thousand people dying each year. JEV crosses the blood-brain barrier (BBB) and forms a complex with receptors on the surface of neurons. GRP78, Src, TLR7, caveolin-1, and dopamine receptor D2 are involved in JEV binding and entry into the neurons, and these receptors also play a role in carcinogenic activity in cells. JEV binds to GRP78, a member of the HSP70 overexpressed on malignant cells to enter neurons, indicating a higher chance of JEV infection in cancer patients. However, JEV enters human brain microvascular endothelial cells via an endocytic pathway mediated by caveolae and the ezrin protein and also targets dopamine-rich areas for infection of the midbrain via altering dopamine levels. In addition, JEV complexed with CLEC5A receptor of macrophage cells is involved in the breakdown of the BBB and central nervous system (CNS) inflammation. CLEC5A-mediated infection is also responsible for the influx of cytokines into the CNS. In this review, we discuss the neuronal and macrophage surface receptors involved in neuronal death.

The spectrum of health complications instigated by coronavirus disease 2019 (COVID-19, caused by the novel severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2) pandemic has been diverse and complex. Besides the evident pulmonary and cardiovascular threats, accumulating clinical data points to several neurological complications, which are more common in elderly COVID-19 patients. Recent pieces of evidence have marked events of neuro infection and neuroinvasion, producing several neurological complications in COVID-19 patients; however, a systematic understanding of neuro-pathophysiology and manifested neurological complications, more specifically in elderly COVID-19 patients is largely elusive. Since the elderly population gradually develops neurological disorders with aging, COVID-19 inevitably poses a higher risk of neurological manifestations to the aged patients. In this report, we reviewed SARS-CoV-2 infection and its role in neurological manifestations with an emphasis on the elderly population. We reviewed neuropathological events including neuroinfection, neuroinvasion, and their underlying mechanisms affecting neuromuscular, central- and peripheral- nervous systems. We further assessed the imminent neurological challenges in the COVID-19 exposed population, post-SARS-CoV-2-infection. Given the present state of clinical preparedness, the emerging role of AI and machine learning was also discussed concerning COVID-19 diagnostics and its management. Taken together, the present review summarizes neurological outcomes of SARS-CoV-2 infection and associated complications, specifically in elderly patients, and underlines the need for their clinical management in advance.

Acetaminophen (APAP) is the most common prescription medicine around the world for the treatment of pain and fever and is considered to be a safe drug at its therapeutic dose. However, a single overdose or frequent use of APAP can cause severe acute liver injury. APAP hepatotoxicity is a prevalent cause of acute liver disease around the world and the lack of suitable treatment makes it a serious problem. In recent years, there has been a surge in interest in using probiotics and probiotic-derived products, known as postbiotics, as health and disease negotiators. A growing body of evidence revealed that they can be equally effective against APAP hepatotoxicity. Different probiotic bacteria were found to be pre-clinically effective against APAP hepatotoxicity. Different postbiotics have also shown exciting results in preclinical models of APAP hepatotoxicity. This review summarized the protective roles and mechanisms of the different probiotic bacteria and postbiotics against APAP hepatotoxicity, with critical discussion. A brief discussion on potential novel probiotics and postbiotics for oxidative liver injury was also included. This review was written in an attempt to pique the interest of researchers in developing a safe therapeutic option against oxidative liver damage using probiotics and/or postbiotics as dietary supplements.

The emergence of a novel coronavirus viz., severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in late 2019 and its subsequent substantial spread produced the coronavirus disease 2019 (COVID-19) pandemic worldwide. Given its unprecedented infectivity and pathogenicity, the COVID-19 pandemic had a devastating impact on human health, and its clinical management has been a great challenge, which has led to the development and speedy trials of several vaccine candidates against SARS-CoV-2 at an exceptional pace. As a result, several COVID-19 vaccines were made commercially available in the first half of 2021. Although several COVID-19 vaccines showed promising results, crucial insights into their epidemiology, protective mechanisms, and the propensities of reinfection are not largely reviewed. In the present report, we provided insights into the prospects of vaccination against COVID-19 and assessed diverse vaccination strategies including DNA, mRNA, protein subunits, vector-based, live attenuated, and inactivated whole/viral particle-based vaccines. Next, we reviewed major aspects of various available vaccines approved by the World Health Organization and by the local administrations to use against COVID-19. Moreover, we comprehensively assessed the success of these approved vaccines and also their untoward effects, including the possibility of reinfection. We also provided an update on the vaccines that are under development and could be promising candidates in the future. Conclusively, we provided insights into the COVID-19 vaccine epidemiology, their potency, and propensity for SARS-CoV-2 reinfection, while a careful review of their current status, strategies, success, and future challenges was also presented.

Hyperactivation of immune responses resulting in excessive release of pro-inflammatory mediators in alveoli/lung structures is the principal pathological feature of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The cytokine hyperactivation in COVID-19 appears to be similar to those seen in rheumatoid arthritis (RA), an autoimmune disease. Emerging evidence conferred the severity and risk of COVID-19 to RA patients. Amid the evidence of musculoskeletal manifestations involving immune-inflammation-dependent mechanisms and cases of arthralgia and/or myalgia in COVID-19, crosstalk between COVID-19 and RA is often debated. The present article sheds light on the pathological crosstalk between COVID-19 and RA, the risk of RA patients in acquiring SARS-CoV-2 infection, and the aspects of SARS-CoV-2 infection in RA development. We also conferred whether RA can exacerbate COVID-19 outcomes based on available clinical readouts. The mechanistic overlapping in immune-inflammatory features in both COVID-19 and RA was discussed. We showed the emerging links of angiotensin-converting enzyme (ACE)-dependent and macrophage-mediated pathways in both diseases. Moreover, a detailed review of immediate challenges and key recommendations for anti-rheumatic drugs in the COVID-19 setting was presented for better clinical monitoring and management of RA patients. Taken together, the present article summarizes available knowledge on the emerging COVID-19 and RA crosstalk and their mechanistic overlaps, challenges, and therapeutic options.

Alzheimer’s disease (AD) is one of the most prominent neurodegenerative diseases, which impairs cognitive function in afflicted individuals. AD results in gradual decay of neuronal function as a consequence of diverse degenerating events. Several neuroimmune players (such as cytokines and growth factors that are key players in maintaining CNS homeostasis) turn aberrant during crosstalk between the innate and adaptive immunities. This aberrance underlies neuroinflammation and drives neuronal cells toward apoptotic decline. Neuroinflammation involves microglial activation and has been shown to exacerbate AD. This review attempted to elucidate the role of cytokines, growth factors, and associated mechanisms implicated in the course of AD, especially with neuroinflammation. We also evaluated the propensities and specific mechanism(s) of cytokines and growth factors impacting neuron upon apoptotic decline and further shed light on the availability and accessibility of cytokines across the blood-brain barrier and choroid plexus in AD pathophysiology. The pathogenic and the protective roles of macrophage migration and inhibitory factors, neurotrophic factors, hematopoietic-related growth factors, TAU phosphorylation, advanced glycation end products, complement system, and glial cells in AD and neuropsychiatric pathology were also discussed. Taken together, the emerging roles of these factors in AD pathology emphasize the importance of building novel strategies for an effective therapeutic/neuropsychiatric management of AD in clinics.

Abstract Garcinol (GAR) is a naturally occurring polyisoprenylated phenolic compound. It has been recently investigated for its biological activities such as antioxidant, anti-inflammatory, anti ulcer, and antiproliferative effect on a wide range of human cancer cell lines. Though the outcomes are very promising, its extreme insolubility in water remains the main obstacle for its clinical application. Herein we report the formulation of GAR entrapped PLGA nanoparticles by nanoprecipitation method using vitamin E TPGS as an emulsifier. The nanoparticles were characterized for size, surface morphology, surface charge, encapsulation efficiency and in vitro drug release kinetics. The MTT assay depicted a high amount of cytotoxicity of GAR-NPs in B16F10, HepG2 and KB cells. A considerable amount of cell apoptosis was observed in B16f10 and KB cell lines. In vivo cellular uptake of fluorescent NPs on B16F10 cells was also investigated. Finally the GAR loaded NPs were radiolabeled with technetium-99m with >95% labeling efficiency and administered to B16F10 melanoma tumor bearing mice to investigate the in vivo deposition at the tumor site by biodistribution and scintigraphic imaging study. In vitro cellular uptake studies and biological evaluation confirm the efficacy of the formulation for cancer treatment.

Diabetes mellitus (DM) is one of the principal manifestations of metabolic syndrome and its prevalence with modern lifestyle is increasing incessantly. Chronic hyperglycemia can induce several vascular complications that were referred to be the major cause of morbidity and mortality in DM. Although several therapeutic targets have been identified and accessed clinically, the imminent risk of DM and its prevalence are still ascending. Substantial pieces of evidence revealed that histone deacetylase (HDAC) isoforms can regulate various molecular activities in DM via epigenetic and post-translational regulation of several transcription factors. To date, 18 HDAC isoforms have been identified in mammals that were categorized into four different classes. Classes I, II, and IV are regarded as classical HDACs, which operate through a Zn-based mechanism. In contrast, class III HDACs or Sirtuins depend on nicotinamide adenine dinucleotide (NAD+) for their molecular activity. Functionally, most of the HDAC isoforms can regulate β cell fate, insulin release, insulin expression and signaling, and glucose metabolism. Moreover, the roles of HDAC members have been implicated in the regulation of oxidative stress, inflammation, apoptosis, fibrosis, and other pathological events, which substantially contribute to diabetes-related vascular dysfunctions. Therefore, HDACs could serve as the potential therapeutic target in DM towards developing novel intervention strategies. This review sheds light on the emerging role of HDACs/isoforms in diabetic pathophysiology and emphasized the scope of their targeting in DM for constituting novel interventional strategies for metabolic disorders/complications.

The present study evaluated the therapeutic potential of myricitrin (Myr), a glycosyloxyflavone extracted from Myrica esculenta bark, against diabetic nephropathy. Myr exhibited a significant hypoglycemic effect in high fat-fed and a single low-dose streptozotocin-induced type 2 diabetic (T2D) rats. Myr was found to improve glucose uptake by the skeletal muscle via activating IRS-1/PI3K/Akt/GLUT4 signaling in vitro and in vivo. Myr significantly attenuated high glucose (HG)-induced toxicity in NRK cells and in the kidneys of T2D rats. In this study, hyperglycemia caused nephrotoxicity via endorsing oxidative stress and inflammation resulting in the induction of apoptosis, fibrosis, and inflammatory damages. Myr was found to attenuate oxidative stress via scavenging/neutralizing oxidative radicals and improving endogenous redox defense through Nrf-2 activation in both in vitro and in vivo systems. Myr was also found to attenuate diabetes-triggered renal inflammation via suppressing NF-κB activation. Myr inhibited hyperglycemia-induced apoptosis and fibrosis in renal cells evidenced by the changes in the expressions of the apoptotic and fibrotic factors. The molecular docking predicted the interactions between Myr and different signal proteins. An in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) study predicted the drug-likeness character of Myr. Results suggested the possibility of Myr to be a potential therapeutic agent for diabetic nephropathy in the future.

Medicinal plants, vegetables and fruits are the sources of huge number of bioactive lead/scaffolds with therapeutic and nutraceutical importance. Bioautography is a means of target-directed isolation of active molecules on chromatogram. Organic solvents employed in chromatographic separation process can be completely removed before biological detection because these solvents cause inactivation of enzymes and/or death of living organisms. They offer a rapid and easy identification of bioactive lead/scaffolds in complex matrices of plant extracts. Bioautography is a technique to isolate hit(s)/lead(s) by employing a suitable chromatographic process followed by a biological detection system. This review critically describes the methodologies to identify antimicrobial, antioxidant, enzyme inhibitor lead/scaffolds by employing bioautography. A significant number of examples have been incorporated to authenticate the methodologies. Keywords: Bioactivity, Bioassay, Bioautography, Detection principle, Thin layer chromatography

Persistent hyperglycemia, impairment of redox status and establishment of inflammatory pathophysiology integrally play important role in the pathogenesis of diabetic cardiomyopathy (DC). Present study examined the therapeutic potential of protocatechuic acid isolated from the Sansevieria roxburghiana rhizomes against DC employing rodent model of type 2 diabetes (T2D). T2D was induced by high fat diet + a low-single dose of streptozotocin (35 mg/kg, i.p.). T2D rats exhibited significantly (p < 0.01) high fasting blood glucose level. Alteration in serum lipid profile (p < 0.01) and increased levels of lactate dehydrogenase (p < 0.01) and creatine kinase (p < 0.01) in the sera of T2D rats revealed the occurrence of hyperlipidemia and diabetic pathophysiology. A significantly (p < 0.01) high levels of serum C-reactive protein and pro-inflammatory mediators revealed the establishment of inflammatory occurrence in T2D rats. Besides, significantly high levels of troponins in the sera revealed the establishment of cardiac dysfunctions in T2D rats. However, protocatechuic acid (50 and 100 mg/kg, p.o.) treatment could significantly reverse the changes in serum biochemical parameters related to cardiac dysfunctions. Molecular mechanism studies demonstrated impairment of signaling cascade, IRS1/PI3K/Akt/AMPK/p 38/GLUT4, in glucose metabolism in the skeletal muscle of T2D rats. Significant (p < 0.01) activation of polyol pathway, enhanced production of AGEs, oxidative stress and up-regulation of inflammatory signaling cascades (PKC/NF-κB/PARP) were observed in the myocardial tissue of T2D rats. However, protocatechuic acid (50 and 100 mg/kg, p.o.) treatment could significantly (p < 0.05–0.01) stimulate glucose metabolism in skeletal muscle, regulated glycemic and lipid status, reduced the secretion of pro-inflammatory cytokines, and restored the myocardial physiology in T2D rats near to normalcy. Histological assessments were also in agreement with the above findings. In silico molecular docking study again supported the interactions of protocatechuic acid with different signaling molecules, PI3K, IRS, Akt, AMPK PKC, NF-κB and PARP, involved in glucose utilization and inflammatory pathophysiology. In silico ADME study predicted that protocatechuic acid would support the drug-likeness character. Combining all, results would suggest a possibility of protocatechuic acid to be a new therapeutic agent for DC in future.

Cadmium (Cd) imparts nephrotoxicity via triggering oxidative stress and pathological signal transductions in renal cells. The present study was performed to explore the protective mechanism of carnosic acid (CA), a naturally occurring antioxidant compound, against cadmium chloride (CdCl2)-provoked nephrotoxicity employing suitable in vitro and in vivo assays. CA (5 µM) exhibited an anti-apoptotic effect against CdCl2 (40 µM) in normal kidney epithelial (NKE) cells evidenced from cell viability, image, and flow cytometry assays. In this study, CdCl2 treatment enhanced oxidative stress by triggering free radical production, suppressing the endogenous redox defence system, and inhibiting nuclear factor erythroid 2-related factor 2 (Nrf2) activation in NKE cells and mouse kidneys. Moreover, CdCl2 treatment significantly endorsed apoptosis and fibrosis via activation of apoptotic and transforming growth factor (TGF)-β1/mothers against decapentaplegic homolog (Smad)/collagen IV signalling pathways, respectively. In contrast, CA treatment significantly attenuated Cd-provoked nephrotoxicity via inhibiting free radicals, endorsing redox defence, suppressing apoptosis, and inhibiting fibrosis in renal cells in both in vitro and in vivo systems. In addition, CA treatment significantly (p < 0.05−0.01) restored blood and urine parameters to near-normal levels in mice. Histological findings further confirmed the protective role of CA against Cd-mediated nephrotoxicity. Molecular docking predicted possible interactions between CA and Nrf2/TGF-β1/Smad/collagen IV. Hence, CA was found to be a potential therapeutic agent to treat Cd-mediated nephrotoxicity.

Sansevieria roxburghiana Schult. & Schult. F. (Family: Asparagaceae) rhizome has been claimed to possess antidiabetic activity in the ethno-medicinal literature in India. Therefore, present experiments were carried out to explore the protective role of edible (aqueous) extract of S. roxburghiana rhizome (SR) against experimentally induced type 2 diabetes mellitus (T2DM) and its associated cardiomyopathy in Wistar rats.SR was chemically characterized by GC-MS analysis. Antidiabetic activity of SR (50 and 100 mg/kg, orally) was measured in high fat diets (ad libitum) + low-single dose of streptozotocin (35 mg/kg, intraperitoneal) induced type 2 diabetic (T2D) rat. Fasting blood glucose level was measured at specific intermissions. Serum biochemical and inflammatory markers were estimated after sacrificing the animals. Besides, myocardial redox status, expressions of signal proteins (NF-κB and PKCs), histological and ultrastructural studies of heart were performed in the controls and SR treated T2D rats.Phytochemical screening of the crude extract revealed the presence of phenolic compounds, sugar alcohols, sterols, amino acids, saturated fatty acids within SR. T2D rats exhibited significantly (p < 0.01) higher fasting blood glucose level with respect to control. Alteration in serum lipid profile (p < 0.01) and increased levels of lactate dehydrogenase (p < 0.01) and creatine kinase (p < 0.01) in the sera revealed the occurrence of hyperlipidemia and cell destruction in T2D rats. T2DM caused significant (p < 0.05-0.01) alteration in the biochemical markers in the sera. T2DM altered the redox status (p < 0.05-0.01), decreased (p < 0.01) the intracellular NAD and ATP concentrations in the myocardial tissues of experimental rats. While investigating the molecular mechanism, activation PKC isoforms was observed in the selected tissues. T2D rats also exhibited an up-regulation in nuclear NF-κB (p65) in the cardiac tissues. So, oral administration of SR (50 and 500 mg/kg) could reduce hyperglycemia, hyperlipidemia, membrane disintegration, oxidative stress, vascular inflammation and prevented the activation of oxidative stress induced signaling cascades leading to cell death. Histological and ultra-structural studies of cardiac tissues supported the protective characteristics of SR.From the present findings it can be concluded that, SR could offer protection against T2DM and its associated cardio-toxicity via multiple mechanisms viz. hypoglycemic, antioxidant and anti-inflammatory actions.

BACKGROUND:Enhydra fluctuans Lour. (Asteraceae), an edible aquatic herb, is traditionally employed against toxic effects of heavy metals in India. The present study was planned to discover the protective effect of edible extract of E. fluctuans (AEEF) against Pb toxicity. METHODS:The cytoprotective role of AEEF was determined on murine hepatocytes employing MTT assay and Hoechst staining. The effects on lipid peroxidation, protein carbonylation, endogenous redox systems and the transcription levels of apoptotic proteins were studied after incubating the hepatocytes with AEEF (400 μg/ml) + Pb-acetate (6.8 μM). The defensive role of AEEF (100 mg/kg) against Pb-acetate (5 mg/kg) intoxication was measured in mice by in vivo assays. Biochemical, haematological and histological parameters, intracellular Pb burden and redox status were measured. RESULTS:AEEF exhibited a concentration dependent cytoprotective effect against Pb-induced cytotoxicity in vitro. Pb-acetate incubation significantly (p < 0.01) altered the extents of ROS production ↑, protein carbonylation ↑, lipid peroxidation ↑, endogenous antioxidant enzymes ↓ and GSH ↓ in vitro. Besides, Pb-acetate significantly (p < 0.01) induced apoptosis in the hepatocytes apparent from the altered expressions of apoptotic proteins viz. Apaf-1 ↑, Bad ↑, Bcl-2 ↓, Cyt C ↑, cleaved caspases↑, Bid ↑ and Fas ↑. However, AEEF (400 μg/ml) could significantly (p < 0.05-0.01) attenuate the Pb-acetate mediated toxic manifestation in vitro. In in vivo assay, Pb-acetate (5 mg/kg) treated mice exhibited significantly (p < 0.01) high intracellular Pb content. A high Pb-burden within the tissues caused significant (p < 0.05-0.01) patho-physiological alterations viz. ROS production ↑, protein carbonylation↑, lipid peroxidation ↑, DNA fragmentation ↑, ATP formation ↑, mitochondrial co-enzymes Q ↓, endogenous antioxidant enzymes ↓ and GSH ↓ within the selected tissues. The haematological and serum biochemical parameters were significantly (p < 0.05-0.01) different in the Pb-acetate treated mice. Finally, histological assessment imposed significant toxic occurrence within the organs of Pb-intoxicated animals. However, concurrent administration of AEEF (100 mg/kg) could significantly (p < 0.05-0.01) reinstate the Pb-acetate mediated toxicity. CONCLUSION:Presence of metal chelators and phyto-antioxidants within AEEF would offer overall protection through promoting Pb clearance coupled with restoring redox balance.

BackgroundIpomoea aquatica (Convolvulaceae), an aquatic edible plant, is traditionally used against heavy metal toxicity in India. The current study intended to explore the protective role of edible (aqueous) extract of I. aquatica (AEIA) against experimentally induced Pb-intoxication.MethodsThe cytoprotective role of AEIA was measured on mouse hepatocytes by cell viability assay followed by Hoechst staining and flow cytometric assay. The effect on ROS production, lipid peroxidation, protein carbonylation, intracellular redox status were measured after incubating the hepatocytes with Pb-acetate (6.8 μM) along with AEIA (400 μg/ml). The effects on the expressions of apoptotic signal proteins were estimated by western blotting. The protective role of AEIA was measured by in vivo assay in mice. Haematological, serum biochemical, tissue redox status, Pb bioaccumulation and histological parameters were evaluated to estimate the protective role of AEIA (100 mg/kg) against Pb-acetate (5 mg/kg) intoxication.ResultsPb-acetate treated hepatocytes showed a gradual reduction of cell viability dose-dependently with an IC50 value of 6.8 μM. Pb-acetate treated hepatocytes exhibited significantly enhanced levels (p < 0.01) of ROS production, lipid peroxidation, protein carbonylation with concomitant depletion (p < 0.01) of antioxidant enzymes and GSH. However, AEIA treatment could significantly restore the aforementioned parameters in murine hepatocytes near to normalcy. Besides, AEIA significantly reversed (p < 0.05-0.01) the alterations of transcription levels of apoptotic proteins viz. Bcl 2, Bad, Cyt C, Apaf-1, cleaved caspases [caspase 3, caspase 8 and caspase 9], Fas and Bid. In in vivo bioassay, Pb-acetate treatment caused significantly high intracellular Pb burden and oxidative pressure in the kidney, liver, heart, brain and testes in mice. In addition, the haematological and serum biochemical factors were changed significantly in Pb-acetate-treated animals. AEIA treatment restored significantly the evaluated-parameters to the near-normal position.ConclusionThe extract may offer the protective effect via counteracting with Pb mediated oxidative stress and/or promoting the elimination of Pb by chelating. The presence of substantial quantities of flavonoids, phenolics and saponins would be responsible for the overall protective effect.

Multidrug resistance (MDR) is regarded as one of the bottlenecks of successful clinical treatment for numerous chemotherapeutic agents. Multiple key regulators are alleged to be responsible for MDR and making the treatment regimens ineffective. In this review, we discuss MDR in relation to P-glycoprotein (P-gp) and its down-regulation by natural bioactive molecules. P-gp, a unique ATP-dependent membrane transport protein, is one of those key regulators which are present in the lining of the colon, endothelial cells of the blood brain barrier (BBB), bile duct, adrenal gland, kidney tubules, small intestine, pancreatic ducts and in many other tissues like heart, lungs, spleen, skeletal muscles, etc. Due to its diverse tissue distribution, P-gp is a novel protective barrier to stop the intake of xenobiotics into the human body. Over-expression of P-gp leads to decreased intracellular accretion of many chemotherapeutic agents thus assisting in the development of MDR. Eventually, the effectiveness of these drugs is decreased. P-gp inhibitors act by altering intracellular ATP levels which are the source of energy and/or by affecting membrane contours to increase permeability. However, the use of synthetic inhibitors is known to cause serious toxicities. For this reason, the search for more potent and less toxic P-gp inhibitors of natural origin is underway. The present review aims to recapitulate the research findings on bioactive constituents of natural origin with P-gp inhibition characteristics. Natural bioactive constituents with P-gp modulating effects offer great potential for semi-synthetic modification to produce new scaffolds which could serve as valuable investigative tools to recognize the function of complex ABC transporters apart from evading the systemic toxicities shown by synthetic counterparts. Despite the many published scientific findings encompassing P-gp inhibitors, however, this article stand alones because it provides a vivid picture to the readers pertaining to Pgp inhibitors obtained from natural sources coupled with their mode of action and structures. It provides first-hand information to the scientists working in the field of drug discovery to further synthesise and discover new P-gp inhibitors with less toxicity and more efficacies.