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Abstract: Type-2 diabetes mellitus is a prime factor for the development of Diabetic Nephropathy (DN) that affects the vital organ namely the kidneys, and further alters the functions of the nephron system. DN is nowadays becoming a challenge for scientists towards the world because of its high pervasiveness and complexity of medication. Various risk factors are involved in the initiation of pathogenic DN, which are associated with different pathways against drug activity. Due to this DN becomes an unpredictable query to the researchers. SIRT1 is a silent information regulator factor 2 related enzyme 1 (SIRT1) is nicotinamide adenine dinucleotide (NAD+) dependent deacetylase that functions as an intracellular regulator of transcriptional activity. An activated version of SIRT-1 improves the metabolic diseased conditions associated with other molecular pathways. SIRT1 attenuates diabetic nephropathy in in vitro and in vivo experimental models of diabetes containing Podocytes, Mesangial cells, and Renal proximal tubular cells. SIRT1 shows nephroprotective effects in DN in part through deacetylation of transcription factors i.e., imply in the disease like p53, PTP1B, FOXO, RelA, NF- kβ, STAT-3, and PGC-1α/ PPARγ. It has been shown that some natural products like resveratrol and synthetic compounds are activating the SIRT1, this further involved the cascade pathways to prevent the DN. This review will help regarding the effectiveness of SIRT1as target in the prevention and treatment of DN.

Background: Glioma refers to the most aggressive tumor in the central nervous system that starts from support cells or glial cells. The glial cell is the most common cell type in the CNS, and they insulate, surround, as well as feed, oxygen, and nutrition to the neurons. Seizures, headaches, irritability, vision difficulties, and weakness are some of the symptoms. Targeting ion channels is particularly helpful when it comes to glioma treatment because of their substantial activity in glioma genesis through multiple pathways. Objective: In this study, we explore how distinct ion channels can be targeted for glioma treatment and summarize the pathogenic ion channels activity in gliomas. Results: Current research found several side effects such as bone marrow suppression, alopecia, insomnia, and cognitive impairments for presently done chemotherapy. The involvement of research on ion channels in the regulation of cellular biology and towards improvements of glioma have expanded recognition of their innovative roles. Conclusion: Present review article has expanded knowledge of ion channels as therapeutic targets and detailed cellular mechanisms in the roles of ion channels in gliomas pathogenesis.

Abstract: Plant derived natural products have multifaceted beneficial roles in human pathophysiology. Plant secondary metabolites have been used as an adjunct medicine for a long time and β- Glucogallin is one such pharmaceutically important plant derived natural product. Β-glucogallin (1-O-galloyl-β-d-glucopyranose), a plant-derived polyphenolic ester, is regarded as the primary metabolite in the biosynthesis of hydrolyzable tannins. It is majorly found in amla, pomegranate, strawberry etc. Owing to its free radical scavenging properties, β-glucogallin (BG) is believed to protect against several diseases like diabetes and related complications like retinopathy, glaucoma, inflammation, hepatic damage, skin damage from UV, etc. Several semisynthetic derivatives of β-Glucogallin are being developed, which have better pharmacokinetic and pharmacodynamic parameters than β-glucogallin. Studies have shown the prophylactic role of β-Glucogallin in developing defence mechanisms against the advent and progression of certain diseases. β- glucogallin formulations have shown a positive effect as a neutraceutical. In this manuscript, we have discussed β-glucogallin, its natural sources, biosynthetic pathways, its semi-synthetic derivatives, and the plethora of its pharmacological activities like antioxidant-antiinflammatory, antidiabetic, cataract-preventing, anti glaucoma, and UV protectant. We have also highlighted various biological pathways, which are modulated by β-glucogallin. The manuscript will convey the importance of β-glucogallin as a compound of natural origin, having multifaceted health benefits.

Abstract: Homeopathy is a widely practiced alternate system of medicine around the world that employs small doses of various medicines to promote auto-regulation and self-healing. It is among the most commonly used alternative approaches in cancer and other diseases and alternative thera-peutic systems. It is widely used as palliative and as supportive therapy in cancer patients. Few cas-es have been reported on patients using homeopathy after surgery, radiotherapy, and chemotherapy, generally for overcoming side effects. The dose of Homoeopathic medicines and their mechanism of action in cancer has also been documented, while clinical trials on the effects of Homoeopathy in cancer treatment are rare. It is found that the anticancer potential of homeopathic medicines is re-ported for different cancer types, which show their efficacy through apoptosis and immune system modulation. Homeopathic treatment is an add-on to conventional therapy, with almost no interac-tion with the conventional drugs due to the small dose, and is largely attributed to improving lives by providing symptomatic relief, increasing survival time and boosting patient immunity. This re-view explores the accountability of the homeopathic system of medicine by highlighting some of the most commonly used homeopathic drugs for different types of cancers.

Abstract: Recent studies have shed light on the role of epigenetic marks in certain diseases like cancer, type II diabetes mellitus (T2DM), obesity, and cardiovascular dysfunction, to name a few. Epigenetic marks like DNA methylation and histone acetylation are randomly altered in the disease state. It has been seen that methylation of DNA and histones can result in down-regulation of gene expression, whereas histone acetylation, ubiquitination, and phosphorylation are linked to enhanced expression of genes. How can we precisely target such epigenetic aberrations to prevent the advent of diseases? The answer lies in the amalgamation of the efficient genome editing technique, CRISPR, with certain effector molecules that can alter the status of epigenetic marks as well as employ certain transcriptional activators or repressors. In this review, we have discussed the rationale of epigenetic editing as a therapeutic strategy and how CRISPR-Cas9 technology coupled with epigenetic effector tags can efficiently edit epigenetic targets. In the later part, we have discussed how certain epigenetic effectors are tagged with dCas9 to elicit epigenetic changes in cancer. Increased interest in exploring the epigenetic background of cancer and non-communicable diseases like type II diabetes mellitus and obesity accompanied with technological breakthroughs has made it possible to perform large-scale epigenome studies.

In eukaryotic organisms, cell-signalling completely relies on Post Translational Modifications (PTMs) that can function as regulatory switches. Phosphorylation is a fundamental and frequently occurring PTM in almost all eukaryotes. Herein, we have studied the importance of protein phosphorylation using classical proteomic techniques in C. elegans upon bacterial infection. The differentially regulated proteins during bacterial infection were excised from SDS-PAGE (One-Dimensional) gel (TiO

The pathophysiology of depression is heavily dependent on inflammation. Evidence suggests that the etiology of depression is linked with NLRP3 inflammasome-induced inflammation. Therefore, blocking the activated NLRP3 inflammasome may be beneficial for treating depression. Due to the limitations of currently available antidepressants, it is necessary to develop novel, safe, and affordable drugs for the treatment of depression. A natural coumarin derivative named 4-methylesculetin (4-MESC) possesses anti-inflammatory properties. However, the role of 4-MESC as an antidepressant has not been elucidated. Therefore, in this study, we explored the antidepressant-like effects of 4-MESC and its underlying molecular mechanism through the modulation of the NLRP3 inflammasome. The docking and molecular dynamic simulation studies revealed that 4-MESC has a higher affinity for the NLRP3 PYD. Blood–brain barrier permeability was confirmed using the SwissADME pharmacokinetic tool. High doses (50 mg/kg) of 4-MESC significantly reduced the immobility duration in the tail-suspension test (TST) and forced swim test (FST) without changing the overall locomotor activity in the female Swiss albino mice that were subjected to lipopolysaccharide (LPS). LPS-induced pro-inflammatory cytokines such as IL-6 and TNF-α were reduced in serum and brain tissues using 4-MESC. 4-MESC’s neuroprotective effects are mediated by increased brain-derived neurotrophic factor (BDNF) and decreased cortisol levels. 4-MESC markedly reduced LPS-induced elevated levels of ROS and lipid peroxidation (malondialdehyde levels) and enhanced the superoxide dismutase (SOD) activity and glutathione levels, which revealed its anti-oxidant potential against oxidative stress. 4-MESC diminished the expression levels of NF-κBp65, IL-6, NLRP3, caspase-1, gasdermin D, and IL-1β in the hippocampus. These findings demonstrated that 4-MESC exhibited antidepressant-like effects by inhibiting the NLRP3 inflammasome. However, other antidepressant mechanisms might also be involved which require further studies.

The cycloaddition of N-sulfonyl and sulfamoylazides with terminal alkynes using a prolinamide ligand selectively provides 1,2,3-triazoles in aqueous media in the presence of CuI.

Metabolomic reprogramming plays a crucial role in the activation of several regulatory mechanisms including neuronal responses of the host. In the present study, alterations at physiological and biochemical levels were initially assessed to monitor the impact of the candidate pathogen Cronobacter sakazakii on the nematode host Caenorhabditis elegans. The abnormal behavioral responses were observed in infected worms in terms of hyperosmolarity and high viscous chemicals. The microscopic observations indicated reduction in egg laying and internal hatching of larvae in the host. An increased level of total reactive oxygen species and reduction in antioxidant agents such as glutathione and catalase were observed. These observations suggested the severe effect of C. sakazakii infection on C. elegans. To understand the small molecules which likely mediated neurotransmission, the whole metabolome of C. elegans during the infection of C. sakazakii was analyzed using liquid chromatography-mass spectrometry. A decrease in the quantity of methyl dopamine and palmitoyl dopamine and an increase in hydroxyl dopamine suggested that reduction in dopamine reuptake and dopamine neuronal stress. The disordered dopaminergic transmission during infection was confirmed using transgenic C. elegans by microscopic observation of Dat-1 protein expression. In addition, reduction in arachidonic acid and short-chain fatty acids revealed their effect on lipid droplet formation as well as neuronal damage. An increase in the quantity of stearoyl CoA underpinned the higher accumulation of lipid droplets in the host. On the other hand, an increased level of metabolites such as palmitoyl serotonin, citalopram N-oxide, and N-acyl palmitoyl serotonin revealed serotonin-mediated potential response for neuroprotection, cytotoxicity, and cellular damage. Based on the metabolomic data, the genes correspond to small molecules involved in biosynthesis and transportation of candidate neurotransmitters were validated through relative gene expression.

Cronobacter sakazakii, an opportunistic foodborne pathogen prevalently detected in contaminated powdered infant formula, is associated with different diseases, including meningitis. It can cross the blood-brain barrier and affects the CNS. The impact of C. sakazakii on host neuronal cells and behavior is largely unknown. Hence, detailed molecular data are required to understand its severity. Caenorhabditis elegans is a unique model for studying chemical communication, as it relies on chemosensation for searching nutritional supplements. Although, C. sakazakii is pathogenic to C. elegans, our analysis indicated that C. elegans was highly attracted toward C. sakazakii compared to its food source, E. coli OP50. To study the cue for the attraction, bioactive components (RNA/Protein/Lipopolysaccharides/Metabolites) of C. sakazakii were isolated and used for observing the chemotaxis behavior of C. elegans. The results signified that C. elegans was more attracted toward acid extracted metabolites than those of the other extraction methods. The combined action of acid extracted metabolites of C. sakazakii and a candidate pathogen drastically reduced the survival of C. elegans. In addition, qPCR analysis suggested that the exposure of isolated metabolites through acid extraction to C. elegans for 24 h modified the candidate immune regulatory genes involved in pathogen recognition and kinase activity such as clec-60, clec-87, lys-7, akt-2, pkc-1, and jnk-1.

Sortase A, a transpeptidase enzyme is present in many Gram-positive bacteria and helps in the recruitment of the cell surface proteins. Over the last two decades, Sortase A has become an attractive tool for performing in vivo and in vitro ligations. Sortase A-mediated ligation has continuously been used for its specificity, robustness, and highly efficient nature. These properties make it a popular choice among protein engineers as well as researchers from different fields. In this review, we give an overview of Sortase A-mediated ligation of various molecules on the cell surfaces, which can have diverse applications in interdisciplinary fields.

Before the discovery of the proteasome complex, the lysosomes with acidic proteases and caspases in apoptotic pathways were thought to be the only pathways for the degradation of damaged, unfolded, and aged proteins. However, the discovery of 26S and 20S proteasome complexes in eukaryotes and microbes, respectively, established that the degradation of most proteins is a highly regulated ATP-dependent pathway that is significantly conserved across each domain of life. The proteasome is part of the ubiquitin-proteasome system (UPS), where the covalent tagging of a small molecule called ubiquitin (Ub) on the proteins marks its proteasomal degradation. The type and chain length of ubiquitination further determine whether a protein is designated for further roles in multi-cellular processes like DNA repair, trafficking, signal transduction, etc., or whether it will be degraded by the proteasome to recycle the peptides and amino acids. Deubiquitination, on the contrary, is the removal of ubiquitin from its substrate molecule or the conversion of polyubiquitin chains into monoubiquitin as a precursor to ubiquitin. Therefore, deubiquitylating enzymes (DUBs) can maintain the dynamic state of cellular ubiquitination by releasing conjugated ubiquitin from proteins and controlling many cellular pathways that are essential for their survival. Many DUBs are well characterized in the human system with potential drug targets in different cancers. Although, proteasome complex and UPS of parasites, like plasmodium and leishmania, were recently coined as multi-stage drug targets the role of DUBs is completely unexplored even though structural domains and functions of many of these parasite DUBs are conserved having high similarity even with its eukaryotic counterpart. This review summarizes the identification & characterization of different parasite DUBs based on in silico and a few functional studies among different phylogenetic classes of parasites including Metazoan (Schistosoma, Trichinella), Apicomplexan protozoans (Plasmodium, Toxoplasma, Eimeria, Cryptosporidium), Kinetoplastidie (Leishmania, Trypanosoma) and Microsporidia (Nosema). The identification of different homologs of parasite DUBs with structurally similar domains with eukaryotes, and the role of these DUBs alone or in combination with the 20S proteosome complex in regulating the parasite survival/death is further elaborated. We propose that small molecules/inhibitors of human DUBs can be potential antiparasitic agents due to their significant structural conservation.

Natural products are being targeted as alternative anticancer agents due to their non-toxic and safe nature. The present study was conducted to explore the in vitro anticancer potential of

Chronic arsenic (As) poisoning is mostly due to subsoil water contaminated with As and its salts. Exposure to As has been found to cause an elevation in reactive oxygen species (ROS), leading to the damage of DNA and proteins, and it also causes immunotoxicity. Treatment regimens are primarily based on chelation therapy and amino acid and vitamin supplementations. Recent studies have established that natural products display effective and progressive relief from arsenicosis without any side effects. β-glucogallin (BGG), a gallo-tannin natural product, is reported to possess anti-oxidant and anti-inflammatory properties. In the present study, we aim to observe the protective role of BGG against As-induced cytotoxicity, apoptosis, mitochondrial dysfunction, and the underlying mechanisms in RAW 264.7 macrophage cells. We found that BGG alleviates As-induced ROS, apoptosis, and mitochondrial dysfunction in RAW 264.7 macrophage cells. Thus, BGG can be used therapeutically to prevent As-induced toxicity.

Cell-mediated immunity (CMI), which includes T-cells (both T helper and cytotoxic), is critical for effective antiviral defenses against coronavirus disease-2019 (COVID-19). To better understand the immunological characteristics of CD markers on T-cells in post-COVID-19 patients, we investigated the expression of differential CD markers in the patient groups in this study.Flow cytometry was used to quantify total lymphocyte count and assess the levels of expression of CD markers in the samples. The percentage of Lymphocytes decreased significantly in the post-SARS-COV-2 patients in comparison to normal subjects, which is usually happening in any viral infection. In contrast to that, expression of CD8 was increased in the patient group having long SARS-COV-2 infection with comorbid complications with respect to the normal individuals and long SARS-COV-2 infection without comorbid complications. This data revealed that the cellular immunological responses corroborated with an earlier report of COVID-19 infection were mediated by CD8 upregulation and cytotoxic T lymphocyte hyperactivation.

The discovery of Clustered Regularly Interspaced Palindromic Repeats (CRISPR) and its associated Cas endonucleases in bacterial and archaeal species allowed scientists to modify, utilized, and revolutionize this tool for genetic alterations in any species. Especially the type II CRISPR-Cas9 system has been extensively studied and utilized for precise and efficient DNA manipulation in plant and mammalian systems over the past few decades. Further, the discovery of the type V CRISPR-Cas12 (Cpf1) system provides more flexibility and precision in DNA manipulation in prokaryotes, plants, and animals. However, much effort has been made to employ and utilize the above CRISPR tools for RNA manipulation but the ability of Cas9 and Cas12 to cut DNA involves the nuisance of off-target effects on genes and thus may not be employed in all RNA-targeting applications. Therefore, the search for new and diverse Cas effectors which can precisely detect and manipulate the targeted RNA begins and this led to the discovery of a novel RNA targeting class 2, type VI CRISPR-Cas13 system. The CRISPR-Cas13 system consists of single RNA-guided Cas13 effector nucleases that solely target single-stranded RNA (ssRNA) in a programmable way without altering the DNA. The Cas13 effectors family comprises four subtypes (a-d) and each subtype has distinctive primary sequence divergence except the two consensuses Higher eukaryotes and prokaryotes nucleotide-binding domain (HEPN) that includes RNase motifs i.e. R-X4-6-H. These two HEPN domains are solely responsible for executing targetable RNA cleavage activity with high efficiency. Further, recent studies have shown that Cas13d exhibits higher efficiency and specificity in cleaving targeted RNA in the mammalian system compared to other Cas13 endonucleases of the Cas13 enzyme family. In addition to that, Cas13d has shown additional advantages over other Cas13 variants, structurally as well as functionally which makes it a prominent and superlative tool for RNA engineering and editing. Therefore considering the advantages of Cas13d over previously characterized Cas13 subtypes, in this review, we encompass the structural and mechanistic properties of type VI CRISPR-Cas13d systems, an overview of the current reported various applications of Cas13d, and the prospects to improve Cas13d based tools for diagnostic and therapeutic purposes.

SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has been confirmed to be a new coronavirus having 79% and 50% similarity with SARS-CoV and MERS-CoV, respectively. For a better understanding of the features of the new virus SARS-CoV-2, we have discussed a possible correlation between some unique features of the genome of SARS-CoV-2 in relation to pathogenesis. We have also reviewed structural druggable viral and host targets for possible clinical application if any, as cases of reinfection and compromised protection have been noticed due to the emergence of new variants with increased infectivity even after vaccination. We have also discussed the types of vaccines that are being developed against SARS-CoV-2. In this review, we have tried to give a brief overview of the fundamental factors of COVID-19 research like basic virology, virus variants and the newly emerging techniques that can be applied to develop advanced treatment strategies for the management of COVID-19 disease.

SARS-CoV-2, a new coronavirus emerged in 2019, causing a global healthcare epidemic. Although a variety of drug targets have been identified as potential antiviral therapies, and effective candidate against SARS-CoV-2 remains elusive. One of the most promising targets for combating COVID-19 is SARS-CoV-2 Main protease (M

SARS-CoV-2, the newly emerged virus of the Coronaviridae family is causing havoc worldwide. The novel coronavirus 2019 was first reported in Wuhan, China marked as the third highly infectious pathogenic virus of the twenty-first century. The typical manifestations of COVID-19 include cough, sore throat, fever, fatigue, loss of sense of taste and difficulties in breathing. Large numbers of SARS-CoV-2 infected patients have mild to moderate symptoms, however severe and life-threatening cases occur in about 5-10% of infections with an approximately 2% mortality rate. For the treatment of SARS-CoV-2, the use of neutralizing monoclonal antibodies (mAbs) could be one approach. The receptor binding domain (RBD) and N-terminal domain (NTD) situated on the peak of the spike protein (S-Protein) of SARS-CoV-2 are immunogenic in nature, therefore, can be targeted by neutralizing monoclonal antibodies. Several bioinformatics approaches highlight the identification of novel SARS-CoV-2 epitopes which can be targeted for the development of COVID-19 therapeutics. Here we present a summary of neutralizing mAbs isolated from COVID-19 infected patients which are anticipated to be a better therapeutic alternative against SARS-CoV-2. However, provided the vast escalation of the disease worldwide affecting people from all strata, affording expensive mAb therapy will not be feasible. Hence other strategies are also being employed to find suitable vaccine candidates and antivirals against SARS-CoV-2 that can be made easily available to the population.

Objectives To explore the effect of Acai berry on the pharmacokinetics of Atorvastatin (ATR), Alogliptin (ALO) and Empagliflozin (EMPA) in SD rats. Method Thirty-six rats were divided into six groups (n = 6). First three groups were treated with Acai berry (PO; 250 mg/kg); fourth, fifth and sixth groups received sodium CMC (vehicle) for 10 days and on eleventh day, first and fourth groups were administered with ATR (PO; 10 mg/kg); second and fifth groups with ALO (PO; 25 mg/kg) and third and sixth groups received EMPA (PO; 25 mg/kg). Key findings Co-intake of ATR with Acai berry resulted in slight decrease in Cmax from 41.78 to 34.65 ng/ml and AUC from 227.66 to 136.31 (µg/ml) *h, while there was an increase in the Cmax from 43.43 to 68.71 ng/ml and AUC from 117.6 to 207.1 (µg/ml) *h in ALO treated groups and Cmax from 173.99 to 250.1 ng/ml and AUC from 400.37 to 518.35 (µg/ml) *h in the EMPA-treated groups. Conclusion There was a significant change in the AUC0-t and Cmax of ATR, ALO and EMPA after co-administration with Acai berry. Further studies are recommended to confirm the clinical significance of these interactions.

Garcinol is an active constituent of Garcinia indica and Garcinia cambogia. Recent studies have proven that garcinol has anti-inflammatory, anti-cancer, and anti-oxidant activities. The objective of this study was to evaluate the inhibitory effects of garcinol on the activities of the drug metabolizing cytochrome P450 (CYP) isozymes to predict potential herb-drug interactions with co-administered drugs. Garcinol was incubated with a mixture of rat liver microsomes and eight CYP probe substrate cocktail under optimized incubation conditions and the samples were analyzed using a validated method on LC-MS/MS. Garcinol showed strong inhibition with IC50 values of CYP1A2 (7.6 µM), CYP2C9 (8.0 µM), CYP2B6 (2.1 µM), CYP2D6 (9.5 µM), and CYP3A4 (5.1 µM), respectively, and moderate inhibition towards CYP2C19 (16.4 µM) and CYP2E1 (19.0 µM). Molecular docking studies were performed on garcinol against the active sites of CYP2B6 and CYP3A4 proteins. These results further confirmed that the inhibitory activity of garcinol occurred by occupying the active sites of these human CYPs and by making favorable interactions with its key residues. In-vivo CYP inhibition studies were carried out in Sprague-Dawley rats. These results suggest garcinol may cause herb-drug interactions, mediated by inhibition of CYPs involved in drug metabolism in-vivo by altering the pharmacokinetic parameters like AUC and Cmax in a clinically significant manner. Garcinol was found to upregulate the expression and activity of P-gp in western blotting study and P-gp inhibition study in-vivo. These findings give a clear understanding to predict potential herb-drug/drug-drug interactions of garcinol for safe clinical use in future.

Visceral leishmaniasis (VL) is a serious public health concern in the Indian state of Bihar, which has been exacerbated by an increasing HIV/AIDS incidence that has resulted in poor clinical outcomes. So far, there has been no investigation into the knowledge, attitude, and practices (KAP) of people who have been subjected to hospital-based supervision for VL or HIV/VL co-infection. This study assessed the KAP toward VL infection among 210 VL-infected patients (126 participants with VL and 84 participants with HIV/VL) using a pretested standard questionnaire. The findings are summarized descriptively and KAP scores are classified dichotomously (good/poor). Multivariable logistic regression and bivariate correlation were used in the analysis. The study showed that both VL-infected and co-infected patients exhibited similar deficits in KAP scores toward VL. The HIV/VL participants who had a personal or family history of VL were more likely to have appropriate awareness of and preventive practices toward VL. The independent predictors of attitude index in HIV/VL participants were education, VL family history, and marital status. There was a weak but significant positive correlation between knowledge and practice (rs = 0.321, prs = 0.294, prs = 0.634, p

Metabolomic reprogramming plays a crucial role in the activation of several regulatory mechanisms including neuronal responses of the host. In the present study, alterations at physiological and biochemical levels were initially assessed to monitor the impact of the candidate pathogen

The fascinating discovery of the first giant virus, Acanthamoeba polyphaga mimivirus (APMV), belonging to the family Mimiviridae in 2008, and its associated virophage, Sputnik, have left the world of microbiology awestruck. To date, about 18 virophages have been isolated from different environmental sources. With their unique feature of resisting host cell infection and lysis by giant viruses, analogous to bacteriophage, they have been assigned under the family Lavidaviridae. Genome of T-27, icosahedral-shaped, non-enveloped virophages, consist of dsDNA encoding four proteins, namely, major capsid protein, minor capsid protein, ATPase and cysteine protease, which are essential in the formation and assembly of new virophage particles during replication. A few virophage genomes have been observed to contain additional sequences like PolB, ZnR and S3H. Another interesting characteristic of virophage is that Mimivirus lineage A is immune to infection by the Zamilon virophage through a phenomenon termed MIMIVIRE, resembling the CRISPR-Cas mechanism in bacteria. Based on the fact that giant viruses have been found in clinical samples of hospital-acquired pneumonia and rheumatoid arthritis patients, virophages have opened a novel era in the search for cures of various diseases. This article aims to study the prospective role of virophages in the future of human therapeutics.

Natural products are being targeted as alternative anticancer agents due to their non-toxic and safe nature. The present study was conducted to explore the in vitro anticancer potential of Justicia adhatoda (J. adhatoda) leaf extract. The methanolic leaf extract was prepared, and the phytochemicals and antioxidant potential were determined by LCMS analysis and DPPH radical scavenging assay, respectively. A docking study performed with five major alkaloidal phytoconstituents showed that they had a good binding affinity towards the active site of NF-κB. Cell viability assay was carried out in five different cell lines, and the extract exhibited the highest cytotoxicity in MCF-7, a breast cancer cell line. Extract-treated cells showed a significant increase in nitric oxide and reactive oxygen species production. Cell cycle analysis showed an arrest in cell growth at the Sub-G0 phase. The extract successfully inhibited cell migration and colony formation and altered mitochondrial membrane potential. The activities of superoxide dismutase and glutathione were also found to decrease in a dose-dependent manner. The percentage of apoptotic cells was found to increase in a dose-dependent manner in MCF-7 cells. The expressions of caspase-3, Bax, and cleaved-PARP were increased in extract-treated cells. An increase in the expression of NF-κB was found in the cytoplasm in extract-treated cells. J. adhatoda leaf extract showed a potential anticancer effect in MCF-7 cells.

Glycogen synthase kinase-3 (GSK-3), a constitutively active serine/threonine kinase, primary regulator of various cellular activities varying from glycogen metabolism to cell proliferation and regulation. GSK-3β is associated with the pathogenesis of numerous human diseases, including cancer, metabolic disorder, and Alzheimer's disease. In this study

The study of tropical diseases like leishmaniasis, a parasitic disease, has not received much attention even though it is the second-largest infectious disease after malaria. As per the WHO report, a total of 0.7–1.0 million new leishmaniasis cases, which are spread by 23 Leishmania species in more than 98 countries, are estimated with an alarming 26,000–65,000 death toll every year. Lack of potential vaccines along with the cost and toxicity of amphotericin B (AmB), the most common drug for the treatment of leishmaniasis, has raised the interest significantly for new formulations and drug delivery systems including nanoparticle-based delivery as anti-leishmanial agents. The size, shape, and high surface area to volume ratio of different NPs make them ideal for many biological applications. The delivery of drugs through liposome, polymeric, and solid-lipid NPs provides the advantage of high biocomatibilty of the carrier with reduced toxicity. Importantly, NP-based delivery has shown improved efficacy due to targeted delivery of the payload and synergistic action of NP and payload on the target. This review analyses the advantage of NP-based delivery over standard chemotherapy and natural product-based delivery system. The role of different physicochemical properties of a nanoscale delivery system is discussed. Further, different ways of nanoformulation delivery ranging from liposome, niosomes, polymeric, metallic, solid-lipid NPs were updated along with the possible mechanisms of action against the parasite. The status of current nano-vaccines and the future potential of NP-based vaccine are elaborated here.

Severe acute respiratory syndromecoronavirus-2 (SARS-CoV-2) is a contagious pathogen responsible for the ongoing coronavirus disease 2019 (COVID-19) pandemic. The pathogenesis and immunological responses of SARS-CoV-2 infection are poorly understood until now. Once a person gets infected by SARS-COV-2, both innate and adaptive immunity gets compromised, which further plays an important role in making the disease more severe. The host's innate immune system forms the first layer of defense for protection from viral infections and initiates activation of the adaptive immune system in order to give maximum protection. The respiratory tract maintains the balance of T cell, B cell pro- and anti-inflammatory responses in order to protect the tissue from damage and diseases. In this review, the current updates related to the involvement of the immune system in the antiviral defense against SARS-CoV-2 have been discussed. These novel insights within the immunological response in the respiratory tract would support the future development of vaccines and immunoregulatory therapy for SARS-CoV-2 infection.

The anti-oxidant and anti-inflammatory effect of beta-glucogallin (BGG), a plant-derived natural product, was evaluated in both in vitro and in vivo studies. For the in vitro study, the ability of BGG pre-treatment to quench LPS-induced effects compared to LPS alone in macrophages was investigated. It was found that BGG pre-treatment showed a significant decrease in ROS, NO, superoxide, and pro-inflammatory cytokines (TNF-alpha, IL-4, IL-17, IL-1β, and IL-6) and increased reduced glutathione coupled with the restoration of mitochondrial membrane potential. Gene profiling and further validation by qPCR showed that BGG pre-treatment downregulated the LPS-induced expression of c-Fos, Fas, MMP-9, iNOS, COX-2, MyD88, TRIF, TRAF6, TRAM, c-JUN, and NF-κB. We observed that BGG pre-treatment reduced nuclear translocation of LPS-activated NF-κB and thus reduced the subsequent expressions of NLRP3 and IL-1β, indicating the ability of BGG to inhibit inflammasome formation. Molecular docking studies showed that BGG could bind at the active site of TLR4. Finally, in the LPS-driven sepsis mouse model, we showed that pre-treatment with BGG sustained toxic shock, as evident from their 100% survival. Our study clearly showed the therapeutic potential of BGG in toxic shock syndrome.

Chronic arsenic (As) poisoning is mostly due to subsoil water contaminated with As and its salts. Exposure to As has been found to cause an elevation in reactive oxygen species (ROS), leading to the damage of DNA and proteins, and it also causes immunotoxicity. Treatment regimens are primarily based on chelation therapy and amino acid and vitamin supplementations. Recent studies have established that natural products display effective and progressive relief from arsenicosis without any side effects. β-glucogallin (BGG), a gallo-tannin natural product, is reported to possess anti-oxidant and anti-inflammatory properties. In the present study, we aim to observe the protective role of BGG against As-induced cytotoxicity, apoptosis, mitochondrial dysfunction, and the underlying mechanisms in RAW 264.7 macrophage cells. We found that BGG alleviates As-induced ROS, apoptosis, and mitochondrial dysfunction in RAW 264.7 macrophage cells. Thus, BGG can be used therapeutically to prevent As-induced toxicity.

Hybrid nanomaterials with inherent physicochemical properties and cytocompatibility are beneficial for healthcare utilities. This paper demonstrates the hybridization of transition-metal oxide (molybdenum trioxide, MoO3), optoelectrochemically active dye complex (Ru(II)), and biopolymer (chitosan, CS) into a single nanosystem. The asafetida-resin-mediated green synthesis of MoO3 nanoparticles (g-MoO3 NPs) enabled chemical adsorption of Ru(II) and CS. Optical imaging functionality of pristine g-MoO3, g-MoO3-Ru(II), and g-MoO3-Ru(II)/CS has been evaluated using Caenorhabditis elegans, as an in vivo animal model, at an excitation wavelength of 450 nm and observed emission of ∼600 nm. The localization of chitosan on the surface of g-MoO3-Ru(II) exhibits cytocompatibility promising for intracellular imaging. The intracellular antioxidant properties of the g-MoO3-Ru(II)/CS nanocomposite are more profound than pristine NPs as assessed by measuring reactive oxygen species and protein carbonyls against the standard drug resveratrol. The electrochemical transducing ability of the hybrid g-MoO3-Ru(II) nanocomposite has been tested using butein, as a model herbaceutical, with nanomolar precision (50-1250 nM). The triad composite of metal oxide, dye, and biopolymer enabled synergistic properties that are suitable for multifunctional application in intracellular imaging, antioxidant, and electrochemical sensor studies.

Herein, we develop a competitive screening method in which G-quadruplex DNA linked magnetic nanoparticles pull down selective ligands for a particular quadruplex topology from a series of small molecules. The screening strategy is first optimized with known G-quadruplex ligands and then used with a new series of G-quadruplex interactive bis-triazolyl ligands that are synthesized by Cu(I)-catalyzed azide-alkyne cycloaddition. The assay enables the identification of c-MYC and BCL2 G-quadruplex selective bis-triazole ligands that specifically target promoter G-quadruplexes in cancer cells.

G-quadruplexes are well-known DNA secondary structures which can be formed both within the DNA and the RNA sequences of the human genome. While many functions of G-quadruplex during cell regulatory events are still unknown, a number of reports have established their role in finding new cancer therapies. In this report, we provide a detailed account of Thioflavin T (ThT) interacting with a promoter gene (c-Myc) which has relevance in several types of human cancers. Using a variety of spectroscopic techniques, we have shown that the binding of ThT is selective to c-Myc G-quadruplex only, having poor interactions with the duplex DNA sequences. UV–Visible titration experiments show that binding involves stacking interactions which were further corroborated by CD experiments. Fluorescence studies showed that the binding of ThT to c-Myc G-quadruplex results in a large increase in the fluorescence emission spectrum of c-Myc G-quadruplex while the same to duplex DNAs was much poor. Binding of ThT to c-Myc G-quadruplex results in thermal stabilization of the quadruplex DNA by up to 7.4 °C and Job plot experiments demonstrated the presence of 1:1 and 2:1 ligand to quadruplex complexes. Finally, the docking study suggested that ThT stacks with the guanine bases in one of the grooves which is in agreement with the CD studies. These results are expected to provide leads into the design of new ThT analogs and derivatives for enhancing the stability and selectivity of new G-quadruplex targeting ligands.

Metal-free cost-efficient biocompatible molecules are beneficial for opto-electrochemical bioassays. Herein, chitosan (CS) conjugated butein is prepared via graft polymerization. Structural integrity between radical active sites of CS and its probable conjugation routes with reactive OH group of butein during grafting were comprehensively studied using optical absorbance/emission property, NMR, FT-IR and XPS analysis. Fluorescence emission of CS-conjugated butein (CSB) was studied in dried flaky state as well as in drop casted form. Cyclic voltammetric study of CSB modified glassy carbon electrode exhibits 2e-/2H+ transfer reaction in phosphate buffered saline electrolyte following a surface-confined process with a correlation coefficient of 0.99. Unlike pristine butein, CSB modified electrode display a highly reversible redox behavior under various pH ranging from 4 to 9. For the proof-of-concept CSB-modified flexible screen printed electrodes were processed for electrochemical biosensing of exosomal CD24 specific nucleic acid at an ultralow sample concentration, promising for ovarian cancer diagnosis.

Hybrid nanomaterials with inherent physicochemical properties and cytocompatibility are beneficial for healthcare utilities. This paper demonstrates the hybridization of transition-metal oxide (molybdenum trioxide, MoO

Wound repair is a multistep process which involves coordination of multiple molecular players from different cell types and pathways. Though the cellular processes that are taking place in order to repair damage is already known, molecular players involved in crucial pathways are still scarce. In this regard, the present study intends to uncover crucial players that are involved in the central repair events through proteomics approach which included 2-D GE and LC-MS/MS using Caenorhabditis elegans wound model. Initial gel-based 2-D GE and following protein-protein interaction (PPI) network analyses revealed active role of calcium signaling, acetylcholine transport and serotonergic neurotransmitter pathways. Further, gel-free LC-MS/MS and following PPI network analyses revealed the incidence of actin nucleation at the initial hours immediately after injury. Further by visualizing the PPI network and the interacting players, pink-1, a mitochondrial Serine/threonine-protein kinase which is known to regulate mitochondrial dynamics, was found to be the central player in facilitating the mitochondrial fission and its role was further verified using qPCR analysis and pink-1 transgenic worms. Overall, the study delivers new insights from crucial regulatory pathways and central players involved in wound repair using high throughput proteomic approaches and the mass spectrometry Data (PXD024629/PXD024744) are available via ProteomeXchange. Significance • Though, C. elegans is being explored as a wound model for more than a decade, global proteomic changes are not looked at yet upon injury and following repair. In this regard, the present study was carried out in C. elegans to uncover new insights from wound repair through global proteomic analysis. • For this purpose, 2-D GE and LC-MS/MS analysis was carried out in unwounded and wounded samples and the PPI network constructed from the identified proteins included 2683 non redundant nodes which is actually 1/10th of the total nodes present in C. elegans whole PPI network available in the database as shown in the figure below. This is an added value of the present study which resulted with fruitful insights into crucial regulatory players and pathways that are regulated during wound repair.

Staphylococcus aureus is one of the most notorious pathogens and is frequently associated with nosocomial infections imposing serious risk to immune-compromised patients. This is in part due to its ability to colonize at the surface of indwelling medical devices and biofilm formation. Combating the biofilm formation with antibiotics has its own challenges like higher values of minimum inhibitory concentrations. Here, we describe a new approach to target biofilm formation by Gram positive bacteria. Sortase A is a transpeptidase enzyme which is responsible for tagging of around ∼22 cell surface proteins onto the outer surface. These proteins play a major role in the bacterial virulence. Sortase A recognizes its substrate through LPXTG motif. Here, we use this approach to install the synthetic peptide substrates onS. aureus. Sortase A substrate mimic, 6His-LPETG peptide was synthesized using solid phase peptide chemistry. Incorporation of the peptide on the cell surface was measured using ELISA. Effect of peptide incubation on Staphylococcus aureus biofilm was also studied. 71.1% biofilm inhibition was observed with 100 μM peptide while on silicon coated rubber latex catheter, 45.82% inhibition was observed. The present work demonstrates the inability of surface modified S. aureus to establish biofilm formation thereby presenting a novel method for attenuating its virulence.

Coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), has emerged into a global health and economic menace. Amidst the COVID-19 turmoil, recent failures/uncertain outcomes in clinical trials involving the anti-malarial (hydroxychloroquine), anti-viral (remdesivir) or the combination of anti-malarial/antibiotic (hydroxychloroquine/azithromycin) regimens have predisposed the physicians to distrust these "highly-touted" drugs for COVID-19. In this milieu, immunotherapy might be a credible modality to target or modify specific/non-specific immune responses that interfere with the survival of intracellular pathogens. This scientific review throws light on the epidemiology of COVID-19, its pathogenesis and the current clinical scenario of immunotherapeutics including convalescent plasma (CP), type-1 interferons (IFN-I) and human monoclonal antibodies (mAbs) to combat COVID-19. The treatment outcomes underscore that immunotherapy might be a reliable tool to assuage COVID-19-associated immunopathology. However, specific patient pool studies are warranted to ascertain the precise (re)purposing of immunotherapeutics for COVID-19.

Infection following injury is one of the major threats which causes huge economic burden in wound care management all over the world. Injury often results with poor healing when coupled by following infection. In contrast to this, we observed enhanced survival of wound infected worms compared to wounded worms in Caenorhabditis elegans wound model while infecting with Staphylococcus aureus. Hence, the study was intended to identify the mechanism for the enhanced survival of wound infected worms through LCMS/MS based high throughput proteomic analysis. Bioinformatics analyses of the identified protein players indicated differential enrichment of several pathways including MAPK signaling, oxidative phosphorylation and phosphatidylinositol signaling. Inhibition of oxidative phosphorylation and phosphatidylinositol signaling through chemical treatment showed complete reversal of the enhanced survival during wound infection nevertheless mutant of MAPK pathway did not reverse the same. Consequently, it was delineated that oxidative phosphorylation and phosphatidylinositol signaling are crucial for the survival. In this regard, elevated calcium signals and ROS including O- and H2O2 were observed in wounded and wound infected worms. Consequently, it was insinuated that presence of pathogen stress could have incited survival in wound infected worms with the aid of elevated ROS and calcium signals.

Anions play crucial roles in the sustenance of life on earth in many ways. Selective detection of specific anions is important in developing new diagnostic tools and therapeutics. A pH-sensitive & selective benzimidazole-based fluorescent sensor has been developed for rapid detection of carbonate ions which can detect carbonate ions in low nanomolar concentrations. NMR based experiments indicate direct interaction of benzimidazole imino protons with the carbonate ions leading to 1:1 ligand carbonate ion complexation events. This is one of the first reports of benzimidazole sensing carbonate ions with high selectivity which may have implications in disease prevention and toxicity assessment.

Simple and versatile methodology to synthesize hybrid nanostructures with multi-functionality for device application is advantageous. Herein, we report the synthesis of MoO 3 nanostructures integrated with [Ru(bpy) 3 ] 2+ and PEGylation to obtain hybrid MoO 3 -[Ru(bpy) 3 ] 2+ nanostructures. Chemically interacted [Ru(bpy) 3 ] 2+ provides optical and electrochemical properties to the hybrid structures. PEG 3k enhances the aqueous solubility of the hybrid system. Morphology, chemical structure, optical and electrochemical properties of hybrid nanostructures were studied from electron microscopic, spectroscopic and voltammetric techniques. The synthesized hybrid nanostructures exhibited a metal-to-ligand charge transfer absorbance and emission bands in the range of 450 nm and 605 nm, respectively. Electrode modified with MoO 3 -[Ru(bpy) 3 ] 2+ and MoO 3 -[Ru(bpy) 3 ] 2+ /PEG 3k exhibit improved voltammetric properties than pristine MoO 3 . Confocal cellular imaging supported that these hybrid particles were easily uptaken by endothelial cells with minimal cytotoxic effects. The hybrid nanocomplex displayed unique opto-electrochemical, cellular biocompatibility and imaging features that may be an ideal platform for electrochemical biosensor devices with simultaneous bioimaging function.

Progress in the development of phytochemistry has delivered advancement in materials functionality for range of inter/trans-disciplinary application. Here, we investigated the structural functionality of chemically synthesized phytoconstitutent, chalcone (butein) and flavanone (butin). Photoactive and electroactive behavior of butein and butin were comprehensively studied using UV–vis absorbance, photoluminescence and cyclic voltammetric techniques. Surface morphology of the butein and butin powders was characterized from scanning electron microscope at an operating voltage of 10 kV. Significant ultraviolet absorbance property are observed from butein and butin due to the distribution of π → π* and n → π* transitions. Photoluminescence emission spectra of the prepared materials are well resolved at visible region via keto-enol tautomerization and can be influenced by solvent pH. Cyclic voltammetric studies on the prepared materials enabled a direct electron-transfer reaction at gold-screen printed electrode, indicating the feasibility for analytical validation in herbal industries. Existence of multiple electroactive hydroxyl groups makes butein and butin a redox-functional species at electrode interface. Dispersion ability in aqueous and organic solvents makes butein and butin suitable for variety of photochemical applications. This phytochemical material offers new degrees of optical and redox functionality similar to inorganic nanostructures, in addition to inherent bioactivity, that may be advantageous for further biomedical function.

Recent research in graphene nanomaterials has witnessed significant contribution in biomedical science. With functional dopants, the inherent properties of graphene are extensively tuned for various applications. With a two-dimensional planar structure, large surface area with functional dopant creates a hybrid graphene as a new amalgam; with a high-performance material for bio-electronics and biomedical. Here, we present an overview of recent advances in the field of hybrid graphene derivatives, focused on drug delivery, cyto-compatabilitys and electrochemical biosensors. The physicochemical properties of graphene and surface functionalization strategies employed for loading of active pharmaceuticals toward drug delivery are discussed. Studies related to the biocompatibility of functionalized graphene for cell proliferation-associated applications are also reviewed. Furthermore, electrochemical biosensors based on hybrid graphene for the detection of metabolic biomarkers, infectious agents and active pharmaceuticals/nutraceuticals are highlighted. In summary, the integration feasibility of hybridized graphene nanomaterials in the subdisciplines of nanotechnology, viz, microelectromechanical system, microfluidics, and biomedical engineering toward its translational scope are provided.

Objective: The present study aimed to develop and evaluate orally administrable dosage form containing bioactive flavonoids viz., Luteolin-7-O-β-D-Glucuronide (II), Kaempferol 3-O-[2-O-(6-O-feruloyl)-β-D-glucopyranosyl]-βD-galactopyranoside (III) from the bark of Givotia rottleriformis and Formononetin-7-O-β-D-glucoside (VI) from the leaves of Cassia tora. Methods: The formulation was developed and evaluated as per official compendia. The developed formulation was evaluated for antipsoriatic activity using rat UV ray photo dermatitis model and cytokine inhibition assay. Results: Evaluation parameters observed optimum range of formulations and the tablets were suitable for oral administration. The formulation exhibited antipsoriatic activity by good reduction in the thickness of epidermis, significant retention of the stratum granulosum and the absence of movement of neutrophils in UV-B induced psoriasis. In cytokine inhibition assay, the formulation showed remarkable inhibition of IL-17 and TNF- α, key cytokines involved in the pathogenesis of psoriasis at higher concentration. Conclusion: The study can be concluded that the developed formulation can be effective and safety as dietary supplements with health benefits to psoriatic patients.

Inflammatory conditions associated with kidney diseases are a global public health issue that requires efficient and safe therapies. Current treatment of renal inflammatory conditions using modern medicines has limitations such as undesired adverse effects, especially in long-term use. Combinations of herbs derived from historical medicinal practice such as Kampo (Japanese herbal formulation) and traditional Chinese medicines were found to synergistically elevate the therapeutic efficacy, and lowering the dose of specific herbal extracts could reduce the side effects if there were any. The clinical practice of traditional Kampo medicine is often followed in Japan for a range of health issues, including acute and chronic renal diseases. Owing to its well-known clinical tradition there has been a significant effort since 1995 devoted to evaluating the individual mechanistic properties of common Kampo formulas. In this chapter, the characteristics of Kampo medicine, especially in renal inflammatory diseases, are briefly reviewed. The pharmacological activity of important Kampo formulations, supported by either in vitro or animal studies, is presented. Reports on randomized clinical trials of traditional herbal medicines for kidney disease and required future directions are also discussed.