Endophytic Fungi: Cellular factories of novel medicinal chemistries.

Inflammation and associated disorders have been a major contributing factor to mortality worldwide. The augmented mortality rate and emerging resistance against the approved therapeutics necessitate the discovery of novel chemistries destined for multiple clinical settings. Cellular factories including endophytic fungi have been tapped for chemical diversity with therapeutic potential. The emerging evidence has suggested the potential of bioactive compounds isolated from the endophytic fungi as putative agents to combat inflammation-associated disorders. The review summarizesand assists the readers in comprehending the structural and functional aspects of the medicinal chemistries identified from endophytic fungi as anticancer, antiobesity, antigout, and immunomodulatory agents.

Redox ticklers and beyond: Naphthoquinone repository in the spotlight against inflammation and associated maladies.

Cellular redox status has been considered as a focal point for the pathogenesis of multiple disorders. High and persistent levels of free radicals kick off inflammation and associated disorders. Though oxidative stress at high levels is harmful but at low levels it has been shown to exert cytoprotective effects. Therefore, cytoprotection by perturbation in cellular redox balance is a leading strategy for therapeutic interventions. Prooxidants are potent redox modifiers that generate mild oxidative stress leading to a spectrum of bioactivities. Naphthoquinones are a group of highly reactive organic chemical species that interact with biological systems owing to their prooxidants nature. Owing to the ability of naphthoquinones and its derivatives to perturb redox balance in a cell and modulate redox signaling, they have been in epicenter of drug development for plausible utilization in multiple clinical settings. The present review highlights the potential of 1,4-naphthoquinone and its natural derivatives (plumbagin, juglone, lawsone, menadione, lapachol and ß-lapachone) as redox modifiers with anti-inflammatory, anti-cancer, anti-diabetic and anti-microbial activities for implication in therapeutic settings.

Thiol dependent NF-κB suppression and inhibition of T-cell mediated adaptive immune responses by a naturally occurring steroidal lactone Withaferin A.

Withaferin A (WA), a steroidal lactone isolated from ayurvedic medicinal plant Withania somnifera, was shown to inhibit tumor growth by inducing oxidative stress and suppressing NF-κB pathway. However, its effect on T-cell mediated adaptive immune responses and the underlying mechanism has not been investigated. Since both T-cell responses and NF-κB pathway are known to be redox sensitive, the present study was undertaken to elucidate the effect of WA on adaptive immune responses in vitro and in vivo. WA inhibited mitogen induced T-cell and B-cell proliferation in vitro without inducing any cell death. It inhibited upregulation of T-cell (CD25, CD69, CD71 and CD54) and B-cell (CD80, CD86 and MHC-II) activation markers and secretion of Th1 and Th2 cytokines. WA induced oxidative stress by increasing the basal ROS levels and the immunosuppressive effects of WA were abrogated only by thiol anti-oxidants. The redox modulatory effects of WA in T-cells were attributed to its ability to directly interact with free thiols. WA inhibited NF-κB nuclear translocation in lymphocytes and prevented the direct binding of nuclear NF-κB to its consensus sequence. MALDI-TOF analysis using a synthetic NF-κB-p50 peptide containing Cys-62 residue suggested that WA can modify the cysteine residue of NF-κB. The pharmacokinetic studies for WA were also carried out and in vivo efficacy of WA was studied using mouse model of Graft-versus-host disease. In conclusion, WA is a potent inhibitor of T-cell responses and acts via a novel thiol dependent mechanism and inhibition of NF-κB pathway.

Unraveling the treasure trove of phytochemicals in mitigating the Salmonella enterica infection.

Foodborne diseases triggered by various infectious micro-organisms are contributing significantly to the global disease burden as well as to increasing mortality rates. Salmonella enterica belongs to the most prevalent form of bacteria accountable for significant burden of foodborne illness across the globe. The conventional therapeutic approach to cater to Salmonella enterica-based infections relies on antibiotic therapy, but the rapid emergence of the antibiotic resistance strains of Salmonella sp. necessitates the development of alternative treatment and prevention strategies. In light of this growing concern, the scientific community is rigorously exploring novel phytochemicals harnessed from medicinally important plants as a promising approach to curb Salmonella enterica infections. A variety of phytochemicals belonging to alkaloids, phenols, flavonoid, and terpene classes are reported to exhibit their inhibitory activity against bacterial cell communication, membrane proteins, efflux pumps, and biofilm formation among drug resistant Salmonella strains. The present review article delves to discuss the emergence of antibiotic resistance among Salmonella enterica strains, various plant sources, identification of phytochemicals, and the current state of research on the use of phytochemicals as antimicrobial agents against Salmonella enterica, shedding light on the promising potential of phytochemicals in the fight against this pathogen.

Artificial Intelligence in Drug Identification and Validation: A Scoping Review.

The end-to-end process in the discovery of drugs involves therapeutic candidate identification, validation of identified targets, identification of hit compound series, lead identification and optimization, characterization, and formulation and development. The process is lengthy, expensive, tedious, and inefficient, with a large attrition rate for novel drug discovery. Today, the pharmaceutical industry is focused on improving the drug discovery process. Finding and selecting acceptable drug candidates effectively can significantly impact the price and profitability of new medications. Aside from the cost, there is a need to reduce the end-to-end process time, limiting the number of experiments at various stages. To achieve this, artificial intelligence (AI) has been utilized at various stages of drug discovery. The present study aims to identify the recent work that has developed AI-based models at various stages of drug discovery, identify the stages that need more concern, present the taxonomy of AI methods in drug discovery, and provide research opportunities. From January 2016 to September 1, 2023, the study identified all publications that were cited in the electronic databases including Scopus, NCBI PubMed, MEDLINE, Anthropology Plus, Embase, APA PsycInfo, SOCIndex, and CINAHL. Utilising a standardized form, data were extracted, and presented possible research prospects based on the analysis of the extracted data.

Synergistic C-TiO2/ZIF-8 type II heterojunction photocatalyst for enhanced photocatalytic degradation of methylene blue.

Zinc imidazolate framework (ZIF-8) and titanium dioxide (TiO2) have been extensively studied as photocatalysts and have shown remarkable potential. In this study, we report the synthesis of a type II heterojunction photocatalyst based on carbon-doped TiO2 (C-TiO2) and ZIF-8 as a potentially improved material for solar light-harvested methylene blue (MB) degradation. Pure ZIF-8 has a wide band gap of 4.9 eV, due to which the application of this material to visible light-assisted photocatalytic performance is a challenging task. Therefore, C-TiO2 has been chosen as a composite material with ZIF-8 owing to its narrow band gap compared to TiO2. This enables the free radical-initiated photocatalytic reaction to shift into the visible region instead of the ultraviolet region. To construct the C-TiO2/ZIF-8 heterostructure, the zinc-based ZIF matrix has been built upon the exterior of C-TiO2 nanoparticles. UV-Vis diffuse reflectance spectroscopy (UV-Vis-DRS) corroborated the decrease in the band gap of ZIF-8 after the fabrication of C-TiO2/ZIF-8, while X-ray diffraction (XRD) analysis demonstrated a decrease in average d-spacing and average crystallite size of the synthesized photocatalyst. Raman spectra and X-ray photoelectron spectroscopy (XPS) analysis of the synthesized samples were also performed to further understand their chemical structure and elemental content. Ultraviolet photoelectron spectroscopy (UPS) and high-resolution transmission electron microscopy (HRTEM) analyses were performed to understand the valence band (VB) states and the morphology of C-TiO2/ZIF-8. The comparison between pure ZIF-8 and C-TiO2/ZIF-8 in the photocatalytic degradation of MB under visible light has also been drawn. A possible charge-transfer mechanism for the same has also been proposed. It is concluded that the synergistic effect of C-TiO2 and ZIF-8 in C-TiO2/ZIF-8 produces an effective material for photocatalytic dye degradation.

Antimicrobial activity of synthesized graphene oxide-selenium nanocomposites: A mechanistic insight.

Nanoparticles have recently gained interest as an anti-bacterial agent due to their large surface area/volume ratio and potential to compromise the integrity of bacterial cell membranes. Due to its versatility and anti-bacterial activity, graphene-based materials have drawn significant interest in biomedical applications. One of the greatest threats to life in the modern technological era is the pervasiveness of infectious diseases since bacteria cells are constantly updating themselves to resist antibiotics. In this presented study, GO-Se nanocomposite has been synthesized using polymer solution via a simple dispersion method. The structural and physicochemical properties of nanocomposite were investigated in detail. Staphylococcus aureus, Proteus vulgaris, and Bacillus subtilis bacterial strains were employed to study the anti-bacterial activity of GO-Se nanocomposite. The results show that the synthesized nanocomposites have good efficacy as an anti-bacterial agent. UV-vis spectroscopy, FTIR spectroscopy, HRTEM, XPS, and Raman spectroscopy were used to analyze the as-prepared GO and GO-Se nanocomposite.

Nano to rescue: repository of nanocarriers for targeted drug delivery to curb breast cancer.

Breast cancer is a heterogeneous disease with different intrinsic subtypes. The conventional treatment of surgical resection, chemotherapy, immunotherapy and radiotherapy has not shown significant improvement in the survival rate of breast cancer patients. The therapeutics used cause bystander toxicities deteriorating healthy tissues. The breakthroughs of nanotechnology have been a promising feat in selective targeting of tumor site thus increasing the therapeutic gain. By the application of nanoenabled carriers, nanomedicines ensure targeted delivery, stability, enhanced cellular uptake, biocompatibility and higher apoptotic efficacy. The present review focuses on breakthrough of nanoscale intervention in targeted drug delivery as novel class of therapeutics. Nanoenabled carriers like polymeric and metallic nanoparticles, dendrimers, quantum dots, liposomes, solid lipid nanoparticles, carbon nanotubes, drug-antibody conjugates and exosomes revolutionized the targeted therapeutic delivery approach. These nanoassemblies have shown additional effect of improving the solubility of drugs such as paclitaxel, reducing the dose and toxicity. The present review provides an insight on the different drug conjugates employed/investigated to curb breast cancer using nanocarrier mediated targeted drug delivery. However, identification of appropriate biomarkers to target, clearer insight of the biological processes, batch uniformity, reproducibility, nanomaterial toxicity and stabilities are the hurdles faced by nanodrugs. The potential of nano-therapeutics delivery necessitates the agglomerated efforts of research community to bridge the route of nanodrugs for scale-up, commercialization and clinical applications.

Cure lies in nature: medicinal plants and endophytic fungi in curbing cancer.

Success of targeted cancer treatment modalities has generated an ambience of plausible cure for cancer. However, cancer remains to be the major cause of mortality across the globe. The emergence of chemoresistance, relapse after treatment and associated adverse effects has posed challenges to the present therapeutic regimes. Thus, investigating new therapeutic agents of natural origin and delineating the underlying mechanism of action is necessary. Since ages and still in continuum, the phytochemicals have been the prime source of identifying bioactive agents against cancer. They have been exploited for isolating targeted specific compounds to modulate the key regulating signaling pathways of cancer pathogenesis and progression. Capsaicin (alkaloid compound in chilli), catechin, epicatechin, epigallocatechin and epigallocatechin-3-gallate (phytochemicals in green tea), lutein (carotenoid found in yellow fruits), Garcinol (phenolic compound present in kokum tree) and many other naturally available compounds are also very valuable to develop the drugs to treat the cancer. An alternate repository of similar chemical diversity exists in the form of endophytic fungi inhabiting the medicinal plants. There is a high diversity of plant associated endophytic fungi in nature which are potent producers of anti-cancer compounds and offers even stronger hope for the discovery of an efficient anti-cancer drug. These fungi provide various bioactive molecules, such as terpenoids, flavonoids, alkaloids, phenolic compounds, quinines, steroids etc. exhibiting anti-cancerous property. The review discusses the relevance of phytochemicals in chemoprevention and as modulators of miRNA. The perspective advocates the imperative role of anti-cancerous secondary metabolites containing repository of endophytic fungi, as an alternative route of drug discovery.

Perturbation in cellular redox homeostasis: Decisive regulator of T cell mediated immune responses.

Cellular redox homeostasis plays a pivotal role in generation and maintenance of physiological responses. Perturbation in cellular redox status causes modulation in redox sensitive signaling pathways determining the cell fate. Depending on the extent of generation and spatio-temporal regulation of reactive oxygen species (ROS) generating oxidative stress, it can act as death stimulus or as secondary messenger. Multiple exogenous oxidants or thiol reactive compounds, endogenous oxidants such as NADPH oxidase, superoxide dismutase regulate T cell mediated immune responses. Thus, a meticulous understanding of the coordinated functioning of T cell mediated immune responses in oxidative niche is essential. The present review aims to delineate the effect of cellular redox status on T cell activation and subsequent regulation of redox sensitive immunoregulatory transcription factors such as NF-κB, NFAT and AP-1, which manifests the onset of inflammation associated disorders.

1,4-Naphthoquinone, a pro-oxidant, ameliorated radiation induced gastro-intestinal injury through perturbation of cellular redox and activation of Nrf2 pathway.

Detrimental effects of ionizing radiation (IR) are observed at the doses above 1 Gy. Treatment modalities are available up to doses of 6 Gy including bonemarrow transplantation and administration of antibiotics. However, exposure to IR doses above 8 Gy results in gastro-intestinal (GI) syndrome characterised by denudated villi, apoptosis of crypt cells and elevated inflammatory responses. Multiple strategies have been employed to investigate novel agents to protect against IR induced injury. Since cellular redox homeostasis plays a pivotal role in deciding the cell fate, present study was undertaken to explore the potential of 1,4-naphthoquinone (NQ), a pro-oxidant, to ameliorate IR induced GI syndrome. NQ protected INT 407 cells against IR induced cell death of intestinal epithelial cells in vitro. NQ induced perturbation in cellular redox status and induced the activation of nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway. Thiol antioxidant and inhibitors of Nrf2 pathway abrogated the radioprotection offered by NQ. Further, knocking down Nrf2 rescind the NQ mediated protection against IR induced cell death. In conclusion, NQ protects against IR radiation induced GI syndrome in vitro by perturbing cellular redox and activating Nrf2 pathway. This is the first report highlighting the potential of a pro-oxidant to ameliorate IR induced GI injury.

Plumbagin induces apoptosis in lymphoma cells via oxidative stress mediated glutathionylation and inhibition of mitogen-activated protein kinase phosphatases (MKP1/2).

Maintaining cellular redox homeostasis is imperative for the survival and normal functioning of cells. This study describes the role and regulation of MAPKinases in oxidative stress mediated apoptosis. Plumbagin, a vitamin K3 analog and a pro-oxidant, was employed and it induced apoptosis in both mouse and human T-cell lymphoma cell lines via increased oxidative stress, caspase activity and loss of mitochondrial membrane potential. The pro-oxidant and cytotoxic effects of plumbagin were sensitive to antioxidants indicating a decisive role of cellular redox balance. Plumbagin induced persistent activation of JNK and pharmacological inhibition as well as shRNA-mediated JNK knock-down rescued cells from plumbagin-induced apoptosis. Further, plumbagin induced cytochrome c release, FasL expression and Bax levels via activation of JNK pathway. Exposure of lymphoma cells to plumbagin led to inhibition of total and specific phosphatase activity, increased total protein S-glutathionylation and induced glutathionylation of dual specific phosphatase- 1 and 4 (MKP-1 and MKP-2). The in vivo anti-tumor efficacy of plumbagin was demonstrated using a mouse model. In conclusion, oxidative stress mediated tumor cytotoxicity operates through sustained JNK activation via a novel redox-mediated regulation of MKP-1 and MKP-2.

1,4-Naphthoquinone, a pro-oxidant, suppresses immune responses via KEAP-1 glutathionylation.

Low levels of oxidative stress have been shown to activate Nrf-2, an important anti-inflammatory transcription factor, by us and also by several other investigators. Earlier we showed that pro-oxidants protect normal lymphocytes against radiation injury by activating Nrf-2. In the present study, we have investigated the effect of oxidative stress on immune responses and delineated the underlying mechanism. Hydrogen peroxide, tert-butylhydroquinone and 1,4-naphthoquinone (NQ) inhibited mitogen induced proliferation of lymphocytes. NQ also inhibited mitogen (Concanavalin A) induced cytokine secretion by murine T cells and lipopolysaccharide induced release of cytokines, nitric oxide and cyclooxygenase-2 expression by macrophages. NQ modulated cellular redox by decreasing GSH/GSSG ratio and the immunosuppressive effects of NQ were significantly abrogated by thiol containing antioxidants and not by non-thiol antioxidants. This redox perturbation led to activation of Nrf-2 pathway and inhibition of NF-κB. NQ treatment increased total protein S-thiolation, induced glutathionylation of KEAP-1 protein and decreased IKKß levels in lymphocytes. Molecular docking studies revealed that NQ can disrupt KEAP-1/Nrf-2 interaction by directly blocking the binding site of Nrf-2 in the KEAP-1 protein. Further, inhibitors of Nrf-2 and HO-1 abrogated the anti-inflammatory effects of NQ. T cells isolated from spleen and gut associated lymphoid tissue of NQ administered mice also showed suppression of NF-κB activation and were hyporesponsive to mitogenic stimulation. These results demonstrate that pro-oxidants modulate inflammatory and immune responses via oxidative stress mediated KEAP-1 glutathionylation and IKKß degradation.