Th17 cell promotes apoptosis of IL-23R+ neurons in experimental autoimmune encephalomyelitis.

Myelin antigen-reactive Th1 and Th17 cells are critical drivers of central nervous system (CNS) autoimmune inflammation. Transcription factors T-bet and RORγt play a crucial role in the differentiation and function of Th1 and Th17 cells, and impart them a pathogenic role in CNS autoimmune inflammation. Mice deficient in these two factors do not develop experimental autoimmune encephalomyelitis (EAE). While T-bet and RORγt are known to regulate the expression of several cell adhesion and migratory molecules in T cells, their role in supporting Th1 and Th17 trafficking to the CNS is not completely understood. More importantly, once Th1 and Th17 cells reach the CNS, how the function of these transcription factors modulates the local inflammatory response during EAE is unclear. In the present study, we showed that myelin oligodendrocyte glycoprotein 35-55 peptide (MOG35-55)-specific Th1 cells deficient in RORγt could cross the blood-brain barrier (BBB) but failed to induce demyelination, apoptosis of neurons, and EAE. Pathogenic Th17 cell-derived cytokines GM-CSF, TNF-α, IL-17A, and IL-21 significantly increased the surface expression of IL-23R on neuronal cells. Furthermore, we showed that, in EAE, neurons in the brain and spinal cord express IL-23R. IL-23-IL-23R signaling in neuronal cells caused phosphorylation of STAT3 (Ser727 and Tyr705) and induced cleaved caspase 3 and cleaved poly (ADP-ribose) polymerase-1 (PARP-1) molecules in an IL-23R-dependent manner and caused apoptosis. Thus, we provided a mechanism showing that T-bet is required to recruit pathogenic Th17 cells to the CNS and RORγt-mediated inflammatory response to drive the apoptosis of IL-23R+ neurons in the CNS and cause EAE. Understanding detailed molecular mechanisms will help to design better strategies to control neuroinflammation and autoimmunity. ONE SENTENCE SUMMARY: IL-23-IL-23R signaling promotes apoptosis of CNS neurons.

To decipher the phytochemical agent and mechanism for Urginea indica mediated green synthesis of Ag nanoparticles and investigation of its antibacterial activity against Methicillin-resistant Staphylococcus aureus.

Globally, Methicillin-Resistant Staphylococcus aureus bacteraemia is one of the commonest bloodstream infections associated with clinical complications and high mortality. Thence, devising effective and targeted biogenic silver based strategies are in great demand. However, limited insights regarding the biosynthesis methodologies impedes the possible scale up and commercial potentials. We, hereby demonstrate the biosynthesis of Ag nanoparticles using the phytochemical agent extracted and purified from bulb extract of Urginea indica. The chemical structure of the phytochemical agent is investigated by various chromatographic and spectroscopic techniques and was found closely relatable to N-ethylacetamide. Ag nanoparticles synthesis by this agent was found to have a strong Surface Plasmon band at 402 nm. X-ray diffraction and transmission electron microscopy further validated the formation of Ag nanoparticles with face-centred cubic structure with a size range of 20-30 nm. The biogenic metal nanoparticles have shown potential antibacterial activity against S. aureus and MRSA (within a range of 10-50 µg/mL). The nanoparticles have also shown promising anti-biofim activity against the above mentioned strains. The nanoparticles were expected to induce ROS mediated bactericidal mechamism. Cell viability and in-vitro infection studies advocate noticeable biocompatibility and future clinical potential of the developed nanoparticles against Staphylococcus infections.

Sonophotocatalytic disinfection of Shigella species under visible light irradiation: Insights into its molecular mechanism, antibacterial resistance and biofilm formation.

Microbial contamination of water is one of the major sources of many diseases worldwide. Evolution of antibacterial resistance (ABR) alongside the caveats in most of the water treatment methods causes the severity of the current problem extremely vexing. This calls for an urgent need to develop new treatment methods aiming to reduce the microbial as well as ABR load in the environment. Herein, we successfully developed a visible light assisted sonophotocatalysis (SPC) using Fe/ZnO nanoparticles (NPs) for the disinfection of Shigella dysenteriae. A consortia containing S. dysenteriae and S. flexineri was also completely disinfected using SPC. Growth conditions of S. dysenteriae like growth phases and growth temperaturehad different outcomes on the overall efficacy of SPC. Compared with catalysts such as ZnO and TiO2, Fe/ZnO resulted in better disinfection. Multi-ROS production, mostly containing h+ and O2· radicals, due to the electron displacement in the catalyst and acoustic cavitation was identified as the factors behind bacterial lethality. The ROS produced was found to interfere with the metabolic activities of S. dysenteriae by causing membrane perturbation. We identified DNA damage inside the cells and the subsequent release of intracellular components. The compositional changes in the fatty acid makeup of the cells were altered as a result of SPC and few fatty acid markers indicating the stress posed by SPC were also identified. Loss of ABR in S. dysenteriae was also recorded post SPC treatment. Abatement in the biofilm forming ability of the injured bacterial cells was also recorded, proving the extremity of stress induced by SPC. Hence, the excellent efficacy of SPC in disinfecting bacteria is proposed for tertiary water treatment applications.

Biogenic Au@ZnO core-shell nanocomposites kill Staphylococcus aureus without provoking nuclear damage and cytotoxicity in mouse fibroblasts cells under hyperglycemic condition with enhanced wound healing proficiency.

The aim of the present study is focused on the synthesis of Au@ZnO core-shell nanocomposites, where zinc oxide is overlaid on biogenic gold nanoparticles obtained from Hibiscus Sabdariffa plant extract. Optical property of nanocomposites is investigated using UV-visible spectroscopy and crystal structure has been determined using X-ray crystallography (XRD) technique. The presence of functional groups on the surface of Au@ZnO core-shell nanocomposites has been observed by Fourier transforms infrared (FTIR) spectroscopy. Electron microscopy studies revealed the morphology of the above core-shell nanocomposites. The synthesized nanocomposite material has shown antimicrobial and anti-biofilm activity against Staphylococcus aureus and Methicillin Resistant Staphylococcus haemolyticus (MRSH). The microbes are notorious cross contaminant and are known to cause infection in open wounds. The possible antimicrobial mechanism of as synthesized nanomaterials has been investigated against Staphylococcus aureus and obtained data suggests that the antimicrobial activity could be due to release of reactive oxygen species (ROS). Present study has revealed that surface varnishing of biosynthesized gold nanoparticles through zinc oxide has improved its antibacterial proficiency against Staphylococcus aureus, whereas reducing its toxic effect towards mouse fibroblast cells under normal and hyperglycaemic condition. Further studies have been performed in mice model to understand the wound healing efficiency of Au@ZnO nanocomposites. The results obtained suggest the possible and effective use of as synthesized core shell nanocomposites in wound healing.

Use and misuse of material transfer agreements: lessons in proportionality from research, repositories, and litigation.

Material transfer agreements exist to facilitate the exchange of materials and associated data between researchers as well as to protect the interests of the researchers and their institutions. But this dual mandate can be a source of frustration for researchers, creating administrative burdens and slowing down collaborations. We argue here that in most cases in pre-competitive research, a simple agreement would suffice; the more complex agreements and mechanisms for their negotiation should be reserved for cases where the risks posed to the institution and the potential commercial value of the research reagents is high.

Effect of traditional medicine brahmi vati and bacoside A-rich fraction of Bacopa monnieri on acute pentylenetetrzole-induced seizures, amphetamine-induced model of schizophrenia, and scopolamine-induced memory loss in laboratory animals.

OBJECTIVE: Brahmi vati (BV) is an Ayurvedic polyherbal formulation used since ancient times and has been prescribed in seizures associated with schizophrenia and related memory loss by Ayurvedic practitioners in India. The aim of the study was to investigate these claims by evaluation of anticonvulsant, antischizophreniac, and memory-enhancing activities. Antioxidant condition of brain was determined by malondialdehyde (MDA) and reduced glutathione (GSH) levels estimations. Acetylcholinesterase (AChE) was quantitatively estimated in the brain tissue. METHODS: Brahmi vati was prepared in-house by strictly following the traditional Ayurvedic formula. Bacoside A rich fraction (BA) of Bacopa monnieri was prepared by extraction and fractionation. It was than standardized by High Performance Liquid Chromatography (HPLC) and given in the dose of 32.5mg/kg body weight to the different groups of animals for 7days. On the seventh day, activities were performed adopting standard procedures. KEY FINDINGS: Brahmi vati showed significant anticonvulsant, memory-enhancing and antischizophrenia activities, when compared with the control groups and BA. It cause significantly higher brain glutathione levels. Acetylcholinesterase activity was found to be significantly low in BV-treated group. CONCLUSION: The finding of the present study suggests that BV may be used to treat seizures associated with schizophrenia and related memory loss.

Screening of acute and sub-chronic dermal toxicity of Calendula officinalis L essential oil.

The objective of the study is to access the safety of Calendula essential oil by studying acute and sub-chronic dermal toxicity. The dermal toxicities of Calendula essential oil were evaluated in accordance with OECD guidelines number 402 and 411 respectively. The animals were exposed to Calendula officinalis (CO) essential oil dose of 20 mL/kg body weight for acute dermal toxicity, whereas for dermal sub-chronic toxicity study, rats were exposed to CO oil 2.5, 5 and 10 mL/kg body weight, respectively, for 7 times in a week for 90 days. The parameters studies included CNS stimulation, depression, hematological parameters (RBC, WBC, Hb, Lymphocyte % etc), biochemical parameters (total protein, albumin, total bilirubin, ALP, AST, etc), relative organ weight, necropsy and histopathology. In toxicity studies, all animals exhibited normal behavior without any change in hematology, blood biochemistry, necroscopical and histopathology. The no observed effect level (NOEL) and no observed adverse effect level (NOAEL) of CO oil were 2.5 and 10 mg/kg/day, respectively. CO oil is under the herbal medicinal product according to the European Medicines Agency with the claim of an LD50 value of 20 mL/kg body weight. The result indicates that CO essential oil did not produce any significant toxic effects.

One-Pot Synthesis of Glycosyl-ß-azido Ester via Diazotransfer Reaction Toward Access of Glycosyl-ß-triazolyl Ester.

A concise and efficacious one-pot protocol for the synthesis of novel glycosyl-ß-azido ester 3 from glycosyl olefinic ester 1 under mild conditions has been devised. The ß-aminoester, formed by the conjugate addition of ammonia on olefinic ester, undergoes a metal-catalyzed diazotransfer reaction to furnish glycosyl-ß-azido ester. The optimized conditions for diazotransfer reaction indicate that imidazole-1-sulphonyl azide and K2CO3 give the best results in the presence of ZnCl2. A diverse range of novel regioselective triazolyl glycoconjugates 6a-u have been achieved in high yields via 1,3-dipolar cycloaddition of compound 3 with various alkynes in the presence of CuI/DIPEA. Structures of all the compounds have been elucidated using IR, NMR, MS, and elemental analysis, and four of them (3a, 3b, 4b, and 6a) have also been characterized by single crystal X-ray diffraction analysis.

Effector and cytolytic function of natural killer cells in anticancer immunity.

Adaptive immune cells play an important role in mounting antigen-specific antitumor immunity. The contribution of innate immune cells such as monocytes, macrophages, natural killer (NK) cells, dendritic cells, and gamma-delta T cells is well studied in cancer immunology. NK cells are innate lymphoid cells that show effector and regulatory function in a contact-dependent and contact-independent manner. The cytotoxic function of NK cells plays an important role in killing the infected and transformed host cells and controlling infection and tumor growth. However, several studies have also ascribed the role of NK cells in inducing pathophysiology in autoimmune diseases, promoting immune tolerance in the uterus, and antitumor function in the tumor microenvironment. We discuss the fundamentals of NK cell biology, its distribution in different organs, cellular and molecular interactions, and its cytotoxic and noncytotoxic functions in cancer biology. We also highlight the use of NK cell-based adoptive cellular therapy in cancer.

Antibacterial Efficacy of ZnO/Bentonite (Clay) Nanocomposites against Multidrug-Resistant Escherichia coli.

The emergence of multidrug-resistant (MDR) bacteria has spurred the exploration of therapeutic nanomaterials such as ZnO nanoparticles. However, the inherent nonspecific toxicity of ZnO has posed a significant obstacle to their clinical utilization. In this research, we propose a novel approach to improve the selectivity of the toxicity of ZnO nanoparticles by impregnating them onto a less toxic clay mineral, Bentonite, resulting in ZB nanocomposites (ZB NCs). We hypothesize that these ZB NCs not only reduce toxicity toward both normal and carcinogenic cell lines but also retain the antibacterial properties of pure ZnO nanoparticles. To test this hypothesis, we synthesized ZB NCs by using a precipitation technique and confirmed their structural characteristics through X-ray diffraction and Raman spectroscopy. Electron microscopy revealed composite particles in the size range of 20-50 nm. The BET surface area of ZB NCs, within a relative pressure (P/P0) range of 0.407-0.985, was estimated to be 31.182 m2/g. Notably, 50 mg/mL ZB NCs demonstrated biocompatibility with HCT 116 and HEK 293 cell lines, supported by flow cytometry and fluorescence microscopy analysis. In vitro experiments further confirmed a remarkable five-log reduction in the population of MDR Escherichia coli in the presence of 50 mg/mL of ZB NCs. Antibacterial activity of the nanocomposites was also validated in the HEK293 and HCT 116 cell lines. These findings substantiate our hypothesis and underscore the effectiveness of ZB NCs against MDR E. coli while minimizing nonspecific toxicity toward healthy cells.

Erratum: Antibacterial Efficacy of ZnO/Bentonite (Clay) Nanocomposites against Multidrug-Resistant Escherichia coli.

[This corrects the article DOI: 10.1021/acsomega.3c07950.].

Molecular targeted therapies for cutaneous squamous cell carcinoma: recent developments and clinical implications.

Cutaneous Squamous Cell Carcinoma (cSCC) is a common and potentially fatal type of skin cancer that poses a significant threat to public health and has a high prevalence rate. Exposure to ultraviolet radiation on the skin surface increases the risk of cSCC, especially in those with genetic syndromes like xerodermapigmentosum and epidermolysis bullosa. Therefore, understanding the molecular pathogenesis of cSCC is critical for developing personalized treatment approaches that are effective in cSCC. This article provides a comprehensive overview of current knowledge of cSCC pathogenesis, emphasizing dysregulated signaling pathways and the significance of molecular profiling. Several limitations and challenges associated with conventional therapies, however, are identified, stressing the need for novel therapeutic strategies. The article further discusses molecular targets and therapeutic approaches, i.e., epidermal growth factor receptor inhibitors, hedgehog pathway inhibitors, and PI3K/AKT/mTOR pathway inhibitors, as well as emerging molecular targets and therapeutic agents. The manuscript explores resistance mechanisms to molecularly targeted therapies and proposes methods to overcome them, including combination strategies, rational design, and optimization. The clinical implications and patient outcomes of molecular-targeted treatments are assessed, including response rates and survival outcomes. The management of adverse events and toxicities in molecular-targeted therapies is crucial and requires careful monitoring and control. The paper further discusses future directions for therapeutic advancement and research in this area, as well as the difficulties and constraints associated with conventional therapies.

Synthesis of glycoconjugate benzothiazoles via cleavage of benzotriazole ring.

A concise and efficacious benzotriazole-mediated novel two-step protocol has been developed for easy access to glycoconjugate benzothiazoles from protected carbohydrates. The benzotriazolemethanethione 3, prepared by the reaction of free alcohol with bis(1H-benzo[1,2,3]triazol-1-yl)methanethione, on treatment with silanes or stannane under heating or microwave irradiation undergoes free radical ß-scission of N-N bond and affords diverse range of 2-O-substituted benzothiazoles 4 via cyclative elimination of molecular nitrogen. The structures of all of the compounds have been elucidated using IR, NMR, MS, and elemental analysis, and five of them have been characterized by single-crystal X-ray analysis.

Recent Advancements in Liquid Chromatographic Techniques to Estimate Pesticide Residues Found in Medicinal Plants around the Globe.

In the present review article, different advanced liquid chromatographic techniques and the advanced techniques other than liquid chromatography that are used to estimate the pesticide residues from different plant-based samples are presented. In the beginning of the article, details of pesticides, their health effects and various cell lines used for the related study has been outlined. Afterward, detailed descriptions regarding pesticides classification are inscribed. In the end, recent advancements in the area of analysis of pesticides for herbal drugs are explained. Solid phase micro extraction (SPME) and solid-phase extraction (SPE) are considered as most common method of sample preparation for pesticides and its residual analysis. The most commonly used analytical separation technique for pesticide analysis is liquid chromatography (LC) integrated with mass spectrometry (MS) and MS/MS as Triple Quadrupole Mass Spectrometer (QqQ) for the samples analysis where high level of sensitivity and accuracy is required in quantification.

Fabrication of ZnO/Gypsum/Gelatine nanocomposites films and their antibacterial mechanism against Staphylococcus aureus.

Staphylococcus aureus (S. aureus) has long been acknowledged as being one of the most harmful bacteria for human civilization. It is the main contributor to skin and soft tissue infections. The gram positive pathogen also contributes to bloodstream infections, pneumonia, or bone and joint infections. Hence, developing an efficient and targeted treatment for these illnesses is greatly desired. Recently, studies on nanocomposites (NCs) have significantly increased due to their potent antibacterial and antibiofilm properties. These NCs provide an intriguing way to control the growth of bacteria without causing the development of resistance strains that come from improper or excessive use of the conventional antibiotics. In this context, we have demonstrated the synthesis of a NC system by precipitation of ZnO nanoparticles (NPs) on Gypsum followed by encapsulation with Gelatine, in the present study. Fourier transform infrared (FTIR) spectroscopy was used to validate the presence of ZnO NPs and Gypsum. The film was characterized by X-ray diffraction (XRD) spectroscopy and scanning electron microscopy (SEM). The system exhibited promising antibiofilm action and was effective in combating S. aureus and MRSA in concentrations between 10 and 50 ug/ml. The bactericidal mechanism by release of reactive oxygen species (ROS) was anticipated to be induced by the NC system. Studies on cell survival and in-vitro infection support the film's notable biocompatibility and its potential for treating Staphylococcus infections in the future.

Vγ2+ γδ T Cells in the Presence of Anti-CD40L Control Surgical Inflammation and Promote Skin Allograft Survival.

γδ T cells represent a small fraction of total T cells in the body and do not use classical polymorphic major histocompatibility complex‒loaded peptides for mounting an immune response. The importance of the effector and regulatory function of γδ T cells in infections, autoimmunity, and tumor models are well characterized. In this study, we investigated the mechanistic role of γδ T cells in costimulatory blockade‒induced transplantation tolerance. We used donor-specific transfusion and anti-CD40L treatment in C57BL/6 mice to induce tolerance to BALB/c skin allografts. We show that depletion of γδ T cells, specifically Vγ2+ γδ T cells, led to the acute rejection of skin allografts despite tolerogen treatment. Tolerogen treatment promoted CD39+Vγ2+ γδ T cells and suppressed IFN-γ‒producing Vγ2+ γδ T cells in the spleen and allografts. Vγ2+ γδ T cells isolated from tolerized mice suppress T helper type 1 cell differentiation. Adoptive transfer of these regulatory Vγ2+ γδ T cells prolonged the survival of allografts in an untreated recipient and Tcrδ‒/‒ mice. Together, our data show that the Vγ2+ subset promotes costimulatory blockade‒induced survival of skin allografts and that tolerogenic Vγ2+ T cells can be used as an adoptive cellular therapy to promote the survival of allografts.

A critical review on nanomaterial based therapeutics for diabetic wound healing.

Diabetes mellitus is a chronic endocrine disease that occurs mostly in the state of hyperglycemia (elevated blood glucose level). In the recent times, diabetes is listed under world's utmost critical health issues. Wound treatment procedures are complicated in diabetic individuals all over the world. Diabetic wound care not only involves high-cost, but also the primary cause of hospitalization, which can lead to amputation thereby reducing diabetic patient life expectancy. To lower the risk of amputation, wound healing requires the development of effective treatments. Traditional management systems for Diabetes are frequently chastised due to their high costs, difficulties in maintaining a sustainable supply chain and limited disposal alternatives. The worrisome rise in diabetes prevalence has sparked a surge of interest in the discovery of viable remedies to supplement existing treatments. Nanomaterials wound healing has a lot of potential for treating and preventing wound infections and it has recently gained popularity owing to its ability to transport drugs to the wound area in a regulated fashion, potentially overpowering the limits of traditional approaches. This research assessed several nanosystems, such as nanocarriers and nanotherapeutics, to explore how they can benefit in diabetic wound healing, with a focus on current obstacles and future prospects.

Internal Transcribed Spacer (ITS) Region of Nuclear Ribosomal DNA as a Suitable DNA Barcode for Identification of Zanthoxylum armatum DC. from Manipur.

Zanthoxylum armatum DC. is a plant with many medicinal values which is extensively used in traditional system of medicine for curing various diseases and ailments, including cancer. The aim of the present study is to identify Zanthoxylum armatum collected from different parts of Manipur, India, at molecular level. Molecular markers like internal transcribed spacer (ITS) region and other DNA barcoding genes such as matK, rbcL, psbA-trnH and trnL-trnF were targeted to find out the most suitable DNA barcode for identifying this species. Sequences obtained using the five primer pairs-ITS An5 and ITS An4, matK-413f-1 and matK-1227r-1, rbcL-1F and rbcL-724R, psbA-F and trnH-R and trnL-F and trnF-R were submitted to GenBank, NCBI. Amongst the five DNA barcoding targets, one nuclear and four chloroplast genes were successfully amplified by PCR (100%) and sequencing (100%) in all the eight plant samples. Sequence similarity of total ITS region (620 bp) when compared to the reference sequence were found to be between 98.55 and 99.68%. In our study, ITS sequence in combination with DNA barcoding sequences of rbcL, trnH-psbA and trnL-trnF was very successful in identification of Z. armatum and differentiate other species clearly in the phylogeny analysis. Our work shows ITS region to be the most suitable DNA barcode which formed a monophyletic group of the species in the phylogenetic tree analysis. The sequences of the barcoding genes of Z. armatum DC. obtained from this study adds to the already available resources which will be helpful in the future research endeavours.

Global challenges of implementing human papillomavirus vaccines.

Human Papillomavirus vaccines are widely hailed as a sweeping pharmaceutical innovation for the universal benefit of all women. The implementation of the vaccines, however, is far from universal or equitable. Socio-economically marginalized women in emerging and developing, and many advanced economies alike, suffer a disproportionately large burden of cervical cancer. Despite the marketing of Human Papillomavirus vaccines as the solution to cervical cancer, the market authorization (licensing) of the vaccines has not translated into universal equitable access. Vaccine implementation for vulnerable girls and women faces multiple barriers that include high vaccine costs, inadequate delivery infrastructure, and lack of community engagement to generate awareness about cervical cancer and early screening tools. For Human Papillomavirus vaccines to work as a public health solution, the quality-assured delivery of cheaper vaccines must be integrated with strengthened capacity for community-based health education and screening.

Microbial synthesis of gold nanoparticles using the fungus Penicillium brevicompactum and their cytotoxic effects against mouse mayo blast cancer C 2 C 12 cells.

Microorganisms, their cell filtrates, and live biomass have been utilized for synthesizing various gold nanoparticles. The shape, size, stability as well as the purity of the bio synthesized nanoparticles become very essential for application purpose. In the present study, gold nanoparticles have been synthesized from the supernatant, live cell filtrate, and biomass of the fungus Penicillium brevicompactum. The fungus has been grown in potato dextrose broth which is also found to synthesize gold nanoparticles. The size of the particles has been investigated by Bio-TEM before purification, following purification and after storing the particles for 3 months under refrigerated condition. Different characterization techniques like X-ray diffraction, Fourier transform infrared spectroscopy, and UV-visible spectroscopy have been used for analysis of the particles. The effect of reaction parameters such as pH and concentration of gold salt have also been monitored to optimize the morphology and dispersity of the synthesized gold nanoparticles. A pH range of 5 to 8 has favored the synthesis process whereas increasing concentration of gold salt (beyond 2 mM) has resulted in the formation of bigger sized and aggregated nanoparticles. Additionally, the cytotoxic nature of prepared nanoparticles has been analyzed using mouse mayo blast cancer C(2)C(12) cells at different time intervals (24, 48, and 72 h) of incubation period. The cells are cultivated in Dulbecco's modified Eagle's medium supplemented with fetal bovine serum with antibiotics (streptopenicillin) at 37°C in a 5% humidified environment of CO(2). The medium has been replenished every other day, and the cells are subcultured after reaching the confluence. The viability of the cells is analyzed with 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide method.