In silico, in vitro, and in vivo acute and sub-acute toxicity profiling of whole plant methanol extract of Equisetum diffusum D. Don from the sub-Himalayan West Bengal, India, having ethnobotanical uses.

BACKGROUND: Equisetum diffusum D. Don commonly known as 'Himalayan horsetail', has been traditionally used in the treatment of back pain, bone fracture and dislocation, and arthritis by various tribal communities of India. Our previous study confirmed the anti-inflammatory efficacy of the plant through in silico, in vitro, and in vivo model studies. Therefore, the current research is focused on safety dose evaluation for the first-time of the whole-plant methanol extract (EDME) of E. diffusum through appropriate in silico, in vitro, and in vivo approaches. METHOD: The whole plant, along with its rhizomes, was collected, and the methanol extract was prepared. The in silico ADMET study was performed to predict the pharmacokinetics profile and toxicity of all the identified phyto-compounds of EDME previously screened by GC-MS study. In vitro cytotoxicity study of EDME was performed using two cell lines: kidney (HEK293) and liver (Huh7) cell lines. The in vivo toxicity study of EDME was validated by the acute toxicity (OECD 423, 2002) and sub-acute toxicity assays (OECD 407, 2008) in the Wistar Albino rat model. RESULTS: The in silico ADMET study of all 47 bioactives predicted good pharmacokinetic and low toxicity profiles. In vitro cytotoxicity showed higher IC50 values of EDME viz., 672 ± 15.7 µg/mL and 1698 ± 6.54 µg/mL for both kidney (HEK293) and liver (Huh7) cell lines, respectively, which were considered as low-toxic. Based on acute oral toxicity, the LD50 value of the extract was considered "non-toxic" up to a feeding range of 2000 mg/kg of body weight. The regular consumption of the extract for an extended period (28 days) was also qualified as safe based on the body and organ weight, hematological, biochemical, and histoarchitecture results in the sub-acute toxicity assay. CONCLUSION: The detailed in silico, in vitro, in vivo (acute and sub-acute oral toxicity) studies gave us a new insight to the safety dose evaluation of Equisetum diffusum, which may serve as a reliable documentation for undertaking the experimental validation of the ethnobotanical uses of the plant which would help in the field of drug development for the treatment of inflammation related complications.

Ag Intercalation in Layered Cs3Bi2Br9 Perovskite for Enhanced Light Emission with Bound Interlayer Excitons.

Cesium bismuth bromide (CBB) has garnered considerable attention as a vacancy-ordered layered perovskite with notable optoelectronic applications. However, its use as a light source has been limited due to its weak photoluminescence (PL). Here, we demonstrate metal intercalation as a novel approach to engineer the room-temperature PL of CBB using experimental and computational methods. Ag, when introduced into CBB, occupies vacant sites in the spacer region, forming octahedral coordination with surrounding Br anions. First-principles density functional theory calculations reveal that intercalated Ag represents the most energetically stable Ag species compared to other potential forms, such as Ag substituting Bi. The intercalated Ag forms a strong polaronic trap state close to the conduction band minimum and quickly captures photoexcited electrons with holes remaining in CBB layers, leading to the formation of a bound interlayer exciton, or BIE. The radiative recombination of this BIE exhibits bright room-temperature PL at 600 nm and a decay time of 38.6 ns, 35 times greater than that of free excitons, originating from the spatial separation of photocarriers by half a unit cell separation distance. The BIE as a new form of interlayer exciton is expected to inspire new research directions for vacancy-ordered perovskites.

Nanogels as novel drug nanocarriers for CNS drug delivery.

Nanogels are highly recognized as adaptable drug delivery systems that significantly contribute to improving various therapies and diagnostic examinations for different human diseases. These three-dimensional, hydrophilic cross-linked polymers have the ability to absorb large amounts of water or biological fluids. Due to the growing demand for enhancing current therapies, nanogels have emerged as the next-generation drug delivery system. They effectively address the limitations of conventional drug therapy, such as poor stability, large particle size, and low drug loading efficiency. Nanogels find extensive use in the controlled delivery of therapeutic agents, reducing adverse drug effects and enabling lower therapeutic doses while maintaining enhanced efficacy and patient compliance. They are considered an innovative drug delivery system that highlights the shortcomings of traditional methods. This article covers several topics, including the involvement of nanogels in the nanomedicine sector, their advantages and limitations, ideal properties like biocompatibility, biodegradability, drug loading capacity, particle size, permeability, non-immunological response, and colloidal stability. Additionally, it provides information on nanogel classification, synthesis, drug release mechanisms, and various biological applications. The article also discusses barriers associated with brain targeting and the progress of nanogels as nanocarriers for delivering therapeutic agents to the central nervous system.

The Diabetes-Heart Disease Connection: Recent Discoveries and Implications.

Diabetes and heart disease are 2 prevalent and interconnected conditions with a significant global burden. Understanding the relationship between diabetes and heart disease is crucial for effective management and prevention strategies. This article provides an overview of the 2 conditions, highlighting their types, risk factors, and global prevalence. Recent research findings establish a strong correlation between diabetes and various aspects of cardiovascular health, including coronary artery disease, heart failure, and stroke. Mechanisms such as insulin resistance, inflammation, and oxidative stress contribute to the interplay between diabetes and heart disease. The implications for clinical practice underscore the importance of early detection, risk assessment, and comprehensive management of both conditions. Lifestyle modifications, such as diet, exercise, and weight management, are essential interventions. Pharmacological interventions, including antidiabetic drugs and cardiovascular medications, play a crucial role in treatment. Managing diabetes and heart disease simultaneously poses challenges that require interdisciplinary collaboration among endocrinologists, cardiologists, and primary care physicians. Ongoing research explores personalized medicine and targeted therapies as potential future directions. Continued research and awareness are paramount to mitigate the impact of the diabetes-heart disease connection and improve patient outcomes.

Transforming growth factor beta orchestrates PD-L1 enrichment in tumor-derived exosomes and mediates CD8 T-cell dysfunction regulating early phosphorylation of TCR signalome in breast cancer.

Tumor cells promote immune evasion through upregulation of programmed death-ligand 1 (PD-L1) that binds with programmed cell death protein 1 (PD1) on cytotoxic T cells and promote dysfunction. Though therapeutic efficacy of anti-PD1 antibody has remarkable effects on different type of cancers it is less effective in breast cancer (BC). Hence, more details understanding of PD-L1-mediated immune evasion is necessary. Here, we report BC cells secrete extracellular vesicles in form of exosomes carry PD-L1 and are highly immunosuppressive. Transforming growth factor beta (TGF-ß) present in tumor microenvironment orchestrates BC cell secreted exosomal PD-L1 load. Circulating exosomal PD-L1 content is highly correlated with tumor TGF-ß level. The later also found to be significantly associated with CD8+CD39+, CD8+PD1+ T-cell phenotype. Recombinant TGF-ß1 dose dependently induces PD-L1 expression in Texos in vitro and blocking of TGF-ß dimmed exosomal PD-L1 level. PD-L1 knocked down exosomes failed to suppress effector activity of activated CD8 T cells like tumor exosomes. While understanding its effect on T-cell receptor signaling, we found siPD-L1 exosomes failed to block phosphorylation of src family proteins, linker for activation of T cells and phosphoinositide phospholipase Cγ of CD8 T cells more than PD-L1 exosomes. In vivo inhibition of exosome release and TGF-ß synergistically attenuates tumor burden by promoting Granzyme and interferon gamma release in tumor tissue depicting rejuvenation of exhausted T cells. Thus, we establish TGF-ß as a promoter of exosomal PD-L1 and unveil a mechanism that tumor cells follow to promote CD8 T-cell dysfunction.

Oxidant mediated one-step complete conversion of multi-walled carbon nanotubes to graphene quantum dots and their bioactivity against mammalian and bacterial cells.

It is essential for any antibacterial agent (for clinical applications) that it should have high and selective toxicity towards bacterial cells only, and should not affect the human cells at the concentration used. Graphene quantum dots (GQDs) have emerged as a potential candidate for biomedical applications. However, a simple, low cost, safe, easy to execute, one-step synthesis of uniform and monodispersed GQDs with selective toxicity towards bacterial cells rather than mammalian cells is difficult to achieve. Herein, we have reported a one-step, low-cost, aqueous-phase, simple approach for the complete conversion of multi-walled carbon nanotubes into water-dispersible GQDs with an average size of ∼3 nm using sodium bismuthate (NaBiO3) as a strong oxidant. The cyclic voltammetry and X-ray photoelectron spectroscopy results indicated that the as-synthesized GQDs suspension possess almost negligible amounts of metallic impurities. The cytotoxicity studies of GQDs against mammalian NIH 3T3 (mouse embryo fibroblast cells) and HEK 293T (human embryonic kidney cells) cells showed that the as-synthesized GQDs were non-cytotoxic up to the concentration of ∼200 µg mL-1. The antimicrobial study shows that the synthesized GQDs have high and selective toxicity towards bacterial cells with a minimum inhibitory concentration of ∼256 µg mL-1 for E. coli and B. subtilis and ∼512 µg mL-1 for P. aeruginosa and S. aureus. The scanning electron microscopy and atomic force microscopy images show extensive cell damage via the perturbation of bacterial cell walls, which was consistent with the enhancement of reactive oxygen species production by almost two times in the bacterial cells upon incubation with ∼256 µg mL-1 GQDs. Our study suggested that the as-synthesized GQDs can be used as a potential candidate for clinical applications as they possess high toxicity to bacterial cells and low toxicity to mammalian cells.