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Diabetic nephropathy (DN), an end-stage renal disorder, has posed a menace to humankind globally, because of its complex nature and poorly understandable intricate mechanism. In recent times, functional foods as potential health benefits have been gaining attention of consumers and researchers alike. Rich in antioxidants, the peel and seed of pomegranate have previously demonstrated protection against oxidative-stress-related diseases, including cardiovascular disorders, diabetes, and cancer. This study was designed to investigate the ameliorative role of pomegranate peel extract-stabilized gold nanoparticle (PPE-AuNP) on streptozotocin (STZ)-induced DN in an experimental murine model. Following the reduction methods, AuNP was prepared using the pomegranate peel ellagitannins and characterized by particle size, physical appearance, and morphological architecture. Modulatory potential of PPE-AuNP was examined through the plethora of biochemical and high throughput techniques, flow cytometry, immunoblotting, and immunofluorescence. The animals treated with PPE-AuNP markedly reduced the fasting blood glucose, renal toxicity indices, and serum TC and TG in a hyperglycemic condition. As evident from an increased level of plasma insulin level, PPE-AuNP normalized the STZ-induced pancreatic β-cell dysfunction. The STZ-mediated suppression of endogenous antioxidant response was restored by the PPE-AuNP treatment, which reduced the generation of LPO as well as iROS. Furthermore, the hyperglycemia-mediated augmentation of protein glycation, followed by the NOX4/p-47 activation, diminished with the application of PPE-AuNP. The histological and immunohistochemical findings showed the protective efficacy of PPE-AuNP in reducing STZ-induced glomerular sclerosis and renal fibrosis. In addition, it reduced proinflammatory burden through the modulation of the MAPK/NF-κB/STAT3/cytokine axis. Simultaneously, PI3K/AKT-guided Nrf2 activation was evident upon the PPE-AuNP application, which enhanced the antioxidant response and maintained hyperglycemic homeostasis. The findings indicate that the use of PPE-AuNPs might act as an economic therapeutic remedy for alleviating DN.

Gold nanoparticles are predominantly used in diagnostics, therapeutics and biomedical applications. The present study has been designed to synthesize differently capped gold nanoparticles (AuNps) by a simple, one-step, room temperature procedure and to evaluate the potential of these AuNps for biomedical applications. The AuNps are capped with glucose, 2-deoxy-D-glucose (2DG) and citrate using different reducing agents. This is the first report of synthesis of 2DG-AuNp by the simple room temperature method. The synthesized gold nanoparticles are characterized with UV-Visible Spectroscopy, Fourier transform infrared spectroscopy (FTIR), Transmission electron microscopy (TEM) and selected area electron diffraction (SAED), Dynamic light scattering (DLS), and Energy-dispersive X-ray spectroscopy (SEM-EDS). Surface-enhanced Raman scattering (SERS) study of the synthesized AuNps shows increase in Raman signals up to 50 times using 2DG. 3-(4, 5-dimethylthiozol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay has been performed using all the three differently capped AuNps in different cell lines to assess cytotoxcity if any, of the nanoparticles. The study shows that 2DG-AuNps is a better candidate for theranostic application.

N-rich organic materials bearing polyphenolic moieties in their building networks and nanoscale porosities are very demanding in the context of designing efficient biomaterials or drug carriers for the cancer treatment. Here, we report the synthesis of a new triazine-based secondary-amine- and imine-linked polyphenolic porous organic polymer material TrzTFPPOP and explored its potential for in vitro anticancer activity on the human colorectal carcinoma (HCT 116) cell line. This functionalized (-OH, -NH-, -C=N-) organic material displayed an exceptionally high BET surface area of 2140 m2 g−1 along with hierarchical porosity (micropores and mesopores), and it induced apoptotic changes leading to high efficiency in colon cancer cell destruction via p53-regulated DNA damage pathway. The IC30, IC50, and IC70 values obtained from the MTT assay are 1.24, 3.25, and 5.25 μg/mL, respectively.

Grape Seed Extract is a natural source of various polyphenols, which have been shown to possess potent antioxidant and free radical-scavenging activities. The earlier studies have reported that grape seed extract exhibits broad-spectrum pharmacological activities. Therefore, studying the hepatoprotective effects and elucidation of mechanisms of action of the Indian Variety, Manjari Medika grape seed extract (GSE), may give an insight into therapeutic benefits. Methotrexate (MTX) is the first-line pharmacological therapy for different rheumatic diseases. The major adverse events such as hepatotoxicity are evident even in the low doses used for the treatment. The present study investigated the role of MTX on hepatic damage in murine liver and the plausible protective effects of the Indian grape variety, Manjari Medika grape seed extract, in ameliorating it. To assess the hepatological modulation, mice were divided into eight groups to investigate the ameliorative potential of this GSE (75 and 125 mg/kg) and correlate the experimental findings. The active components of the extract were assessed through UPLC-(ESI)-QToF-MS analysis. On the other hand, various biochemical and immunological indices were carried out to correlate the experimental data. The result demonstrated that the prophylactic administration of GSE reduced MTX-induced hepatic toxicity indices, which subsequently restored the hepatic morphological architecture. Moreover, the application of GSE in a dual dosage (75 and 125 mg/kg) suppressed MTX-induced reactive oxygen species generation, followed by lipid peroxidation and cellular nitrite formation. MTX-induced inflammasome activation through the redox-assisted cascade of TLR4/NF-κB signaling was further reduced by applying the GSE. The results showed that the activation of cytoprotective transcription factor Nrf2 enhanced the level of endogenous antioxidants. Furthermore, through the regulation of TLR4/NF-κB and Nrf2/HO-1 axis, this extract could reduce the MTX-mediated hepatic damage. Our findings suggest that Manjari Medika seed extract could be used as a therapeutic agent to relieve the side effects of MTX and other hepatic disorders.

Many of present chemotherapeutics are inadequate and also resistant against visceral leishmaniasis (VL), an immunosuppressive ailment caused by . Despite the interest in plant-based drug development, no antileishmanial drugs from plant source are currently available. had been reported in favor of being immune modulators along with other traditional uses. Novel anti-VL therapies can rely on host immune-modulation with associated leishmanicidal action. Discovery of novel plant-based antileishmanial compound from having permissible side effects. With this rationale, an n-BuOH fraction of the methanolic extract of were evaluated against acellular and intracellular . Immunostimulatory activity of them was confirmed by elevated TNF-α and extracellular NO production from treated MФs and was found nontoxic to the host cells. Identification and structure confirmation for isolated Spergulin-A was performed by ESI-MS, C, and H NMR. Spergulin-A was found ineffective against the acellular forms while, against the intracellular parasites at 30 μg/mL, the reduction was 92.6% after 72 hrs. Spergulin-A enhanced ROS and nitric oxide (NO) release and changes in Gp91-phox, i-NOS, and pro and anti-inflammatory cytokines elaborated its intracellular anti-leishmanial activity. The results supported that can potentiate new lead molecules for the development of alternative drugs against VL.

Objective: Grape Seed Extract is a natural source of various polyphenols, which have been shown to possess potent antioxidant and free radical-scavenging activities. The earlier studies have reported that grape seed extract exhibits broad-spectrum pharmacological activities. Therefore, studying the hepatoprotective effects and elucidation of mechanisms of action of the Indian Variety, Manjari Medika grape seed extract (GSE), may give an insight into therapeutic benefits. Methotrexate (MTX) is the first-line pharmacological therapy for different rheumatic diseases. The major adverse events such as hepatotoxicity are evident even in the low doses used for the treatment. The present study investigated the role of MTX on hepatic damage in murine liver and the plausible protective effects of the Indian grape variety, Manjari Medika grape seed extract, in ameliorating it. Methods and Results: To assess the hepatological modulation, mice were divided into eight groups to investigate the ameliorative potential of this GSE (75 and 125 mg/kg) and correlate the experimental findings. The active components of the extract were assessed through UPLC-(ESI)-QToF-MS analysis. On the other hand, various biochemical and immunological indices were carried out to correlate the experimental data. The result demonstrated that the prophylactic administration of GSE reduced MTX-induced hepatic toxicity indices, which subsequently restored the hepatic morphological architecture. Moreover, the application of GSE in a dual dosage (75 and 125 mg/kg) suppressed MTX-induced reactive oxygen species generation, followed by lipid peroxidation and cellular nitrite formation. MTX-induced inflarnmasome activation through the redox-assisted cascade of TLR4/NF-[kappa]B signaling was further reduced by applying the GSE. The results showed that the activation of cytoprotective transcription factor Nrf2 enhanced the level of endogenous antioxidants. Furthermore, through the regulation of TLR4/NF-KB and Nrf2/HO-1 axis, this extract could reduce the MTX-mediated hepatic damage. Conclusion: Our findings suggest that Manjari Medika seed extract could be used as a therapeutic agent to relieve the side effects of MTX and other hepatic disorders. Keywords: hepatic fibrosis, Kupffer cells, Manjari Medika grape seed extract, proanthocyanidins, inflarnmasome, antioxidant response

Consumptive hypothyroidism, a rare pediatric disorder, arises from aberrant Dio3 expression, which inactivates thyroid hormones and disrupts skeletal development. This study investigates the regulatory role of the long non-coding RNA Dio3os, which activates Dio3 in cis and suppresses osteoblast differentiation in trans. We focused on mouse Dio3os variant 203 and human variants 203 and 205. Chromatin accessibility and histone modification analyses revealed higher chromatin openness and active histone H3 modifications at the Dio3os promoter and exons 2 and 3, followed by increased RUNX2 binding with reduced histone H3 modifications during maturation. Dio3os expression is enhanced by HDAC1/2, HIF1a, and thyroid hormones, but repressed by BMP2, TGFb, Runx2, and Brg1. Overexpression of Dio3os upregulated Dio3 while downregulating osteogenic markers. CRISPR-mediated deletion of Dio3os exons or premature intronic polyadenylation suppressed Dio3 and restored osteogenic gene expression. RNA-seq and ATAC-seq confirmed enhanced thyroid hormone-responsive osteoblast gene activity in Dio3os-CRISPR-knockout cells. These findings reveal Dio3os as a key regulator of thyroid hormone metabolism and bone formation, presenting a novel target for treating skeletal abnormalities in early childhood hypothyroidism.

Although GBM's immunosuppressive environment is well known, the tumor's resistance to CD8+ T cell killing is not fully understood. Our previous study identified Checkpoint Kinase 2 (Chek2) as the key driver of CD8+ T cell resistance in mouse glioma through an in vivo CRISPR screen and demonstrated that Chk2 inhibition, combined with PD-1/PD-L1 blockade, significantly enhanced CD8+ T cell-mediated tumor killing and improved survival in preclinical model. Here, we aimed to elucidate the immunosuppressive function of Chek2. Immunoprecipitation (IP) followed by mass spectrometry (MS) and phosphoproteomics identified an association between Chek2 with the DNA/RNA-binding proteins YBX1 and YBX3 that are implicated in transcriptional repression of pro-inflammatory genes. Single-gene knock-out and overexpression studies of CHEK2, YBX1, and YBX3 in multiple glioma cell lines revealed that these proteins positively regulate each other's expression. RNA sequencing coupled with chromatin immunoprecipitation-sequencing (ChIP-seq) analysis demonstrated common inflammatory genes repressed by CHK2-YBX1&YBX3 hub. Targeting one of the hub proteins, YBX1, with the YBX1 inhibitor SU056 led to degradation of CHK2-YBX1&YBX3 hub. Targeting of this hub by SU056 led to enhanced antigen presentation and antigen specific CD8+ T cell proliferation. Further, combination of SU056 with ICB significantly improved survival in multiple glioma models. Collectively, these findings reveal an immunosuppressive mechanism mediated by the CHK2-YBX1&YBX3 hub proteins. Therefore, CHK2-YBX1&YBX3 hub targeting in combination with immune checkpoint blockade therapies in gliomas is warranted.

While peptide-based drug development is now extensively explored, this strategy does have limitations, which come from their rapid excretion from the body (or shorter half-life in the body), and vulnerability to protease-mediated degradation. To overcome these limitations, here we introduce a novel strategy for the development of a peptide-based anticancer agent using the conformation switch property of a chameleon sequence stretch, which we derived from a mycobacterium secretory protein, MPT63. Then, we loaded this peptide in a new porous organic polymer (PG-DFC-POP) synthesized using phloroglucinol and acresolderivative via condensation reaction for delivering the peptide selectively to the cancer cells. Employing an ensemble and single molecule approaches, we demonstrate that this peptide undergoes a disordered to alpha-helical conformational transition, which is triggered by a low pH environment inside cancer cells. This adopted alpha-helical conformation results in the formation of proteolysis-resistant oligomers, which show efficient membrane pore-forming activity selectively for negatively charged phospholipid which is accumulated in cancer cell membrane. Our in vitro and in vivo experimental results demonstrate that the peptide-loaded nanomaterial PG-DFC-POP-PEP 1 exhibits significant cytotoxicity in cancer cells, leading to cell death through the Pyroptosis pathway that is confirmed by monitoring numerous associated events starting from lysosome membrane damage to GSDMD-induced cell membrane demolition. We believe that this novel conformational switch-based drug design strategy has great potential in endogenous environment-responsive cancer therapy and the development of future drug candidates to mitigate cancers.Competing Interest StatementThe authors have declared no competing interest.

Effect of pH and high-pressure process treatments viz. pressure, temperature, and dwell time on inactivation of polyphenoloxidase (PPO), peroxidase (POD), bromelain (BRM), and pectinmethylesterase (PME) in pineapple puree was studied. Experiments were conducted according to rotatable central composite design (RCCD) within the range (− α to +  α ) of 100–600 MPa, 20–70 °C, and 0–30 min at three different pH levels (3.0, 3.5, and 4.0) followed by analysis through response surface methodology (RSM). Enzyme inactivation was significantly ( p  < 0.05) affected by all the process parameters, and temperature had the highest contribution among those. Enzyme inactivation kinetics was demonstrated with dynamic pressure-buildup period (pressure pulse effect) followed by static pressure-hold period (isobaric-isothermal first-order inactivation). Increased pulse effect (PE in log scale) values were obtained at lower pH and higher values of both pressure and temperature. Maximum PE values, obtained at 500 MPa/60 °C/pH 3, were 0.332, 0.319, 0.392, and 0.278 for PPO, POD, PME, and BRM, respectively. The inactivation rate ( k in min −1 ) revealed that PPO was the most resistive ( k ranged between 0.0020 and 0.0379 min −1 ) when compared with other three enzymes within the experimental domain. Increased k at lower pH with constant pressure and temperature depicted that pH had negative effect on the inactivation process. The optimized conditions targeting maximum inactivation of PPO, POD and PME with simultaneous retention of BRM in pineapple puree, were 600 MPa/60 °C/9 min, 600 MPa/60 °C/10 min and 600 MPa/60 °C/10 min for the samples of pH 3.0, 3.5, and 4.0, respectively.