Potential Treatment Research Articles

Lobetyolin protects mice against LPS-induced sepsis by downregulating the production of inflammatory cytokines in macrophage

Introduction: Sepsis is a clinical syndrome characterized by dysregulation of the host immune response due to infection, resulting in life-threatening organ damage. Despite active promotion and implementation of early preventative measures and bundle treatments, sepsis continues to exhibit high morbidity and mortality rates with no optimal pharmacological intervention available. Lobetyolin (LBT), the crucial component of polyacetylenes found in Codonopsis pilosula, has been scientifically proven to possess potent antioxidant and antitumor properties. However, its therapeutic potential for sepsis remains unknown.Methods: The mice received pretreatment with intraperitoneal injections of LBT, followed by injection with lipopolysaccharide (LPS) to induce sepsis. Peripheral blood samples were collected to detect TNF-α, IL-1β, and IL-6 levels. The survival status of different groups was recorded at various time intervals. RNA-Seq was utilized for the analysis of gene expression in peritoneal macrophages treated with LBT or LPS.Results: In this study, we observed a significant increase in the survival rate of mice pretreated with LBT in LPS induced sepsis mouse model. LBT demonstrated a remarkable reduction in the production of IL-6, TNF-α, and IL-1β in the serum, along with mitigated lung and liver tissue damage characterized by reduced inflammatory cell infiltration. Additionally, through RNA-seq analysis coupled with GO and KEGG analysis, it was revealed that LBT effectively suppressed genes associated with bacterium presence, cellular response to lipopolysaccharide stimulation, as well as cytokine-cytokine receptor interaction involving Cxcl10, Tgtp1, Gbp5, Tnf, Il1b and IRF7 specifically within macrophages. We also confirmed that LBT significantly downregulates the expression of IL-6, TNF-α, and IL-1β in macrophage activation induced by LPS.Discussion: Therefore, our findings demonstrated that LBT effectively inhibits the production of inflammatory cytokines (IL-6, TNF-α, and IL-1β) and mitigates sepsis induced by LPS through modulating macrophages' ability to generate these cytokines. These results suggest that LBT holds promise as a potential therapeutic agent for sepsis treatment.

Glycyrrhetinic Acid as a Hepatocyte Targeting Ligand-Functionalized Platinum(IV) Complexes for Hepatocellular Carcinoma Therapy and Overcoming Multidrug Resistance.

Promising targeted therapy options to overcome drug resistance and side effects caused by platinum(II) drugs for treatment in hepatocellular carcinoma are urgently needed. Herein, six novel multifunctional platinum(IV) complexes through linking platinum(II) agents and glycyrrhetinic acid (GA) were designed and synthesized. Among them, complex 20 showed superior antitumor activity against tested cancer cells including cisplatin resistance cells than cisplatin and simultaneously displayed good liver-targeting ability. Moreover, complex 20 can significantly cause DNA damage and mitochondrial dysfunction, promote reactive oxygen species generation, activate endoplasmic reticulum stress, and eventually induce apoptosis. Additionally, complex 20 can effectively inhibit cell migration and invasion and trigger autophagy and ferroptosis in HepG-2 cells. More importantly, complex 20 demonstrated stronger tumor inhibition ability than cisplatin or the combo of cisplatin/GA with almost no systemic toxicity in HepG-2 or A549 xenograft models. Collectively, complex 20 could be developed as a potential anti-HCC agent for cancer treatment.

Naphthoquinones and anthraquinones: Exploring their impact on acetylcholinesterase enzyme activity.

The identification of novel acetylcholinesterase inhibitors holds significant relevance in the treatment of Alzheimer's disease (AD), the prevailing form of dementia. The exploration of alternative inhibitors to the conventional acetylcholinesterase inhibitors is steadily gaining prominence. Quinones, categorized as plant metabolites, represent a specific class of compounds. In this study, the inhibitory effects of various naphthoquinone derivatives, along with anthraquinone and its derivatives, on the acetylcholinesterase (AChE) enzyme were investigated for this purpose. An in vitro investigation was conducted to examine the effects of these compounds in order to clarify the possible mechanism of inhibition in the interaction between the enzyme and chemicals. In addition, an in silico investigation was carried out to understand the conceivable inhibitor binding process to the enzyme's active site. The acquired outcomes corroborated the in vitro results. The AChE enzyme was found to be effectively inhibited by both naphthoquinones and anthraquinones, with inhibition constant (KI) values ranging from 0.014 to 0.123μM (micormolar). The AChE enzyme was inhibited differently by this quinone and its derivatives. Although derivatives of naphthoquinone and anthraquinone exhibited a competitive inhibitory effect, derivatives of anthraquinone exhibited a noncompetitive inhibition effect. Furthermore, because it had the lowest KI value of any of these substances, 1,5-dihydroxyanthraquinone (1c) was shown to be the most potent inhibitor. The findings will add to the body of knowledge on the creation of fresh, potent, and successful treatment approaches.

Pharmacological inhibition of STING reduces neuroinflammation-mediated damage post-traumatic brain injury.

Traumatic brain injury (TBI) remains a major public health concern worldwide with unmet effective treatment. Stimulator of interferon genes (STING) and its downstream type-I interferon (IFN) signalling are now appreciated to be involved in TBI pathogenesis. Compelling evidence have shown that STING and type-I IFNs are key in mediating the detrimental neuroinflammatory response after TBI. Therefore, pharmacological inhibition of STING presents a viable therapeutic opportunity in combating the detrimental neuroinflammatory response after TBI. This study investigated the neuroprotective effects of the small-molecule STING inhibitor n-(4-iodophenyl)-5-nitrofuran-2-carboxamide (C-176) in the controlled cortical impact mouse model of TBI in 10- to 12-week-old male mice. Thirty minutes post-controlled cortical impact surgery, a single 750-nmol dose of C-176 or saline (vehicle) was administered intravenously. Analysis was conducted 2h and 24 h post-TBI. Mice administered C-176 had significantly smaller cortical lesion area when compared to vehicle-treated mice 24 h post-TBI. Quantitative temporal gait analysis conducted using DigiGait™ showed C-176 administration attenuated TBI-induced impairments in gait symmetry, stride frequency and forelimb stance width. C-176-treated mice displayed a significant reduction in striatal gene expression of pro-inflammatory cytokines Tnf-α, Il-1β and Cxcl10 compared to their vehicle-treated counterparts 2h post-TBI. This study demonstrates the neuroprotective activity of C-176 in ameliorating acute neuroinflammation and preventing white matter neurodegeneration post-TBI. This study highlights the therapeutic potential of small-molecule inhibitors targeting STING for the treatment of trauma-induced inflammation and neuroprotective potential.

Activity of hydrogel-vitamin D3 /bacterioruberin nanoparticles on imiquimod-induced fibroblasts-keratinocytes spheroids

Topical administration of vitamin D3 (VD3) analogs and corticosteroids is the mainstay treatment for mild localized psoriasis. VD3 however is an unstable class II drug (insoluble and permeable), classically formulated as unattractive viscous and oil-based ointments or creams. In this work, nanostructured archaeolipid carriers (NAC) with a core loaded with VD3 and the C50 dipolar carotenoid from halophilic archaea bacterioruberin (BR): NAC-VD3, were formulated into a carbopol hydrogel: gNAC-VD3. After its rheological characterization, its anti-inflammatory and antioxidant activity was assessed on bi-cellular spheroids, consisting of a core of fibroblasts surrounded by a ring of keratinocytes activated with imiquimod (IMQ) as a psoriasis model. gNAC-VD3 (0.8 mg VD3/135 μg BR/gram gel) conserved the antioxidant activity, showed pseudoplastic non-Newtonian behaviour, stability over time, good occlusion capacity and spreadability, all suitable properties for topical application in patients with psoriasis. gNAC-VD3 did not decrease the viability of spheroids but significantly reduced the release of proinflammatory cytokines (IL-8, IL-6, TNF-α), oxidative stress (ROS), and matrix metalloproteinases from IMQ-induced spheroids to levels similar to the uninduced spheroids. Results suggest that gNAC-VD3 may constitute a potential anti-inflammatory agent for the topical treatment of mild psoriasis and deserves further in vivo exploration.

At the Forefront: Social Workers' Role in Psilocybin Treatment for Depression and Substance Misuse.

This article underscores the critical role of social workers in harnessing the potential therapeutic benefits of psilocybin for treating major depressive disorder (MDD) and substance use disorder (SUD). Contemporary treatments for MDD often have side effects, and the success rate for SUD treatments remains low. The pervasiveness of MDD, combined with the challenges in treating SUD, highlights a need for innovative treatments. This article provides an overview of the resurgence of literature over the past two decades that illuminates the therapeutic promise of psilocybin for mental health treatment; clinical trials elucidate the efficacy of psilocybin-assisted therapy in mitigating MDD and demonstrate great promise in reducing SUD symptoms. The long-lasting posttreatment effect emphasizes its potential as a novel treatment modality. Furthermore, psilocybin's recognition as a "breakthrough therapy" by the U.S. Food and Drug Administration (FDA) and the accelerating pace of psychedelic reform bills indicate growing acceptance and interest in its therapeutic capacities. Psilocybin-assisted therapy emerges as a potent treatment option, showcasing remarkable effectiveness even after a single dose. Recommendations and pathways for social workers to be involved in psilocybin-assisted therapy investigation, advocacy, and implementation are provided.

Investigation of FABr treatment's potential for triple-cation multi-halide perovskite solar cells

In order to preserve the effectual potential of triple-cation coupled with multi-halide perovskites (PVTs), the phase-related conflict amongst different precursors have to be resolved. There arises the necessity of post-growth passivation treatments, especially using formamidinium bromide (FABr) upon such PVT films. In this research, a methodical comparison assessment is performed on triple-cation, multi-halide (CsFAMAPbIBr)-based PVT solar cells (PSCs) with and without FABr passivation using numerical study. A meticulous estimation of all the performance parameters of both PSCs were implemented in accordance with transformations in thickness, effective density, and acceptor density of the PVT absorber layer together with the charge transport layer thickness variations. The investigation revealed that the charge carrier generation rate remained the same after FABr passivation, however,the recombination rate was lowered by ∼ 32 % (from 7.27 × 1021 to 4.92 × 1021 cm-3s−1). The analysis discerned that at minimum valence band effective density of PVT absorber: 1 × 1017 cm−3, FABr-treated CsFAMAPbIBr-based PSC ensures the highest power conversion efficiency of 24.62 % against its un-passivated correspondent of 22.25 %. Further, this investigation imparts the remarkableness of FABr passivation treatment in regulating the overall performance of triple-cation and multi-halide-based PSCs.

Adjudin protects blood–brain barrier integrity and attenuates neuroinflammation following intracerebral hemorrhage in mice

Secondary brain injury exacerbates neurological dysfunction and neural cell death following intracerebral hemorrhage (ICH), targeting the pathophysiological mechanism of the secondary brain injury holds promise for improving ICH outcomes. Adjudin, a potential male contraceptive, exhibits neuroprotective effects in brain injury disease models, yet its impact in the ICH model remains unknown. In this study, we investigated the effects of adjudin on brain injury in a mouse ICH model and explored its underlying mechanisms. ICH was induced in male C57BL/6 mice by injecting collagenase into the right striatum. Mice received adjudin treatment (50 mg/kg/day) for 3 days before euthanization and the perihematomal tissues were collected for further analysis. Adjudin significantly reduced hematoma volume and improved neurological function compared with the vehicle group. Western blot showed that Adjudin markedly decreased the expression of MMP-9 and increased the expression of tight junctions (TJs) proteins, Occludin and ZO-1, and adherens junctions (AJs) protein VE-cadherin. Adjudin also decreased the blood–brain barrier (BBB) permeability, as indicated by the reduced albumin and Evans Blue leakage, along with a decrease in brain water content. Immunofluorescence staining revealed that adjudin noticeably reduced the infiltration of neutrophil, activation of microglia/macrophages, and reactive astrogliosis, accompanied by an increase in CD206 positive microglia/macrophages which exhibit phagocytic characteristics. Adjudin concurrently decreased the generation of proinflammatory cytokines, such as TNF-α and IL-1β. Additionally, adjudin increased the expression of aquaporin 4 (AQP4). Furthermore, adjudin reduced brain cell apoptosis, as evidenced by increased expression of anti-apoptotic protein Bcl-2, and decreased expression of apoptosis related proteins Bax, cleaved caspase-3 and fewer TUNEL positive cells. Our data suggest that adjudin protects against ICH-induced secondary brain injury and may serve as a potential neuroprotective agent for ICH treatment.

Gastrointestinal Tract and Kidney Injury Pathogenesis in Post-COVID-19 Syndrome.

COVID-19 is a global health emergency that requires worldwide collaboration to control its spread. The scientific community is working to understand the different aspects of the post-COVID-19 syndrome and potential treatment strategies. Interestingly, there have been reports of gastrointestinal tract (GIT) involvement in the post-COVID-19 syndrome, suggesting the presence of both severe and mild GIT disorders. The development of the post-COVID-19- GIT syndrome involves various factors, such as impaired GIT mucosa cells, disruptions in the feeling of satiety, reduced blood supply due to the formation of small blood clots, and increased prostaglandin secretion caused by an excessive immune response. GIT symptoms have been observed in around 16% of COVID-19 patients. Other complications include kidney damage and prolonged impairment in the filtration and excretion functions of the glomeruli and tubules. The pathogenesis of post-COVID-19 renal syndrome involves factors, like an overactive immune response, reduced lung perfusion and oxygenation, viral infection in kidney tissues, endothelial dysfunction, and decreased blood volume. Roughly 20% of hospitalized patients experience renal manifestations after recovering from COVID-19.

Pancreatic Cancer: A Review on Pathophysiology, Naturopathy, Clinical Treatment and Outcomes

Abstract: The study aimed to comprehend the molecular mechanisms and pathophysiology of pancreatic cancer with an emphasis on the advances in treatment options and the use of natural products as anticancer agents. The study involved a literature survey using PubMed, Web of Science and Google scholar database. The literature search was done using keywords “Pancreatic cancer”, “Chemotherapy”, “Mutations”, and “Natural compounds”. 266 articles were studied of which 201 were taken into consideration based on relevance to the topic. Pancreatic cancer is associated with mutations of CDKN2A (encoding p16), KRAS, TP53 and SMAD4. MAPK, PI3K-AKT, and TGF- β pathway dysfunction also led to pancreatic cancer. Current clinical trial activities in pancreatic cancer target angiogenesis, surface receptors, cell cycle, DNA damage response, etc. Studies have shown that combining surgical resection with adjuvant chemotherapy increases survival rates in patients. New treatment options are on the rise for this cancer type, which is perioperative or neo-adjuvant therapy. Gemcitabine as a single treatment agent in pancreatic cancer has shown promising response with chemotherapy regimens using two combinations- Folfirinox and Gemcitabine/Nab-Paclitaxel giving a better response rate. Numerous natural substances, including curcumin, aloe vera, and taxol, which suppress oxidative stress, angiogenesis, JAK2 STAT3 pathways, and enhanced natural killer cell activity, have been explored as potential treatments for pancreatic cancer. With pancreatic cancer having a poor prognosis, investigations to comprehend its molecular underpinnings and research on natural chemicals could lead to the development of safer treatment alternatives with enhanced survival rates for pancreatic cancer patients.

Marine natural products: potential agents for depression treatment

Depression is a common psychiatric disorder. Due to the disadvantages of current clinical drugs, including poor efficacy and unnecessary side effects, research has shifted to novel natural products with minimal or no adverse effects as therapeutic alternatives. The ocean is a vast ecological home, with a wide variety of organisms that can produce a large number of natural products with unique structures, some of which have neuroprotective effects and are a valuable source for the development of new drugs for depression. In this review, we analyzed preclinical and clinical studies of natural products derived from marine organisms with antidepressant potential, including the effects on the pathophysiology of depression, and the underlying mechanisms of these effects. It is expected to provide a reference for the development of new antidepressant drugs.

Novel Inositol 1,4,5-Trisphosphate Receptor Inhibitor Antagonizes Hepatic Stellate Cell Activation: A Potential Drug to Treat Liver Fibrosis.

Liver fibrosis, characterized by excessive extracellular matrix (ECM) deposition, can progress to cirrhosis and increases the risk of liver cancer. Hepatic stellate cells (HSCs) play a pivotal role in fibrosis progression, transitioning from a quiescent to activated state upon liver injury, wherein they proliferate, migrate, and produce ECM. Calcium signaling, involving the inositol 1,4,5-trisphosphate receptor (IP3R), regulates HSC activation. This study investigated the efficacy of a novel IP3R inhibitor, desmethylxestospongin B (dmXeB), in preventing HSC activation. Freshly isolated rat HSCs were activated in vitro in the presence of varying dmXeB concentrations. The dmXeB effectively inhibited HSC proliferation, migration, and expression of fibrosis markers without toxicity to the primary rat hepatocytes or human liver organoids. Furthermore, dmXeB preserved the quiescent phenotype of HSCs marked by retained vitamin A storage. Mechanistically, dmXeB suppressed mitochondrial respiration in activated HSCs while enhancing glycolytic activity. Notably, methyl pyruvate, dimethyl α-ketoglutarate, and nucleoside supplementation all individually restored HSC proliferation despite dmXeB treatment. Overall, dmXeB demonstrates promising anti-fibrotic effects by inhibiting HSC activation via IP3R antagonism without adverse effects on other liver cells. These findings highlight dmXeB as a potential therapeutic agent for liver fibrosis treatment, offering a targeted approach to mitigate liver fibrosis progression and its associated complications.

Comparative Study of Cardiovascular Effects of Selected Pulmonary Vasodilators in Canine Models of Mitral Valve Disease

Previous reports have shown that various oral pulmonary vasodilators are effective against canine pulmonary hypertension (PH). However, no studies have compared their hemodynamic effects. We aimed to compare the hemodynamic effects of 15 µg/kg beraprost sodium, 1.0 mg/kg sildenafil, and their combination, in dogs with experimentally induced mitral regurgitation. This experimental crossover study evaluated the hemodynamic and functional effects of oral pulmonary vasodilators by application of right-sided heart catheterization and echocardiography. Beraprost significantly decreased pulmonary and systemic vascular resistance. Additionally, beraprost increased right-ventricular stroke volume and left-ventricular cardiac output without worsening left-heart size and left-atrial pressure. The pulmonary vasodilatory effects of sildenafil were stronger, and its systemic vasodilatory effects were weaker than those of beraprost. However, sildenafil significantly increased the left-ventricular volume, left-atrial pressure indicator, and right-ventricular cardiac output. Combination therapy resulted in the strongest pulmonary and systemic vasodilating effects without worsening the left-heart size and left-atrial pressure indicators. Both beraprost and sildenafil were effective against canine PH; however, sildenafil was associated with the risk of worsening left-heart loading. Combination therapy with beraprost and sildenafil synergistically dilated pulmonary and systemic vessels, indicating a more potent treatment option for severe PH cases.

Assessment of the in Vitro Effects of Folate Core-Shell Conjugated Iron Oxide Nanoparticles as a Potential Agent for Acute Leukemia Treatment.

There is a growing need to comprehend the potential outcomes of nanoparticles (NPs) on human well-being, including their potential for detecting and treating leukemia. This study examined the role of iron folate core-shell and iron oxide nanoparticles in inducing apoptosis and altering the expression of the B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X-protein (Bax), and Caspase-3 genes in leukemia cells. The obtained iron oxide and iron folate core-shell nanoparticles were analyzed using a variety of analytical techniques, including ultraviolet-visible (UV-Vis) absorption spectroscopy, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), dynamic light scattering (DLS), zeta potential, and transmission electron microscopy (TEM). Additionally, FTIR and UV-Vis were used to characterize doxorubicin. The MTT test was utilized to investigate the cytotoxicity of iron oxide and iron folate core-shell nanoparticles. The expression of the apoptotic signaling proteins Bcl-2, Bax, and Caspase-3 was evaluated using the real-time reverse transcription polymerase chain reaction (RT-qPCR) method. Additionally, flow cytometry was performed to gauge the degrees of necrosis and apoptosis. UV-Visible spectroscopy analysis showed that the generated iron oxide and iron folate core-shell NPs had a distinctive absorption curve in the 250-300 nm wavelength range. The XRD peaks were also discovered to index the spherical form with a size of less than 50 nm, which validated the crystal structure. The FTIR analysis determined the bonds and functional groups at wavenumbers between 400 and 4000 cm-1. A viable leukemia treatment approach is a nanocomposite consisting of iron and an iron folate core-shell necessary for inhibiting and activating cancer cell death. The nearly resistant apoptosis in the CCRF-CEM cells may have resulted from upregulating Bax and Casepase-3 while downregulating Bcl-2 expression. Our study documents the successful synthetization and characterization of iron oxide, which has excellent anticancer activities. A metal oxide conjugation with the nanoparticles' core-shell enhanced the effect against acute leukemia.

Efficient enzymatic synthesis of vitamin E succinate using an organic solvent‐stable immobilized lipase

AbstractVitamin E succinate has gained substantial attention as a potential therapeutic agent for cancer treatment due to its biomedical activities. One of the prominent methods of synthesizing vitamin E succinate is through enzymatic processes, which, although advantageous, presents inherent challenges related to optimization, scalability, and particularly, the poor stability of lipases in organic solvents. Our study addresses these challenges by conducting a comprehensive comparative analysis between Lipase UM1 and three other immobilized commercial lipases, demonstrating Lipase UM1's enhanced resistance to organic solvents and its superior efficiency in vitamin E succinate production. Further optimization experiments with Lipase UM1 led to an unprecedented conversion of 99%. Additionally, we scaled the reaction to a proof‐of‐concept industrial level. The synthesized product was verified using Fourier transform infrared spectroscopy and nuclear magnetic resonance analysis, ensuring its quality and consistency. This study validates Lipase UM1 as an efficient catalyst for vitamin E succinate synthesis, offering a promising avenue for industrial production with potential applications in cancer therapy and beyond.

RNA-mediated epigenetic regulation in exercised heart: Mechanisms and opportunities for intervention

Physical exercise has been widely acknowledged as a beneficial lifestyle alteration and a potent non-pharmacological treatment for heart disease. Extensive investigations have revealed the beneficial effects of exercise on the heart and the underlying mechanisms involved. Exercise is considered one of the key factors that can lead to epigenetic alterations. The increasing number of identified molecules in the exercised heart has led to many studies in recent years that have explored the cellular function of ncRNAs and RNA modifications in the heart. Investigating the regulatory role of RNA-mediated epigenetic regulation in exercised hearts will contribute to the development of therapeutic strategies for the management of heart diseases. This review aims to summarize the positive impact of exercise on cardiac health. We will first provide an overview of the mechanisms through which exercise offers protection to the heart. Subsequently, we will delve into the current understanding of ncRNAs, specifically miRNAs, lncRNAs, and circRNAs, as well as RNA modification, focusing on RNA m6A and RNA A-to-I editing, and how they contribute to exercise-induced benefits for the heart. Lastly, we will explore the emerging therapeutic strategies that utilize exercise-mediated RNA epigenetic regulation in the treatment of heart diseases, while also addressing the challenges faced in this field.

Dihydrotanshinone I inhibits gallbladder cancer growth by targeting the Keap1-Nrf2 signaling pathway and Nrf2 phosphorylation

BackgroundGallbladder cancer (GBC) poses a significant risk to human health. Its development is influenced by numerous factors, particularly the homeostasis of reactive oxygen species (ROS) within cells. This homeostasis is crucial for tumor cell survival, and abnormal regulation of ROS is associated with the occurrence and progression of many cancers. Dihydrotanshinone I (DHT I), a biologically effective ingredient isolated from Salvia miltiorrhiza, has exhibited cytotoxic properties against various tumor cells by inducing apoptosis. However, the precise molecular mechanisms by which dht I exerts its cytotoxic effects remain unclear. PurposeTo explore the anti-tumor impact of dht I on GBC and elucidate the potential molecular mechanisms. MethodsThe proliferation of GBC cells, NOZ and SGC-996, was assessed using various assays, including CCK-8 assay, colony formation assay and EdU staining. We also examined cell apoptosis, cell cycle progression, ROS levels, and alterations in mitochondrial membrane potential to delve into the intricate molecular mechanism. Quantitative PCR (qPCR), immunofluorescence staining, and Western blotting were performed to evaluate target gene expression at both the mRNA and protein levels. The correlation between nuclear factor erythroid 2-related factor 2 (Nrf2) and kelch-like ECH-associated protein 1 (Keap1) were examined using co-immunoprecipitation. Finally, the in vivo effect of dht I was investigated using a xenograft model of gallbladder cancer in mice. ResultsOur research findings indicated that dht I exerted cytotoxic effects on GBC cells, including inhibiting proliferation, disrupting mitochondrial membrane potential, inducing oxidative stress and apoptosis. Our in vivo studies substantiated the inhibition of dht I on tumor growth in xenograft nude mice. Mechanistically, dht I primarily targeted Nrf2 by promoting Keap1 mediated Nrf2 degradation and inhibiting protein kinase C (PKC) induced Nrf2 phosphorylation. This leads to the suppression of Nrf2 nuclear translocation and reduction of its target gene expression. Moreover, Nrf2 overexpression effectively counteracted the anti-tumor effects of dht I, while Nrf2 knockdown significantly enhanced the inhibitory effect of dht I on GBC. Meanwhile, PKC inhibitors and nuclear import inhibitors increased the sensitivity of GBC cells to dht I treatment. Conversely, Nrf2 activators, proteasome inhibitors, antioxidants and PKC activators all antagonized dht I induced apoptosis and ROS generation in NOZ and SGC-996 cells. ConclusionOur findings indicated that dht I inhibited the growth of GBC cells by regulating the Keap1-Nrf2 signaling pathway and Nrf2 phosphorylation. These insights provide a strong rationale for further investigation of dht I as a potential therapeutic agent for GBC treatment.

Critical assessment of G0W0 calculations for 2D materials: the example of monolayer MoS2

Two-dimensional (2D) materials combine many fascinating properties that make them more interesting than their three-dimensional counterparts for a variety of applications. For example, 2D materials exhibit stronger electron-phonon and electron-hole interactions, and their energy gaps and effective carrier masses can be easily tuned. Surprisingly, published band gaps of several 2D materials obtained with the GW approach, the state-of-the-art in electronic-structure calculations, are quite scattered. The details of these calculations, such as the underlying geometry, the starting point, the inclusion of spin-orbit coupling, and the treatment of the Coulomb potential can critically determine how accurate the results are. Taking monolayer MoS2 as a representative material, we employ the linearized augmented planewave + local orbital method to systematically investigate how all these aspects affect the quality of G0W0 calculations, and also provide a summary of literature data. We conclude that the best overall agreement with experiments and coupled-cluster calculations is found for G0W0 results with HSE06 as a starting point including spin-orbit coupling, a truncated Coulomb potential, and an analytical treatment of the singularity at q = 0.

A new approach of nano-metformin as a protector against radiation-induced cardiac fibrosis and inflammation via CXCL1/TGF-Β pathway.

The present work investigates the potential role of metformin nanoparticles (MTF-NPs) as a radio-protector against cardiac fibrosis and inflammation induced by gamma radiation via CXCL1/TGF-β pathway. Lethal dose fifty of nano-metformin was determined in mice, then 21 rats (male albino) were equally divided into three groups: normal control (G1), irradiated control (G2), and MTF-NPs + IRR (G3). The possible protective effect of MTF-NPs is illustrated via decreasing cardiac contents of troponin, C-X-C motif Ligand 1 (CXCL1), tumor growth factor β (TGF-β), protein kinase B (AKT), and nuclear factor-κB (NF-κB). Also, the positive effect of MTF-NPs on insulin-like growth factor (IGF) and platelet-derived growth factor (PDGF) in heart tissues using immunohistochemical technique is illustrated in the present study. Histopathological examination emphasizes the biochemical findings. The current investigation suggests that MTF-NPs might be considered as a potent novel treatment for the management of cardiac fibrosis and inflammation in patients who receive radiotherapy or workers who may be exposed to gamma radiation.

Metabolic Profiling, in vitro Cytotoxicity and in silico Investigation of Lycium shawii Roem. Extract

Background: Breast cancer is a prevalent global health concern. Traditional medicine often incorporates the use of medicinal plants to address various diseases. Methods: The cytotoxicity, oxidative stress and cell migration effects of saponin and phenol extracts were evaluated through MTT assay, ROS analysis and wound-healing assay. Following the identification of the active extract, it underwent GC-MS analysis and in silico investigations. Result: Our results revealed significant inhibition of cell proliferation in MDA-MB-231 (IC50:407.3 μg/mL) and HUVECs (IC50:500 μg/mL), which was achieved only with the ethyl acetate extract (Fraction 2). Fraction 2 extract induced notable morphological changes and significantly inhibited time-dependent migration in MDA-MB-231 cells. Additionally, it elevated cellular ROS levels compared to the control cells. In molecular docking analysis, out of the 51 chosen secondary metabolites from L. shawii, stigmast-5-en-3-ol, (3α,24S) (-10.0 kcal/mol) and lup-20(29)-ene-3,28-diol (-9.5 kcal/mol) were found to be the best docked to their respective targets-6CHZ and 4MAN, respectively. Therefore, this plant holds promise as a potential therapeutic agent for breast cancer treatment.