Inhibitory Effect Research Articles

Human umbilical cord mesenchymal stem cells small extracellular vesicles-derived miR-370-3p inhibits cervical precancerous lesions by targeting DHCR24

Abstract Background Cervical cancer is often caused by persistent high-risk human papillomavirus (HPV) infection, causing precancerous lesions. Human umbilical cord mesenchymal stem cells-derived small extracellular vesicles (hucMSC-sEV) exhibit diverse effects on tumors. This study investigates hucMSC-sEV, the impact and mechanisms on HPV-positive cervical precancerous lesion cells to provide new treatment insights. Materials and Methods We previously obtained hucMSC and hucMSC-sEV. In vitro experiments evaluated hucMSC-sEV effects on the proliferation and migration of S12 cells (derived from cervical precancerous lesions). Bioinformatics identified key microRNA components, and their impact on S12 cell proliferation and migration was investigated. The target gene of the microRNA component was predicted and confirmed via bioinformatics and dual-luciferase reporter assays. Lentiviral systems overexpressed target gene in S12 cells to examine the effects on microRNA impacts. SH-42 inhibitor was used to investigate target gene treatment potential. Immunohistochemistry assessed target gene expression in cervical precancerous lesions tissue. Results hucMSC-sEV significantly inhibited S12 cell proliferation and migration. Bioinformatics identified miR-370-3p as an effective cargo, which also suppressed S12 cell proliferation and migration. miR-370-3p was confirmed targeting DHCR24 (24-Dehydrocholesterol Reductase). DHCR24 overexpression reversed miR-370-3p’s inhibitory effects, while SH-42 counteracted DHCR24 overexpression’s promoting effects. Clinical specimen analysis supported these findings, demonstrating a positive correlation between DHCR24 protein expression and cervical precancerous lesions’ progression. Conclusions hucMSC-sEV inhibits S12 cell proliferation and migration, mediated by miR-370-3p targeting DHCR24 to regulate cellular cholesterol content. DHCR24 inhibition reduces the cholesterol level and cell functions, suggesting its potential as a therapeutic target in cervical precancerous lesions.

A Comprehensive Review and Update on Cannabis Hyperemesis Syndrome

Cannabis, derived from Cannabis sativa plants, is a prevalent illicit substance in the United States, containing over 400 chemicals, including 100 cannabinoids, each affecting the body’s organs differently upon ingestion. Cannabis hyperemesis syndrome (CHS) is a gut–brain axis disorder characterized by recurring nausea and vomiting intensified by excessive cannabis consumption. CHS often goes undiagnosed due to inconsistent criteria, subjective symptoms, and similarity to cyclical vomiting syndrome (CVS). Understanding the endocannabinoid system (ECS) and its dual response (pro-emetic at higher doses and anti-emetic at lower doses) is crucial in the pathophysiology of CHS. Recent research noted that type 1 cannabinoid receptors in the intestinal nerve plexus exhibit an inhibitory effect on gastrointestinal motility. At the same time, the thermoregulatory function of endocannabinoids might explain compulsive hot bathing in CHS patients. The prevalence of cannabis CHS is expected to rise as legal restrictions on its recreational use decrease in several states. Education and awareness are vital in diagnosing and treating CHS as its prevalence increases. This comprehensive review explores the ECS’s involvement, CHS management approaches, and knowledge gaps to enhance understanding of this syndrome.

An Empirical Study on the Digital Economy, Fiscal Policy, and Regional Sustainable Development—Based on Data from Less Developed Regions in China

Reducing inequality within and between countries and enhancing social welfare are important components of the United Nations’ sustainable development goals. Based on the experience of developed countries or regions, the digital economy and fiscal policy are effective ways of promoting inclusive regional economic growth. Fully considering the completeness and availability of the data, we select the data of China’s less developed regions from 2001 to 2011 for empirical testing. This study empirically examined the effect of the digital economy on regional sustainable development and the underlying mechanism, taking an analysis of the regulatory effect of fiscal policy into account. The results show the following: (1) The digital economy and regional sustainable development exhibit an inverted “U” curve relationship. In the early stage of development, relying on its own economies of scale, the digital economy releases the “digital dividend”, positively affecting the sustainable development of the regional economy; in the later stage, the “digital divide” has a positive impact on the development of the regional economy. The inhibitory effect of the “digital divide” is greater than the enhancement effect of the “digital dividend”, negatively affecting the sustainable development of regional economies. (2) There is regional heterogeneity in the mechanism of the effect of the digital economy on regional sustainable development. The digital economy affects the level of regional sustainable development through the two paths of “comprehensive prosperity” and “holistic well-being”. For the samples in the eastern and western regions, the digital economy plays the role of promoting and then inhibiting, while for the samples in the central region, it plays the role of inhibiting and then promoting. (3) Fiscal policy negatively regulates the effect of the digital economy on regional sustainable development, but the regulatory effect is not significant.

Chemical profile, biological activities, and molecular docking of Algerian Juniperus phoenicea berries

The chemical composition, antioxidant activities, and α-amylase enzyme inhibitory activity of Algerian Juniperus phoenicea L berries were quantitatively and qualitatively determined in this study. Essential oil (EO) and non-polar crude extracts from cyclohexane and ethyl acetate were prepared, and the chemical profile was determined using GC-MS technique. The predominant compound in the EO was α-pinene (76.03%), while communic acid (23.66% and 22.38%) was the main compound in both non-polar crude extracts. The antioxidant potential of the samples was evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,20-azino-bis(3-ethylbenzothiazoline-6-sulfonicacid)-diammonium salt (ABTS), and phenanthroline. All samples showed weak antioxidant capacity. The antidiabetic effect was assessed in vitro using the α-amylase assay; a strong inhibitory effect against the α-amylase enzyme was detected for both cyclohexane and ethyl acetate extracts with IC50 (IC50 = 186.91 ± 5.74 mg/mL and IC50 = 351.48 ± 0.17 mg/mL, respectively). Finally, an in silico study was performed for both α-amylase and α-glucosidase proteins to enhance our outcomes.

Designing a linear accelerator-based "X irradiation system" for platelet products: an efficient, safe, accessible and cost-effective alternative for conventional X- or gamma irradiators.

X-irradiation of blood products is an alternative for gamma-ray to prevent post-transfusion GvHD. However, commercial X-irradiators are not widely available while little is known about their safety and efficacy for platelet products. This study introduces an efficient, accessible and cost-effective "X irradiation system" for platelet concentrates (PCs). By constructing a suitable radiation box (phantom) for a clinically available linear accelerator, an "X irradiation system" was designed specifically for PCs. PCs were divided into three equal bags either exposed to X- and gamma-irradiation or kept unirradiated (control). Irradiation-induced inhibition of T cells proliferation was examined by MTT and cell cycle assays on mononuclear cells (MNCs) obtained from PCs. The inhibitory effect of irradiation on allorecognition ability of MNCs was assessed by mixed lymphocyte reaction where MTT evaluated lymphocyte proliferation responses and flowcytometry examined CD8+T lymphocytes activity. Platelet activation was also examined with P-selectin expression and PAC-1 binding by flowcytometry. X- and gamma-irradiation reduced T cell proliferation while disturbing the cell-cycle with reduced entry of T-cells into the S phase and their G2 arrest. Both types of irradiations also effectively reduced "lymphocyte allorecognition responses" while inactivating CD8+T lymphocytes in platelet products but with no significant effect on platelet activity. This is the first study that showed "X irradiation system" effectively suppresses T cell proliferation and CD8+T lymphocyte activity in platelet products, with no effect to platelet quality and activation markers. This may suggest the LINAC-based "X irradiation system" with a dose of 30Gy as efficient and safe as gamma-irradiation for platelet products.

Evaluating the drug-drug interactions of SHR4640 on repaglinide and midazolam in healthy subjects

ABSTRACT Background SHR4640, a highly selective URAT1 inhibitor, was evaluated to investigate its inhibitory effects on CYP2C8 and CYP3A4 in vivo clinical trial. This study assessed the pharmacokinetic (PK) impact of SHR4640 when co-administered with the CYP2C8 probe substrate repaglinide and the CYP3A4 probe substrate midazolam. Research design and methods In this single-center, randomized, double-blind, placebo-controlled study, participants were randomly allocated in a 1:1:1 ratio to SHR4640 Group A, SHR4640 Group B, and placebo group and received oral repaglinide, midazolam, SHR4640 or placebo at specific times. The primary endpoints included the main PK parameters of repaglinide and midazolam, both alone and in combination with SHR4640 (AUC0-inf, AUC0-t, and Cmax). Results The increase in the area under the concentration-time curve (AUC) for repaglinide, when co-administered with SHR4640, was less than 1.25-fold, while the AUC for midazolam exhibited a slight increase of 46%. Conclusions SHR4640 exerts a weak inhibitory effect on the AUC of CYP enzyme probe substrates and has minimal potential for drug-drug interactions and presents a favorable safety profile. Clinical trial registration www.clinicaltrials.gov identifier is NCT06196580 (Name: PK Effects of SHR4640 on Repaglinide and Midazolam, and the Impact of SHR4640 on QT Interval).

Bioinformatics combined with network pharmacology and experimental validation to identify key biomarkers of hepatocellular carcinoma and corresponding compounds in Radix Astragali and Pueraria Mirifica.

The occurrence and death rates of primary hepatocellular carcinoma (HCC) are increasing, and there remains a shortage of effective oral medications with minimal side effects. We aim to identify potential biomarkers and compounds from Radix Astragali (RA) and Pueraria Mirifica (PM) to treat liver cancer and improve prognosis. Differentially expressed genes (DEGs) associated with HCC were identified by bioinformatics analysis of three datasets, GSE112791, GSE101685, and GSE45114. Using public databases to predict the bioactive components and possible targets of RA and PM. Target crossover from Gene Expression Omnibus (GEO) and public databases were used to identify potential biomarkers for HCC. Subsequently, validation and prognostic value analyses were performed using the Gene Expression Profile Interaction Analysis (GEPIA) platform. The Cytoscape software created a network of "compound targets" to pinpoint compounds linked to the biomarkers. Molecular docking techniques were utilized to validate the connection between these compounds and the identified biomarkers. Ultimately, the HepG2 liver cancer cell line was chosen to assess the inhibitory effect of Hederagenin (HDG) and to confirm the expression of ADH1B through Western blot analysis. In this study, four key biomarkers (NR1I2, ADH1B, NQO1, GHR) were identified. Molecular docking showed that these four core targets could form stable conformations with the corresponding compounds. As the drug concentration decreases, the inhibitory effect on HepG2 diminishes, and the survival rate of HepG2 cells significantly declines following the administration of 100 µmol/L HDG. Compared to the control, the expression of ADH1B protein is significantly increased in HepG2 cells treated with 100 µmol/L HDG. The study identified four key biomarkers (ADH1B, GHR, NQO1, NR1I2) that have prognostic ability for HCC. This study provides biomarkers and potential targeted monomeric medicines for treating HCC.

Contribution of amyloid deposition from oligodendrocytes in a mouse model of Alzheimer's disease.

The accumulation of β-amyloid (Aβ) peptides into insoluble plaques is an early pathological feature of Alzheimer's disease (AD). BACE1 is the sole β-secretase for Aβ generation, making it an attractive therapeutic target for AD therapy. While BACE1 inhibitors have been shown to reduce Aβ levels in people with AD, clinical trials targeting BACE1 have failed due to unwanted synaptic deficits. Understanding the physiological role of BACE1 in individual cell types is essential for developing effective BACE inhibitors for the treatment of AD. Recent single-cell RNA transcriptomic assays revealed that oligodendrocytes are enriched with genes required for generating Aβ. However, the contribution of oligodendrocytes to amyloid plaque burden in AD and the side effects of oligodendrocyte-specific Bace1 deletion remain to be explored. We generated an oligodendrocyte-specific Bace1 knockout model (Bace1fl/fl;Olig2-Cre) to monitor potential disruptions in myelination using standard electron microscopy. Long-term potentiation (LTP) was monitored to measure synaptic integrity. We crossed the Bace1fl/fl;Olig2-Cre model with heterozygous AppNL-G-F/wt knock-in AD mice to generate AD mice lacking oligodendrocyte Bace1 (Bace1fl/fl;Olig2-Cre; AppNL-G-F/wt) and examined amyloid plaque number and insoluble Aβ levels and gliosis in these animals. Single nuclei RNA sequencing experiments were conducted to examine molecular changes in response to Bace1 deficiency in oligodendrocytes in the wild type or APP knock-in background. Bace1 deletion in oligodendrocytes caused no change in myelin thickness in the corpus callosum but a marginal reduction in myelin sheath thickness of the optic nerve. Synaptic strength measured by LTP was not different between Bace1fl/fl;Olig2-Cre and age-matched Bace1fl/fl control animals, suggesting no major effect on synaptic plasticity. Intriguingly, deletion of Bace1 in 12-month-old heterozygous AD knock-in mice (Bace1fl/fl;Olig2-Cre; AppNL-G-F/wt mice) caused a significant reduction of amyloid plaques by ~ 33% in the hippocampus and ~ 29% in the cortex compared to age-matched AD mice (Bace1fl/fl;AppNL-G-F/wt). Insoluble Aβ1-40 and Aβ1-42 levels were reduced comparably while more astrocytes and microglia were observed in surrounding amyloid plaques. Unbiased single-nuclei RNA sequencing results revealed that deletion of oligodendrocyte Bace1 in APPNL-G-F/wt knock-in mice increased expression of genes associated with Aβ generation and clearance such as ADAM10, Ano4, ApoE, Il33, and Sort1. Our results provide compelling evidence that the amyloidogenic pathway in oligodendrocytes contributes to Aβ plaque formation in the AD brain. While specifically targeting BACE1 inhibition in oligodendrocytes for reducing Aβ pathology in AD is likely challenging, this is a potentially explorable strategy in future studies.

Biological control of nosemosis in Apis mellifera L. with Acacia nilotica extract.

Nosemosis is one of the most devastating diseases of Apis mellifera (Honey bees) caused by the single-celled spore-forming fungiNosema apis,N. ceranae and N. neumanii, causing a severe loss on the colony vitality and productivity. Fumagillin, a MetAP2 inhibitor, was a certified treatment for controlling nosemosis, nevertheless, due to its deleterious effects on honey bees and humans, it is prohibited. So, searching for novel biological agents with affordable selectivity to target Nosema species infecting Apis mellifera, with nil toxicity to bees and humans is the main objective of this study. Nosema species were isolated from naturally infected honey bees. The methanolic extracts of Acacia nilotica, Elaeis guineensis, and Catharanthus roseus were tested to selectively control the growth of Nosema spp of honeybees. The spores of Nosema species were molecularly and morphologically identified. Among the tested plant extracts, the methanolic extracts (0.1%) of A. nilotica had the most activity towards Nosema spp causing about 37.8 and 32.5% reduction in the spores' load at 5- and 9-days post-infection, respectively, compared to the untreated control. At 0.1%, the A. nilotica methanolic extract exhibited the highest inhibitory effect for Nosema spores, without any obvious bee mortality. Catharanthus roseus displayed a reduction of spores by 27.02%, with bee mortality rate of 27.02%. At 1% for 5 dpi, the A. nilotica extracts led to 18.18% bee mortality, while the C. roseus extracts resulted in 100% mortality, as revealed from the toxicity and quantification bioassays. So, the extracts of A. nilotica and C. roseus had a significant effect in controlling the N. apis and N. ceranae titer compared to the infected untreated control at both time points. The titer of N. apis and N. ceranae was noticeably decreased by more than 80% and 90%, in response to A. nilotica, compared to the control. From the metabolic profiling by GC-MS analysis, the most frequent active compounds of A. nilotica were 2,4,6-trihy-droxybenzoic acid, 1,2-dihydroxybenzene, myristic acid, and linoleic acid. These compounds were analyzed in silico to assess their binding affinity to the ATP binding protein, methionine aminopeptidase and polar tube protein of Nosema species as target enzymes. The compound 2,4,6-trihydroxybenzoic acid had the lowest energy to bind with ATP binding protein, methionine aminopeptidase and polar tube protein of Nosema, followed by 1,2-dihydroxybenzene and myristic acid, compared to fumagilin. So, from the experimental and molecular docking analysis, the extracts of A. nilotica had the highest activity to attack the cellular growth machinery of Nosema species without an obvious effect to the honeybees, ensuring their prospective promising application.

The inhibitory effect of Maillard reaction products on fish and chicken muscle oxidation

The inhibitory effect of Maillard reaction products on fish and chicken muscle oxidation

Study on the mechanism of hyperoside in affecting the biological progression and radiosensitivity of esophageal carcinoma by modulating the STAT3/AKT/ERK pathway

Hyperoside (HYP) exhibits diverse pharmacological effects and holds potential for enhancing chemotherapy sensitivity. However, few studies have reported the impact of HYP on the malignant progression of esophageal carcinoma (EC) and its sensitivity to radiotherapy. The impact of HYP on the viability of esophageal carcinoma cells (TE-1 and KYSE-150) was assessed using Cell Counting Kit-8 (CCK-8) assays. The biological characteristics and radiosensitivity of esophageal carcinoma cells following HYP treatment were evaluated through colony formation experiments, flow cytometry, scratch wound-healing assays, and transwell migration and invasion assays. Western blot analysis was performed to determine the levels of proteins associated with cell death and epithelial-mesenchymal transition (EMT), as well as to explore whether HYP interferes with the radiosensitivity of esophageal carcinoma cells via the STAT3/AKT/ERK pathways. Finally, a subcutaneous graft tumor model was constructed to investigate the effects of HYP and X-ray treatments on in vivo tumor growth. The findings indicated a dose-dependent decrease in the survival rate of KYSE-150 and TE-1 cells following HYP treatment. HYP treatment also inhibited cell proliferation, invasion, migration, and EMT, while increasing the apoptotic rate and radiosensitivity of the cells. Notably, HYP suppressed the malignant progression of EC and enhanced radiosensitivity via the STAT3/AKT/ERK pathway. Moreover, HYP impaired the growth of esophageal carcinoma tumors in mice, with the combined HYP and X-ray treatment exerting a stronger inhibitory effect. In conclusion, HYP increases the radiosensitivity of esophageal carcinoma cells, offering considerable promise for application in the clinical treatment of EC.

FATS inhibits the Wnt pathway and induces apoptosis through degradation of MYH9 and enhances sensitivity to paclitaxel in breast cancer.

Breast cancer is one of the most prevalent and diverse malignancies, and, with global cases increasing, the need for biomarkers to inform individual sensitivity to chemotherapeutics has never been greater. Our retrospective clinical analysis predicted that the expression of the fragile site-associated tumor suppressor (FATS) gene was associated with the sensitivity of breast cancer to neoadjuvant chemotherapy with paclitaxel. In vitro experiments subsequently demonstrated that FATS significantly increased the inhibitory effects of paclitaxel on breast cancer cells' migration, growth, and survival. An interaction screen revealed that FATS interacted with MYH9 and promoted its degradation via the ubiquitin-proteasome pathway, thereby downregulating Wnt signaling. By overexpressing FATS and MYH9, we demonstrated that FATS enhanced paclitaxel-induced apoptosis in breast cancer cells by degrading MYH9 to downregulate the Wnt pathway. We also demonstrated in a mouse xenograft model that FATS significantly increased the chemosensitivity of breast cancer cells to paclitaxel in vivo. This study presents a new mechanism by which FATS interacts with MYH9 to suppress the Wnt/β-catenin signaling pathway and induce apoptosis, thus enhancing the sensitivity of breast cancer cells to paclitaxel chemotherapy. The results also propose novel biomarkers for predicting breast cancer sensitivity to neoadjuvant chemotherapy with paclitaxel. Finally, we provide in vivo evidence that the combination of paclitaxel with IWR-1, a novel Wnt pathway inhibitor, synergistically suppresses breast cancer growth, laying the foundation for future trials with this drug combination. These results therefore provide a number of potential solutions for more precise treatment of patients with breast cancer in the future.

Antibacterial efficacy of berry juices against Bacillus cereus relative to their phytochemical composition and antioxidant properties.

Ensuring the safety and stability of minimally processed foods using natural preservatives is of great scientific and commercial interest in modern biotechnology. Berry juice supplementation is increasingly recognized within this field. This study investigated the effectiveness of juices from four berry species Aronia melanocarpa, Ribes nigrum, Vaccinium macrocarpon, and Sambucus nigra, against the food pathogen Bacillus cereus. Overall, the antibacterial potency of juice supplements (up to 10% v/v in tryptic soy broth) followed the order of chokeberry > blackcurrant > cranberry > elderberry, with the latter showing no inhibitory effects. Notably, chokeberry and elderberry juices presented lower acidity and significantly greater phenolic contents (p < 0.05) than blackcurrant and cranberry juices did, suggesting that B. cereus susceptibility is not strictly dependent upon low extracellular pH or elevated anthocyanin levels. Instead, it is inferred to correlate with pro-oxidative effects induced directly at the intracellular level. Accordingly, this paper discusses the antioxidative, acidic, and lipophilic attributes of juices and their constituent fractions, including anthocyanins, to elucidate their biopreservative potential. The results of this study increase our understanding of the antibacterial susceptibility of B. cereus.

In Silico Study of the Potential Inhibitory Effects on Escherichia coli DNA Gyrase of Some Hypothetical Fluoroquinolone–Tetracycline Hybrids

Background/Objectives: Despite the discovery of antibiotics, bacterial infections persist globally, exacerbated by rising antimicrobial resistance that results in millions of cases, increased healthcare costs, and more extended hospital stays. The urgent need for new antibacterial drugs continues as resistance evolves. Fluoroquinolones and tetracyclines are versatile antibiotics that are effective against various bacterial infections. A hybrid antibiotic combines two or more molecules to enhance antimicrobial effectiveness and combat resistance better than monotherapy. Fluoroquinolones are ideal candidates for hybridization due to their potent bactericidal effects, ease of synthesis, and ability to form combinations with other molecules. Methods: This study explored the mechanisms of action for 40 hypothetical fluoroquinolone–tetracycline hybrids, all of which could be obtained using a simple, eco-friendly synthesis method. Their interaction with Escherichia coli DNA Gyrase and similarity to albicidin were evaluated using the FORECASTER platform. Results: Hybrids such as Do-Ba, Mi-Fi, and Te-Ba closely resembled albicidin in physicochemical properties and FITTED Scores, while Te-De surpassed it with a better score. Similar to fluoroquinolones, these hybrids likely inhibit DNA synthesis by binding to enzyme–DNA complexes. Conclusions: These hybrids could offer broad-spectrum activity and help mitigate bacterial resistance, though further in vitro and in vivo studies are needed to validate their potential.

Generating and validating renewable affimer protein binding reagents targeting SH2 domains.

Despite SH2 domains, being pivotal in protein interactions linked to various diseases like cancer, we lack specific research tools for intracellular assays. Understanding SH2-mediated interactions and creating effective inhibitors requires tools which target individual protein domains. Affimer reagents exhibit promise, yet their potential against the extensive SH2 domain family remains largely unexplored. Our study aimed to bridge this gap by identifying Affimer reagents that selectively bind to 22 out of 41 SH2 domains. These reagents enabled a medium-throughput screening approach resembling siRNA studies, shedding light on their functionality. Notably, select Affimers demonstrated the ability to curtail the nuclear translocation of pERK, with Grb2 being a prominent target. Further analyses revealed that these Grb2-specific Affimer reagents displayed competitive inhibition with impressive metrics: IC50s ranging from 270.9 nM to 1.22 µM, together with low nanomolar binding affinities. Moreover, they exhibited the ability to pull down endogenous Grb2 from cell lysates, illustrating their efficacy in binding the Grb2 SH2 domain. This comprehensive assessment underscores the potential of Affimer reagents as domain-specific inhibitors. Their viability for medium/high-throughput phenotypic screening presents a promising avenue via which to identify and characterize potential drug targets within the SH2 domain family.

Triterpenoids from Ganoderma lucidum inhibit cytochrome P450 enzymes interfering with the metabolic process of specific clinical drugs

BackgroundGanoderma lucidum (G. lucidum), which possesses various biological effects, has been widely used as traditional medicine and functional food in Asian countries, especially China. In consideration of its various biological effects on human healthcare, G. lucidum was usually used in combination with other drugs. However, the potential drug-drug interaction induced by G. lucidum through cytochrome P450 enzymes (CYPs) remain unknown.MethodsUsing the in vivo activity assay of CYPs, the inhibitory effects of G. lucidum and its constituents could be evaluated. The interference of G. lucidum on the metabolic processes of clinical drugs could be investigated. The chemical constituents of G. lucidum could be identified using LC-MS. The interaction between bioactive compounds and CYPs could be proposed through in silico docking analysis and molecular dynamics.ResultsThe dichloromethane extract of G. lucidum could inhibit various CYP450 subtypes in vitro and interfere with the pharmacokinetics of four drugs in rats. Triterpenoids were identified as the main constituents of the dichloromethane extract by Q-TOF-MSn in preliminary analyses. Then, a triterpenoid library containing 66 compounds was established to evaluate their inhibitory effects against CYP 1A2, 2D6, 3A4, 2A6, 2B6, 2C9, and 2C19. CYP 1A2 was inhibited by most lanostane triterpenoids, indicating a strong affinity for these compounds. Among triterpenoids, compound 25 displayed a broad inhibitory effect against CYPs, except for CYP 3A4, 2D6, 2C9, and 2C19. Finally, compounds 6 and 25 exhibited interference with the metabolism of 16 drugs through the inhibition of CYPs in vitro. In silico molecular docking analyses for assaying the interaction between compound 25 and CYPs indicated that the hydrogen bonds formed between the hydroxyl groups and amino acid residues.ConclusionG. lucidum displayed broad inhibitory effects on CYPs, with triterpenoids as the main bioactive constituents, which may induce potential drug-drug interaction. This information should be helpful for the rational use of G. lucidum in promoting human health.

MiR-101-3p suppresses proliferation of orbital fibroblasts by targeting pentraxin-3 in thyroid eye disease

Background Excessive proliferation of orbital fibroblasts (OFs) is an essential factor in the pathogenesis of thyroid eye disease (TED). While existing evidence indicates that various microRNAs (miRNAs) significantly contribute to TED development, the precise function and targets of miR-101-3p in TED pathogenesis remain unknown. This research aims to elucidate the effects of miR-101-3p on TED-OFs and identify its potential targets. Methods Orbital adipose tissues were harvested from both TED patients and healthy controls to culture their fibroblasts. MiR-101-3p mimic or mimic negative control (mimic NC) was transfected into OFs from TED patients, with untreated OFs serving as an additional blank control group. Cell proliferation was assessed using cell counting kit-8 (CCK-8) assay, Ki-67 immunofluorescence staining, and the EdU assay, while apoptosis was evaluated via flow cytometry. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to measure the expression levels of miR-101-3p and pentraxin-3 (PTX3), and PTX3 protein levels were quantified using western blot. A dual-luciferase assay was conducted to ascertain how miR-101-3p and PTX3 interacted. Results The results demonstrated a significant downregulation of miR-101-3p in fibroblasts and TED orbital adipose tissues. Transfection with the miR-101-3p mimic upregulated miR-101-3p levels, significantly reducing OFs proliferation without affecting apoptosis. Overexpression of miR-101-3p led to the downregulation of PTX3 in OFs. The dual-luciferase assay validated miR-101-3p binding to PTX3’s 3’UTR, thereby repressing its expression. Moreover, overexpression of PTX3 partially rescued the miR-101-3p mimic’s inhibitory effect on TED-OFs proliferation. Conclusion Our findings illustrate miR-101-3p’s role in targeting PTX3 to regulate TED-OFs proliferation, providing novel insights into the pathological mechanisms underlying TED development.

Humanin-G Ameliorates Hemorrhage-Induced Acute Lung Injury in Mice Through AMPKα1-Dependent and -Independent Mechanisms

Background/Objectives: The severity of acute lung injury is significantly impacted by age and sex in patients with hemorrhagic shock. AMP-activated protein kinase (AMPK) is a crucial regulator of energy metabolism but its activity declines with aging. Humanin is a mitochondrial peptide that exerts cytoprotective effects in response to oxidative stressors and is associated with longevity. Using a mouse model of hemorrhagic shock that mimics the clinical condition of adult patients, we investigated whether treatment with a humanin analog, humanin-G, mitigates lung injury and whether its mechanisms of action are dependent on the catalytic AMPKα1 subunit activation. Methods: Male and female AMPKα1 wild-type (WT) and knock-out (KO) mice (8–13 months old) were subjected to hemorrhagic shock by blood withdrawal, followed by resuscitation with shed blood and lactated Ringer’s solution. The mice were treated with PEGylated humanin-G or vehicle and euthanized 3 h post-resuscitation. Results: Sex- and genotype-related differences were observed after hemorrhagic shock as lung neutrophil infiltration was more pronounced in the male AMPKα1 WT mice than the female WT mice; also, the male AMPKα1 KO mice experienced a significant decline in mean arterial blood pressure when compared to the male WT mice after resuscitation. The scores of histological lung injury were similarly elevated in all the male and female AMPKα1 WT and KO mice when compared to the control mice. At molecular analysis, acute lung injury was associated with the downregulation of AMPKα1/α2 catalytic subunits in the WT mice, whereas an increased activation of the signal transducer and activator of transcription-3 (STAT3) was observed in all the vehicle-treated groups. The in vivo administration of humanin-G ameliorated histological lung damage in all the groups of animals and ameliorated mean arterial blood pressure in the male AMPKα1 KO mice. The in vivo administration of humanin-G lowered lung neutrophil infiltration in the male and female AMPKα1 WT mice only but not in the KO mice. The beneficial results of humanin-G correlated with the lung cytosolic and nuclear activation of AMPKα in the male and female AMPKα1 WT groups, whereas STAT3 activation was not modified. Conclusions: In adult age, hemorrhage-induced acute lung injury manifests with sex-dependent characteristics. Humanin-G has therapeutic potential and the AMPKα1subunit is an important requisite for its inhibitory effects on lung leucosequestration, but not for the amelioration of lung alveolar structure or the hemodynamic effects of the peptide.

Fas Apoptosis Inhibitory Molecule 2 Inhibits Pathological Cardiac Hypertrophy by Regulating the MAPK Signaling Pathway.

Pathological cardiac hypertrophy stands as a pivotal mechanism contributing to diverse cardiovascular diseases, ultimately leading to heart failure. Despite its clinical significance, the intricate molecular mechanisms instigating pathological cardiac hypertrophy remain inadequately understood. In this study, we aim to further reveal its complex pathogenesis by exploring the role of Fas apoptotic inhibitory molecule 2 (FAIM2) in modulating pathological cardiac hypertrophy. We used phenylephrine-induced hypertrophic cardiomyocytes and also generated cardiac-specific knockout mice and adeno-associated virus serotype 9-Faim2 mice to evaluate the function of FAIM2 in pathological myocardial hypertrophy. Furthermore, unbiased RNA-sequencing analysis was used to identify the direct target and corresponding molecular events contributing to FAIM2 function. Ultimately, our study revealed a downregulation of FAIM2 expression in phenylephrine-induced hypertrophic cardiomyocytes and pressure overload-induced hypertrophic hearts. FAIM2 exhibited a significant attenuation of phenylephrine-induced enlargement of primary neonatal rat cardiomyocytes, whereas FAIM2 knockdown aggravated the hypertrophic response. Furthermore, Faim2 gene knockout significantly exacerbated cardiac hypertrophy and heart fibrosis invivo. Mechanistic investigations unveiled that FAIM2 exerts its inhibitory effect by suppressing TAK1-JNK1/2-p38 MAPK signaling cascades, thereby mitigating cardiac hypertrophy. Our findings position FAIM2 as a novel negative regulator of pathological cardiac hypertrophy through its inhibitory action on mitogen-activated protein kinase signaling activation. This identification of FAIM2's role provides crucial insights that may pave the way for the development of effective therapeutic strategies aimed at mitigating pathological cardiac hypertrophy, addressing a critical need in cardiovascular disease management.

Revitalizing sumatriptan: transforming expired medication into a potent solution for corrosion control in acidic environments

The concerns regarding pharmaceutical waste, particularly expired drugs have prompted the exploration of their alternative applications. This research highlights the potential of repurposing expired pharmaceuticals as eco-friendly corrosion inhibitors for their industrial applications. An expired drug sumatriptan was investigated for its anticorrosive properties on MS in 1 M HCl medium. Electrochemical techniques, including potentiodynamic polarization and electrochemical impedance spectroscopy, were employed to evaluate the inhibition efficiency and complemented by surface characterization studies (SEM, EDAX, CA and AFM). The results demonstrated that sumatriptan acts as an effective mixed-type inhibitor, achieving maximum inhibition efficiencies of 94.51% and 93.85% from PDP and EIS studies respectively for 500 ppm at 318 K. The adsorption of sumatriptan on the metal surface followed the Langmuir isotherm having an R2 value of ∼1, suggesting a physical adsorption behaviour with Δ G° values ranging from −16.286 to −21.518 kJ mol−1. The results demonstrate the effectiveness of sumatriptan as a corrosion inhibitor and the potential of repurposing expired pharmaceuticals as eco-friendly and sustainable alternatives.