Honokiol induces apoptosis and autophagy in dexamethasone-resistant T-acute lymphoblastic leukemia CEM-C1 cells.

Objective: To study whether and, if so, how honokiol overcome dexamethasone resistance in DEX-resistant CEM-C1 cells. Methods: We investigated the effect of honokiol (0-20 µM) on cell proliferation, cell cycle, cell apoptosis and autophagy in DEX-resistant CEM-C1 cells and DEX-sensitive CEM-C7 cells. We also determined the role of c-Myc protein and mRNA in the occurrence of T-ALL associated dexamethasone resistance western blot and reverse transcription-qPCR (RT-qPCR) analysis. Results: Cell Counting Kit (CCK)-8 assay shows that DEX-resistant CEM-C1 cell lines were highly resistant to dexamethasone with IC50 of 364.1 ± 29.5 µM for 48 h treatment. However, upon treatment with dexamethasone in combination with 1.5 µM of honokiol for 48 h, the IC50 of CEM-C1 cells significantly decreased to 126.2 ± 12.3 µM, and the reversal fold was 2.88. Conversely, the IC50 of CEM-C7 cells was not changed combination of dexamethasone and honokiol as compared to that of CEM-C7 cells treated with dexamethasone alone. It has been shown that honokiol induced T-ALL cell growth inhibition by apoptosis and autophagy via downregulating cell cycle-regulated proteins (Cyclin E, CDK4, and Cyclin D1) and anti-apoptotic proteins BCL-2 and upregulating pro-apoptotic proteins Bax and led to PARP cleavage. Honokiol may overcome dexamethasone resistance in DEX-resistant CEM-C1 cell lines via the suppression of c-Myc mRNA expression. Conclusion: The combination of honokiol and DEX were better than DEX alone in DEX-resistant CEM-C1 cell lines. Honokiol may regulate T-ALL-related dexamethasone resistance by affecting c-Myc.

Risk assessment and molecular mechanism of Sclerotium rolfsii resistance to boscalid.

Boscalid, a widely used SDHI fungicide, has been employed in plant disease control for over two decades. However, there is currently no available information regarding its antifungal activity against Sclerotium rolfsii and the potential risk of resistance development in this pathogen. In this study, we evaluated the sensitivity of 100 S. rolfsii strains collected from five different regions in China during 2018-2019 to boscalid using mycelial growth inhibition method and assessed the risk of resistance development. The EC50 values for boscalid ranged from 0.2994 µg/mL to 1.0766 µg/mL against the tested strains, with an average EC50 value of 0.7052 ± 0.1473 µg/mL. Notably, a single peak sensitivity baseline was curved, indicating the absence of any detected resistant strains. Furtherly, 10 randomly selected strains of S. rolfsii were subjected to chemical taming to evaluate its resistance risk to boscalid, resulting in the successful generation of six stable and inheritable resistant mutants. These mutants exhibited significantly reduced mycelial growth, sclerotia production, and virulence compared to their respective parental strains. Cross-resistance tests revealed a correlation between boscalid and flutolanil, benzovindiflupyr, pydiflumetofen, fluindapyr, and thifluzamide; however, no cross-resistance was observed between boscalid and azoxystrobin. Thus, we conclude that the development risk of resistance in S. rolfsii to boscalid is low. Boscalid can be used as an alternative fungicide for controlling peanut sclerotium blight when combined with other fungicides that have different mechanisms of action. Finally, the target genes SDHB, SDHC, and SDHD in S. rolfsii were initially identified, cloned and sequenced to elucidate the mechanism of S. rolfsii resistance to boscalid. Two mutation genotypes were found in the mutants: SDHD-D111H and SDHD-H121Y. The mutants carrying SDHD-H121Y exhibited moderate resistance, while the mutants with SDHD-D111H showed low resistance. These findings contribute to our comprehensive understanding of molecular mechanisms underlying plant pathogens resistance to SDHI fungicides.

Description of Solvent-Extractable Chemicals in Thermal Receipts and Toxicological Assessment of Bisphenol S and Diphenyl Sulfone.

Research on thermal receipts has previously focused on the toxic effects of dermal exposure from the most publicized developers (e.g., bisphenol A (BPA) and bisphenol S (BPS)), while no studies have reported on the other solvent-extractable compounds therein. Diphenyl sulfone (DPS) is a sensitizer added to thermal receipts, but little is known about DPS concentrations in receipts or potential toxicity. Here, we quantified BPA, BPS, and DPS concentrations and tentatively identified the solvent-extractable compounds of thermal receipts collected from three South Dakota (USA) cities during 2016-2017. An immortalized chicken hepatic cell line, cultured as 3D spheroids, was used to screen effects of DPS, BPS, and 17ß estradiol (E2; 0.1-1000 µM) on cell viability and gene expression changes. These chemicals elicited limited cytotoxicity with LC50 values ranging from 113 to 143 µM, and induced dysregulation in genes associated with lipid and bile acid homeostasis. Taken together, this study generated novel information on solvent-extractable chemicals from thermal receipts and toxicity data for DPS.

Comparison of sacubitril/valsartan with olmesartan for hypertension: A meta-analysis of randomized controlled trials.

INTRODUCTION: The efficacy of sacubitril/valsartan versus olmesartan remains controversial for the control of hypertension. We conduct a systematic review and meta-analysis to explore the influence of sacubitril/valsartan versus olmesartan on the control of hypertension. METHODS: We have searched PubMed, Embase, Web of science, EBSCO, and Cochrane library databases through July 2023 for randomized controlled trials assessing the effect of sacubitril/valsartan versus olmesartan on the control of hypertension. This meta-analysis is performed using the random-effect model or fixed-effect model based on the heterogeneity. RESULTS: Seven randomized controlled trials and 3677 patients were included in the meta-analysis. Overall, compared with olmesartan treatment for hypertension, sacubitril/valsartan treatment was associated with substantially decreased systolic blood pressure (mean difference [MD] = -4.58; 95% confidence interval [CI] = -7.90 to -1.25; P = .007), diastolic blood pressure (MD = -1.70; 95% CI = -3.24 to -0.17; P = .03), and pulse pressure (MD = -2.31; 95% CI = -4.41 to -0.21; P = .03), as well as improved systolic blood pressure control (odds ratio [OR] = 1.65; 95% CI = 1.15 to 2.38; P = .006), but had no influence on diastolic blood pressure control (OR = 1.33; 95% CI = 0.93 to 1.88; P = .11) or adverse events (OR = 1.06; 95% CI = 0.90 to 1.24; P = .51). CONCLUSIONS: Sacubitril/valsartan is better than olmesartan for the reduction of blood pressure for patients with hypertension.

The protective effects of Irbesartan in cognitive impairment in hypertension.

Vascular cognitive impairment (VCI) is claimed as the second most common type of dementia after Alzheimer's disease (AD), in which hypertension is a critical inducer. Currently, hypertension-induced cognitive impairment lacks clinical treatments. Irbesartan is a long-acting angiotensin receptor antagonist with promising antihypertensive properties. Our research will focus on the potential function of Irbesartan on hypertension-induced cognitive impairment. Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats were orally dosed with normal saline or 20 mg/kg/day Irbesartan for 14 consecutive days, with 4 groups divided shown as below: WKY, Irbesartan, SHR, SHR+ Irbesartan. Firstly, the markedly increased systolic blood pressure observed in SHR rats was signally repressed by Irbesartan on Day 7 and 14 post-dosing. Moreover, notably decreased time of exploring the novel object in the object recognition task (ORT) test, elevated escape latency, and reduced time in the target quadrant in the Morris water maze (MWM) test were observed in SHR rats, which were prominently reversed by Irbesartan. Furthermore, the declined superoxide dismutase (SOD) activity, elevated malondialdehyde (MDA) level, increased cyclin-dependent kinase-5 (CDK5) activity, and enhanced protein level of p35/p25, p-Tau (pSer214)/Tau46, and brain-derived neurotrophic factor (BDNF) were memorably rescued by Irbesartan. Lastly, the activity of cAMP/cAMP response element binding protein (CREB) signaling in the hippocampus of SHR rats was markedly repressed, accompanied by an upregulation of phosphodiesterase 4B (PDE4B), which was observably rescued by Irbesartan. Collectively, Irbesartan protected against the hypertension-induced cognitive impairment in SHR rats by regulating the cAMP/CREB signaling.

Sacubitril/valsartan can improve the cardiac function in heart failure patients with a history of cancer: An observational study.

Sacubitril/Valsartan, the combination of angiotensin receptor inhibitor and neprilysin inhibitor, is now becoming the class 1 recommendation for HFrEF. Some studies have shown the positive effect of Sacubitril/Valsartan on HFrEF cancer patients, while there is devoid of evidence about the effect of this drug in aged cancer patients with HFmrEF and HFpEF. By searching the patients with a diagnosis of both cancer and Heart failure (HF) over 65, the patients who had received treatment with Sacubitril/Valsartan were selected as the candidates for Sacubitril/Valsartan group, and the patients who had received conventional HF therapy without Sacubitril/Valsartan were chosen as the control group. Data were collected for up to 9 months. We filtered 38 patients and 50 patients valid for Sacubitril/Valsartan group and control group, respectively. After initiation of heart failure management, our study found a better cardiac condition in Sacubitril/Valsartan group, having better LVEF, LVFS, NT-proBNP in 3rd, 6th, 9th month (P < .05) and better NYHA function classification after the treatment. We also observed fewer cases of deterioration on LAD (P = .029) and LVEDD (P = .023) in Sacubitril/Valsartan group. In subgroup analysis, our study showed that all 3 kinds of HF patients had better LVEF, LVFS, and NT-proBNP in Sacubitril/Valsartan group (P < .05). Our study further indicated that Sacubitril/Valsartan can improve cardiac function and benefit cardiac remolding in aged cancer patients of all 3 kinds of HF. This is the first study to provide new evidence for the use of Sacubitril/Valsartan in aged cancer patients of 3 kinds of HF.

Sacubitril/Valsartan in Patients Hospitalized With Decompensated Heart Failure.

BACKGROUND: The efficacy and safety of sacubitril/valsartan in patients hospitalized with heart failure (HF) across the spectrum of left ventricular ejection fraction (EF) has not been described. OBJECTIVES: Data from randomized trials of sacubitril/valsartan in HF patients with EF ≤40% (PIONEER-HF [Comparison of Sacubitril/Valsartan Versus Enalapril on Effect of NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode] trial) and >40% (PARAGLIDE-HF [Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF] trial) following recent worsening heart failure (WHF) were pooled to examine treatment effect across the EF spectrum. METHODS: The PIONEER-HF and PARAGLIDE-HF trials were double-blind, randomized trials of sacubitril/valsartan vs control therapy (enalapril or valsartan, respectively). All participants in the PIONEER-HF trial and 69.5% in the PARAGLIDE-HF trial were enrolled during hospitalization for HF after stabilization. The remainder in the PARAGLIDE-HF trial were enrolled ≤30 days after a WHF event. The primary endpoint of both trials was time-averaged proportional change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline through weeks 4 and 8. Adjudicated clinical endpoints were analyzed through the end of follow-up, adjusting for trial. RESULTS: The pooled analysis included 1,347 patients (881 from PIONEER-HF, 466 from PARAGLIDE-HF). Baseline characteristics included median age 66 years, 36% women, 31% Black, 34% de novo HF, and median EF 30%. The reduction in NT-proBNP was 24% greater with sacubitril/valsartan vs control therapy (n = 1,130; ratio of change = 0.76; 95% CI: 0.69-0.83; P < 0.0001). Cardiovascular death or hospitalization for HF was reduced by 30% with sacubitril/valsartan vs control therapy (HR: 0.70; 95% CI: 0.54-0.91; P = 0.0077). This effect was consistent across the spectrum of EF ≤60%. Sacubitril/valsartan increased symptomatic hypotension (risk ratio: 1.35; 95% CI: 1.05-1.72). CONCLUSIONS: In patients stabilized after WHF, sacubitril/valsartan led to a greater reduction in plasma NT-proBNP and improved clinical outcome compared with control therapy, in particular across the spectrum of EF ≤60%. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect of NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890; Changes in NT-proBNP, Safety, and Tolerability in HFpEF Patients With a WHF Event [HFpEF Decompensation] Who Have Been Stabilized and Initiated at the Time of or Within 30 Days Post-decompensation [PARAGLIDE-HF]; NCT03988634).

Magnolol attenuates macrophage pyroptosis triggered by Streptococcus equi subsp. zooepidemicus.

Streptococcus equi subsp. zooepidemicus (SEZ) is a zoonotic bacterial pathogen that causes life-threatening infections and various diseases such as meningitis, endocarditis and pneumonia. With the use of antibiotics being severely restricted in the international community, an alternative to antibiotics is urgently needed against bacterial. In the present study, the herbal extract magnolol protected mice against SEZ infection, reflected by increased survival rate and reduced bacterial burden. A pro-inflammatory form of cell death occurred in SEZ-infected macrophage. Magnolol downregulated the expression of pyroptosis-related proteins and reduced the formation of cell membrane pores in infected macrophages to suppress the development of subsequent inflammation. We further demonstrated that magnolol directly suppressed SEZ-induced macrophage pyroptosis, which partially protected macrophages from SEZ infection. Our study revealed that magnolol suppressed inflammation and protected mice against SEZ infection, providing a possible treatment for SEZ infection.

Magnolol derivatives as specific and noncytotoxic inhibitors of breast cancer resistance protein (BCRP/ABCG2).

The breast cancer resistance protein (BCRP/ABCG2) transporter mediates the efflux of numerous antineoplastic drugs, playing a central role in multidrug resistance related to cancer. The absence of successful clinical trials using specific ABCG2 inhibitors reveals the urge to identify new compounds to attend this critical demand. In this work, a series of 13 magnolol derivatives was tested as ABCG2 inhibitors. Only two compounds, derivatives 10 and 11, showed partial and complete ABCG2 inhibitory effect, respectively. This inhibition was selective toward ABCG2, since none of the 13 compounds inhibited neither P-glycoprotein nor MRP1. Both inhibitors (10 and 11) were not transported by ABCG2 and demonstrated a low cytotoxic profile even at high concentrations (up to 100 µM). 11 emerged as the most promising compound of the series, considering the ratio between cytotoxicity (IG50) and ABCG2 inhibition potency (IC50), showing a therapeutic ratio (TR) higher than observed for 10 (10.5 versus 1.6, respectively). This derivative showed a substrate-independent and a mixed type of inhibition. The effect of compound 11 on the ABCG2 ATPase activity and thermostability revealed allosteric protein changes. This compound did not affect the expression levels of ABCG2 and increased the binding of the conformational-sensitive antibody 5D3. A docking study showed that 11 did not share the same binding site with ABCG2 substrate mitoxantrone. Finally, 11 could revert the chemoresistance to SN-38 mediated by ABCG2.

Association Between Use of Sodium-Glucose Cotransporter-2 Inhibitors or Angiotensin Receptor-Neprilysin Inhibitor and the Risk of Atherosclerotic Cardiovascular Disease With Coexisting Diabetes and Heart Failure.

PURPOSE: This study was to investigate the association between the use of Sodium-glucose Cotransporter-2 inhibitors (SGLT2i) or angiotensin receptor-neprilysin inhibitor (ARNI; ie, Sacubitril + valsartan, Product name ENTRESTO) and the risk of atherosclerotic cardiovascular disease (ASCVD) in patients with coexisting diabetes and heart failure. Specifically, the study compared outcomes between patients using SGLT2i or valsartan + sacubitril and those not using these medications. METHODS: This study utilized data from the National Health Insurance Research Database (NHIRD) from 2017 to 2018. The case group consisted of 8691 patients with coexisting diabetes and heart failure who did not use SGLT2i or Entresto, while the control group consisted of 8691 patients with coexisting diabetes and heart failure who used SGLT2i or Entresto. The primary outcome was ASCVD, including a composite of cardiovascular death and hospitalization for worsening heart failure. Secondary outcomes included all-cause death, cause of cardiovascular death, and recurrence of heart failure, non-fatal myocardial infarction, non-fatal stroke (including ischemic stroke and hemorrhagic stroke) and new renal replacement therapy. RESULTS: The study found that the use of SGLT2 inhibitors or ARNI was associated with a lower risk of ASCVD in patients with coexisting diabetes and heart failure. CONCLUSION: The study suggests that the use of SGLT2 inhibitors, alone or in combination with Entresto, may be effective in reducing the risk of ASCVD and its associated adverse outcomes in patients with diabetes and heart failure. This finding has important implications for the management of these conditions.

[Total saponins of Panax japonicus alleviates CCl4-induced acute liver injury in rats by regulating the PI3K/AktNF-κB signaling pathway].

OBJECTIVE: To investigate the protective effect of total saponins of Panax japonicus (TSPJ) against CCl4-induced acute liver injury (ALI) in rats and explore the underlying pharmacological mechanisms. METHODS: Male SD rat models of CCl4-induced ALI were given intraperitoneal injections of distilled water, 100 mg/kg biphenyl bisabololol, or 50, 100, and 200 mg/kg TSPJ during modeling (n=8). Liver functions (AST, ALT, TBil and ALP) of the rats were assessed and liver pathologies were observed with HE staining. Immunohistochemistry was used to detect the expressions of PI3K/Akt/NF-κB signaling pathway molecules in liver tissue; ELISA was used to determine the levels of T-SOD, GSH-Px, and MDA. Western blotting was performed to detect the expression levels of PI3K-Akt and SIRT6-NF-κB pathways in the liver tissue. RESULTS: Network pharmacological analysis indicated that the key pathways including PI3K/Akt mediated the therapeutic effect of TSPJ on ALI. In the rat models of ALI, treatments with biphenyl bisabololol and TSPJ significantly ameliorated CCl4-induced increase of serum levels AST, ALT, ALP, TBil and MDA and decrease of T-SOD and GSH-Px levels (all P < 0.01). The rat models of ALI showed significantly increased expression of p-NF-κB (P < 0.01), decreased expressions of PI3K, p-Akt and SIRT6 proteins, and elevated expression levels of p-NF-κB, TNF-α and IL-6 proteins in the liver, which were all significantly improved in the treatment groups (P < 0.05 or 0.01). CONCLUSION: TSPJ can effectively alleviate CCl4-induced ALI in rats by suppressing inflammatory responses and oxidative stress in the liver via regulating the PI3K/Akt and SIRT6/NF-κB pathways.

Lactic acid responsive sequential production of hydrogen peroxide and consumption of glutathione for enhanced ferroptosis tumor therapy.

Ferroptosis is characterized by the lethal accumulation of lipid reactive oxygen species (ROS), which has great potential for tumor therapy. However, developing new ferroptosis-inducing strategies by combining nanomaterials with small molecule inducers is important. In this study, an enzyme-gated biodegradable natural-product delivery system based on lactate oxidase (LOD)-gated biodegradable iridium (Ir)-doped hollow mesoporous organosilica nanoparticles (HMONs) loaded with honokiol (HNK) (HNK@Ir-HMONs-LOD, HIHL) is designed to enhance ferroptosis in colon tumor therapy. After reaching the tumor microenvironment, the outer LOD dissociates and releases the HNK to induce ferroptosis. Moreover, the released dopant Ir4+ and disulfide-bridged organosilica frameworks deplete intracellular glutathione (GSH), which is followed by GSH-mediated Ir(IV)/Ir(III) conversion. This leads to the repression of glutathione peroxidase 4 (GPX4) activity and decomposition of intratumoral hydrogen peroxide (H2O2) into hydroxyl radicals (•OH) by Ir3+-mediated Fenton-like reactions. Moreover, LOD efficiently depletes lactic acid to facilitate the generation of H2O2 and boost the Fenton reaction, which in turn enhances ROS generation. With the synergistic effects of these cascade reactions and the release of HNK, notable ferroptosis efficacy was observed both in vitro and in vivo. This combination of natural product-induced and lactic acid-responsive sequential production of H2O2 as well as the consumption of glutathione may provide a new paradigm for achieving effective ferroptosis-based cancer therapy.

Candesartan upregulates angiotensin-converting enzyme 2 in kidneys of male animals by decreased ubiquitination.

Candesartan is a common angiotensin-II receptor-1 blocker used for patients with cardiovascular and renal diseases. Angiotensin-converting enzyme 2 (ACE2) is a negative regulator of blood pressure (BP), and also a major receptor for coronaviruses. To determine whether and how candesartan upregulates ACE2, we examined BP and ACE2 in multi-organs from male and female C57BL/6J mice treated with candesartan (1 mg/kg, i.p.) for 7 days. Relative to the vehicle, candesartan lowered BP more in males than females; ACE2 protein abundances were increased in kidneys, not lungs, hearts, aorta, liver, spleen, brain, or serum, only from males. Ace2-mRNA was similar in kidneys. Candesartan also decreased BP in normal, hypertensive, and nephrotic male rats. The renal ACE2 was increased by the drug in normal and nephrotic male rats but not spontaneously hypertensive ones. In male mouse kidneys, ACE2 was distributed at sodium-hydrogen-exchanger-3 positive proximal-convoluted-tubules; ACE2-ubiquitination was decreased by candesartan, accompanied with increased ubiquitin-specific-protease-48 (USP48). In candesartan-treated mouse renal proximal-convoluted-tubule cells, ACE2 abundances and activities were increased while ACE2-ubiquitination and colocalization with lysosomal and proteosomal markers were decreased. The silence of USP48 by siRNA caused a reduction of ACE2 in the cells. Thus, the sex-differential ACE2 upregulation by candesartan in kidney from males may be due to the decreased ACE2-ubiquitination, associated with USP48, and consequent degradation in lysosomes and proteosomes. This is a novel mechanism and may shed light on candesartan-like-drug choice in men and women prone to coronavirus infections.

[Research progress on pollution status and toxic effects of organophosphorus flame retardants 2-ethylhexyl diphenyl phosphate].

The environmental pollution and health hazards caused by the extensive use of organophosphorus flame retardants (OPFRs) have become a problem of wide concern around the world. As a typical OPFR, 2-ethylhexyl diphenyl phosphate (EHDPP) can be detected in water, atmosphere, soil and other environmental media. It widely exists in production and life and can accumulate in organisms, causing great risks the ecosystem and human health. This paper reviews the research of EHDPP domestically and abroad, and summarizes the physicochemical properties of EHDPP and the population situation of occupational exposure, environmental exposure, and population exposure in recent years. Besides, it summarizes the toxic effects and mechanisms of EHDPP, including acute toxicity, hepatotoxicity, neurotoxicity, reproductive and developmental toxicity, and carcinogenesis effects. This paper also proposes the future direction of toxicity and health risks of EHDPP, which provides a theoretical basis for further research on environmental hazards and safety evaluation of EHDPP.

Surface enhanced Raman spectroscopy for the characterization of the metabolites of the biodesulfurization of dibenzothiophene carried out by Tsukamurella paurometabola.

Large amount of sulphur is released by the combustion of fossil fuels in the form of SoX which affects human health and leads to acid rain. To overcome this issue, it is essential to eliminate sulphur moieties from heterocyclic organo-sulphur compounds like Dibenzothiophene (DBT) present in the petrol. In this study Surface enhanced Raman scattering (SERS) spectroscopy is used to analyze the desulfurizing activity of Tsukamurella paurometabola bacterial strain. The most prominent SERS peaks observed at 791, 837, 944 and 1032 cm-1, associated to C-S stretching, are solely observed in dibenzothiophene and its metabolite-I (DBTS) but absent in 2-Hydroxybiphenyl (metabolite-II) and extraction sample of supernatant as a result of biodesulfurization. Moreover, the SERS peaks observed at 974 (characteristic peak of benzene ring) and 1015 cm-1 is associated to C-C ring breathing while 1642 and 1655 cm-1 assigned to CC bonds of aromatic ring. These peaks are only observed in 2-Hydroxybiphenyl (metabolite-II) and extraction sample of supernatant as a result of biodesulfurization. Notably, these peaks are absent in the Dibenzothiophene and its metabolite-I which indicate that aromatic ring is carrying sulfur in this fraction. Moreover, multivariate data analytical tools like principal component analysis (PCA) and PCA-loadings are applied to further differentiate between dibenzothiophene and its metabolites that are Dibenzothiophene sulphone (metabolite-I) and 2-Hydroxybiphenyl (metabolite-II).

Revealing receptor-ligand interactions of atypical antipsychotic drugs and screening anti-schizophrenia ingredients in Magnolia officinalis based on 5-HTR2A-SNAP-Tag/CMC and DRD2-SNAP-Tag/CMC models.

Schizophrenia is a serious mental illness with unknown etiology, and shows increasing incidence and high lifetime prevalence rate. The main receptors related to the disease are DRD2 and 5-HTR2A. Thus, a comprehensive understanding of the interaction mode between antipsychotic drugs with relevant receptors is very important for developing more effective drugs. 5-HTR2A-SNAP-Tag/CMC and DRD2-SNAP-Tag/CMC models constructed in this work provided a new method for studying the interaction between atypical antipsychotics and the two receptors. The results of comparative experiments showed that the new models not only met the high selectivity and specificity of the screening requirements but were also more stable and long-lasting than the traditional CMC model. Binding assays showed that the effects of three atypical antipsychotics (including clozapine, olanzapine, and quetiapine) on 5-HTR2A were stronger than their effects on DRD2. Additionally, two potentially active components, magnolol and honokiol, were screened in Magnolia officinalis methanol extract using the 5-HTR2A-SNAP-Tag/CMCHPLC-MS system. Nonlinear chromatographic analysis and molecular docking were conducted to study the interactions between screened compounds and the two receptors. The binding constants (KA) of magnolol and honokiol with 5-HTR2A were 17,854 ± 1,117 M-1 and 38,858 ± 4,964 M-1, respectively, and KA values with DRD2 were 4,872 ± 1,618 M-1 and 20,692 ± 10,267 M-1, respectively. We concluded that the established models are reliable for studying receptor-ligand interactions and screening antagonists of schizophrenia.

Construction of Magnolol Nanoparticles for Alleviation of Ethanol-Induced Acute Gastric Injury.

Ethanol (EtOH) has been identified as a potential pathogenic factor in gastric ulcer development primarily due to its association with gastric injury and excessive production of reactive oxygen species. Magnolol (Mag), the principal active compound in Magnolia officinalis extract, is well studied for its notable anti-inflammatory and antioxidant properties. However, its limited solubility, propensity for agglomeration, and low absorption and utilization rates significantly restrict its therapeutic use. This study aims to overcome these challenges by developing a Mag nanoparticle system targeting the treatment and prevention of EtOH-induced gastric ulcers in mice. Utilizing a click chemistry approach, we successfully synthesized this system by reacting thiolated bovine serum albumin (BSA·SH) with Mag. The in vitro analysis revealed effective uptake of the BSA·SH-Mag nanoparticle system by human gastric epithelial cells (GES-1), showcasing its antioxidant and anti-inflammatory capabilities. Additionally, BSA·SH-Mag exhibited gradual disintegration and release in simulated gastric fluid, resulting in a notable reduction of oxidative stress in gastric tissues and mucosal tissue repair and effectively reducing inflammatory expression. Furthermore, BSA·SH-Mag attenuated EtOH-induced gastric inflammation by decreasing the level of NOX4 protein expression and augmenting the level of Nrf2 protein expression. In conclusion, our findings indicate that BSA·SH-Mag represents a promising candidate as an oral therapeutic for gastric ulcer treatment.

Modular preparation of biphenyl triazoles via click chemistry as non-competitive hyaluronidase inhibitors.

Hyaluronidase is a promising target in drug discovery, given its overexpression in a range of physiological and pathological processes, including tumor migration, skin aging, sagging, and wrinkling, as well as inflammation and bacterial infections. In this study, to identify novel hyaluronidase inhibitors, we applied click chemistry for the modular synthesis of 370 triazoles in 96-well plates, starting with biphenyl azide. Utilizing an optimized turbidimetric screening assay in microplates, we identified Fmoc-containing triazoles 5 and 6, as well as quinoline-containing triazoles 15 and 16, as highly effective hyaluronidase inhibitors. Subsequent research indicated that these triazoles potentially interact with a novel binding site of hyaluronidase. Notably, these inhibitors displayed minimal cytotoxicity and showed promising anti-inflammatory effects in LPS-stimulated macrophages. Remarkably, compound 6 significantly reduced NO release by 74 % at a concentration of 20 µM.

New diarylcyclopentenone enantiomers and biphenyl derivatives from the fungus Talaromyces adpressus.

Ten new compounds, including three pairs of diarylcyclopentenone enantiomers (±) talaromycesins A-C (1-3) and four biphenyl derivatives talaromycesins D-G (4-7), along with four known compounds (8-11), were isolated from the fungus Talaromyces adpressus. Their structures were determined by analyses of extensive NMR spectroscopic and HRESIMS data, and their absolute configurations were elucidated by the dimolybdenum tetraacetate [Mo2(AcO)4]-induced ECD spectra, X-ray crystallographic studies, and ECD calculations. These new compounds were evaluated for their immunosuppressive activities for the first time, and compound 7 probably exerted liver-protective and anti-inflammatory effects on Con A-induced AIH by decreasing the levels of inflammatory cytokines, modulating immune homeostasis, and decreasing hepatocyte apoptosis, which may become a potential drug for the treatment of autoimmune diseases.