Pharmaceutical Biology最新文献

Context: Systemic lupus erythematosus (SLE) is an autoimmune disease involving multiple systems. Jianpi Zishen Decoction (JZD) is a TCM formula used to improve proteinuria in SLE, which has been widely used in the treatment of renal damage in SLE.

Objective: To investigate the potential targets and action mechanisms of JZD in ameliorating renal damage in SLE through network pharmacology and in-vivo and in-vitro experiments.

Methods: The main components of JZD were determined using UPLC-Q-TOF-MS/MS. The potential targets and action mechanisms of JZD were explored using network pharmacology and molecular docking techniques. MRL/lpr mice were used as animal models, and their renal pathological changes were observed by HE staining, periodic acid-Schiff staining, and Masson staining. Additionally, mouse glomerular ultrastructure was observed using TEM. The level of urinary protein, immunoinflammatory indicators, and TLR4/MAPK pathway-related molecules were detected through a variety of experimental methods. Furthermore, the effects of JZD on LPS-stimulated HMCs were evaluated.

Results: A total of 27 prototype components were identified in the blood-entered component of JZD. Animal experiments showed that JZD effectively ameliorated renal damage and immune disorders, reduced glomerular scores and vascular wall scores, as well as attenuated IgG and C3 deposition in the kidneys of MRL/lpr mice. Network pharmacological analysis and molecular docking identified TLR4 as a core potential target of JZD's efficacy. JZD inhibited the expression of TLR4, p38, JNK, AP-1, and pro-inflammatory factors in the kidneys of MRL/lpr mice. In-vitro experiments further showed that JZD inhibited LPS-induced HMC proliferation.

Conclusion: JZD could ameliorate SLE renal damage and its active ingredients exerted therapeutic effects by inhibiting the TLR4/MAPK pathway, highlighting the therapeutic potential of JZD in modulating immunoinflammation.

Context: Angiogenesis is one of the essential protective mechanisms that promote neural repair and regeneration after ischemic stroke (IS). Salvianolic Acid B (SAB) and Benzoyl paeoniflorin (BP) are compounds extracted from the Chinese medicines Salvia miltiorrhiza Bunge and Paeonia suffruticosa Andrews, respectively.

Objective: We investigated whether SAB combined with BP alleviated IS by promoting micrangium angiogenesis and determined the potential molecular mechanisms.

Materials and methods: The impact of SAB-BP on angiogenesis after IS was investigated in middle cerebral artery occlusion (MCAO) rat model, ponatinib-induced ischemic stroke in zebrafish, and human umbilical vein endothelial cells (HUVECs). The neuroprotective effect of SAB-BP in rats was assessed using behavior tests and histopathological staining. The cerebral thrombosis assessment and angiogenesis assay were performed in the zebrafish model. Cell proliferation and angiogenesis in oxygen-glucose deprivation and reperfusion (OGD/R) HUVECs were assessed through cell viability, tube formation, migration, and invasion assays. Western blot analysis and immunofluorescence staining were used to determine the protein expression levels of Nrf2, HO-1, and VEGFA.

Results: The findings indicated that SAB-BP significantly reduced neurological impairment following IS and promoted the formation of functional vessels in the cerebral ischemic penumbra. Furthermore, SAB-BP up-regulated the protein expression of Nrf2, HO-1, HIF-1α, and VEGFA. Intriguingly, the pro-angiogenic effect of SAB-BP markedly restrained by adding the inhibitor of Nrf2 (ML385).

Discussion and conclusion: Our study demonstrates that SAB-BP enhances angiogenesis following IS by modulating the Nrf2/HO-1/VEGFA signaling axis both in vivo and in vitro. SAB-BP could serve as a promising therapeutic agent for IS recovery.

Context: Chronic heart failure (CHF) is the common concern following myocardial infarction. Xijiaqi Formula (XJQ) effectively treats CHF clinically while the underlying mechanism remains unclarified.

Objective: This study was designed to investigate the effect and mechanism of XJQ on CHF in rats following MI.

Materials and methods: UHPLC-Q-TOF-MS/MS was utilized to analyze the constituents of XJQ. Post-MI CHF was induced in rats by permanent ligation of the left anterior descending coronary artery. Cardiac function was assessed by echocardiogram and hemodynamic. Myocardial morphology, fibrosis, and ultrastructure were evaluated through HE staining, Masson staining, and transmission electron microscopy, respectively. Myocardial transcriptomics were employed to identify genes that may be altered in response to XJQ treatment. Consistently, XJQ inhibited TGF-β1-induced myofibroblast activation in vitro.

Results: XJQ significantly improved cardiac function and structure, mitigating fibrosis, edema, and mitochondrial damage, while reducing key biomarkers (BNP, NT-proBNP, cTnT, Ang II). Transcriptomic analysis indicated that the differentially expressed genes influenced by XJQ were predominantly associated with extracellular matrix (ECM) remodeling. Notably, XJQ inhibited the upregulation of ECM proteins, including Adamts2, Fbln1, Itgbl1, and Ltbp3 mRNAs, as well as the proteins TGF-β1, P-Smad2/3, and MMP2. Additionally, in vitro experiments revealed that XJQ significantly suppressed the activation of myofibroblasts induced by TGF-β1.

Conclusions: XJQ significantly attenuated the progression from MI to CHF by inhibiting fibroblast activation mediated by TGF-β1/Smads signaling. The molecular mechanisms underlying this effect appear to be intricately linked to its regulation of ECM remodeling proteins, specifically Adamts2, Itgbl1, Fbln1, and Ltbp3.

Context: The growing multidrug resistance (MDR) of Pseudomonas aeruginosa presents a pressing global health challenge and demands novel solutions. Medicinal plants offer a largely untapped reservoir of structurally diverse compounds with promising antibacterial and adjuvant potential.

Objective: This study investigated Sida acuta Burm.f. (Malvaceae) as a reservoir of dual-target phytochemicals capable of modulating resistance.

Materials and methods: An integrated workflow combining LC/Q-TOF-MS metabolomic profiling, molecular docking (MD), dynamics simulations (MDS), and microbiological assays was applied to the ethyl acetate fraction of the aerial parts (SAAP-EA).

Results: Metabolomic analysis identified 35 compounds, including biochanin A (BCA), resveratrol (RSV), methyl gallate (MG), 3-hydroxycinnamic acid (3-HCA), and azelaic acid (AZA), with favorable drug-likeness. Their toxicity predictions indicated low risks of acute toxicity (LD₅₀ >900 mg/kg), mutagenicity, and carcinogenicity, but flagged a potential nephrotoxicity risk requiring further investigation. MD and MDS revealed stable RSV and BCA binding to both BamB (outer membrane biogenesis) and OprM (efflux), while 3-HCA and AZA preferentially targeted OprM with higher affinities than reference inhibitors. Hydrogen-bonding supported specificity and complex stability. Experimentally, SAAP-EA showed potent bactericidal activity against clinical MDR P. aeruginosa (MIC 32-256 µg/mL) and synergized with β-lactams, fluoroquinolones, and tetracyclines, achieving up to 64-fold MIC reductions at sub-inhibitory doses. The dual inhibition of membrane assembly and efflux likely underlies the observed resistance-breaking effects, facilitating intracellular antibiotic accumulation.

Discussion and conclusions: These findings establish a mechanistic basis for translating ethnopharmacology into therapeutic strategies against MDR Gram-negative pathogens. Future work should prioritize in vivo validation and preclinical optimization of lead dual-target adjuvants.

Background: Triptolide (TP), derived from Tripterygium wilfordii, exhibits anti-inflammatory, immunosuppressive, and antifibrotic properties with potential for treating renal diseases, but its clinical use is restricted by dose-dependent nephrotoxicity.

Objective: The aim of this review is to comprehensively summarize the dual roles of TP, elucidate its therapeutic mechanisms and nephrotoxic pathways, and to explore strategies to mitigate its toxicity.

Methods: A literature search was performed using the PubMed and Web of Science databases. The search covered publications from the earliest available date until November 2025. The key search terms included 'triptolide', 'renal', 'kidney' and their combinations.

Results: TP exerts dose-dependent dual effects in renal models. Therapeutic doses (typically ≤200 μg/kg in vivo) demonstrate efficacy in modulating immune responses, protecting podocytes, promoting apoptosis in hyperproliferative cells and inhibiting renal fibrosis. Conversely, its nephrotoxicity manifests at supratherapeutic doses (often >400 μg/kg in vivo) through oxidative stress, inflammation, metabolic dysregulation, and direct damage to renal tubular cells. The therapeutic efficacy and toxicity of TP are critically contingent on both dose and temporal parameters.

Conclusion: TP holds significant but challenging potential for renal therapy. Future research should define its therapeutic window and advance strategies such as structural analogs, targeted delivery systems, and combination therapies to effectively separate efficacy from toxicity for clinical translation.

Context: Unique ecozones, such as those in Canada, play an important role in the production of distinct natural product chemicals that help plants survive highly variable abiotic conditions and herbivory. Extracts prepared from Arnica cordifolia Hook. (heartleaf arnica), a North American species related to the European medicinal plant Arnica montana L., induce mitotic arrest in human cancer cell lines with a mitotic spindle morphology distinct from other mitotic inhibitors isolated from prairie plant species.

Objective: This study aimed to identify the anti-mitotic compound(s) of A. cordifolia.

Materials and methods: The cytotoxic and anti-mitotic activities of A. cordifolia extracts and their active compounds on human cancer cells were characterized by MTT assays, light microscopy, flow cytometry, and immunofluorescence microscopy. The active compounds were isolated by bioassay-guided HPLC fractionation and identified by NMR.

Results: Five anti-mitotic sesquiterpene lactones were isolated from A. cordifolia: three previously unidentified structures, and the known compounds aromaticin and pulchellin-2α-O-isovalerate. These compounds induced rounded cells positive for the mitotic marker phospho-histone H3 at concentrations of 5 µM, yet had distinct effects on mitotic spindle morphology. Furthermore, aromaticin treatment induced ubiquitin foci in cells, indicating that it may target the ubiquitin-proteasome pathway.

Discussion and conclusion: This is the first report of mitotic inhibitors from Arnica cordifolia. Of these five compounds, three have previously undescribed chemical structures, whereas new anti-mitotic activities have been identified for aromaticin and pulchellin-2α-O-isovalerate. Differences in their biological activities suggest that they possess distinct cellular targets. These findings support continued exploration of Canadian botanical species as sources of structurally diverse bioactive compounds.

Context: The pharmacological effects of Kaempferia parviflora have been extensively documented. A solid self-microemulsifying drug delivery system (SMEDDS) has been developed to address limitations such as poor water solubility and low bioavailability.

Objective: This study evaluated the safety and anti-aging efficacy of the solid SMEDDS containing K. parviflora extract (KPS-SMEDDS) in rats.

Materials and methods: A sub-chronic toxicity study was performed to assess the safety of KPS-SMEDDS. Healthy rats (n = 10/group) received oral doses of 125, 250, or 500 mg/kg body weight daily for 90 days. Clinical signs, body weight, hematological and biochemical parameters, and major organ histopathology were evaluated. Separately, the anti-aging effects of KPS-SMEDDS were investigated in a different cohort of rats (n = 9/group) with D-galactose-induced aging. Rats received intraperitoneal D-galactose (50 mg/kg/day) and oral KPS-SMEDDS at the same doses for 60 days. Oxidative stress markers, hormone levels, histopathology, and the expression of proteins related to aging, apoptosis, and inflammation were assessed.

Results: No significant changes were observed in clinical signs, body weight, organ weights, hematological or biochemical parameters, or histopathology in KPS-SMEDDS-treated rats, indicating its safety. KPS-SMEDDS treatment significantly improved testicular weight, reduced malondialdehyde levels, normalized hormone levels, and restored testicular structure in rats with D-galactose-induced aging. Additionally, it upregulated SIRT-1 and Bcl-2, downregulated SA-β-gal, p53, and caspase-3, and modulated inflammatory cytokines (TNF-α, IL-6, and IL-10).

Discussion and conclusion: KPS-SMEDDS was well-tolerated in rats and exerted protective effects against D-galactose-induced aging. These findings support its potential as a safe, natural anti-aging agent and highlight the value of formulation enhancement in traditional herbal medicine.

Context: Several coumarins have been isolated from Ruta graveolens L., but the chirality of many remains uncharacterized or their absolute configurations unresolved.

Objective: This study aimed to comprehensively separate and characterize the chirality of 3'-methyl-3'-butenylcoumarins from R. graveolens extracts, determine their absolute configurations, and evaluate their anticoagulant and anti-inflammatory activities.

Materials and methods: Comprehensive chromatographic separation and chiral HPLC analysis were employed on the R. graveolens extract. The structures of isolated compounds were elucidated using extensive spectroscopic data analysis (HR-ESI-MS, NMR) and by comparing experimental circular dichroism (CD) spectra with calculated electronic circular dichroism (ECD) spectra. The anticoagulant and anti-inflammatory (specifically inhibition of nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages) activities of the isolated compounds were evaluated.

Results: The study led to the isolation of two pairs of enantiomeric 3'-methyl-3'-butenylcoumarins, present in both equivalent and inequivalent ratios. This included two previously undescribed chiral 3'-methyl-3'-butenylcoumarins with specific absolute configurations [(+)-2'R-2 and (-)-2'S-3] and one undescribed achiral 3'-methyl-3'-butenylcoumarin (1). Among the tested compounds, only the racemic mixture (±)-3 exhibited moderate inhibition of NO production in the anti-inflammatory assay. No significant anticoagulant activity was reported for the compounds.

Conclusions: This study successfully characterized the chirality and determined the absolute configurations of specific 3'-methyl-3'-butenylcoumarins from R. graveolens, including the discovery of three new compounds. While most isolated compounds lacked significant anticoagulant or anti-inflammatory activity in the tested models, racemic (±)-3 showed moderate anti-inflammatory potential by inhibiting NO production. These findings provide new insights for the future development and utilization of coumarins from R. graveolens.

Context: No vaccine or effective therapy for cryptosporidiosis currently exists, except for nitazoxanide (NTZ), which has limited effectiveness in immunocompromised hosts. Kaempferol (KPF), a naturally occurring flavonoid, has various pharmacological effects and promising antiparasitic properties.

Objective: The current work aimed to examine the impact of KPF compared with NTZ on Cryptosporidium parvum (C. parvum) using both in silico molecular docking and in vivo studies with an experimentally infected immunocompromised mouse model.

Materials and methods: The present study utilized KPF and NTZ as multi-target ligands to predict, determine, and evaluate their in silico target-interacted forms, thereby demonstrating their therapeutic properties against C. parvum. Mice were immunosuppressed and divided into six groups: DEXA, Model, KPF as prophylaxis, treatment with KPF, NTZ, and a combination of KPF and NTZ. Treatment efficacy was assessed through parasitological, histopathological examination, and immunohistochemical analysis of intestinal tissues using NLRP3 protein.

Results: The in silico findings supported the use of KPF and NTZ as inhibitors of C. parvum growth by blocking the action of C. parvum choline and pyruvate kinases. The in vivo study demonstrated that KPF exhibits anti-cryptosporidial efficacy, particularly when combined with NTZ. The KPF+NTZ had the best results, as evidenced by a significant decrease (p < 0.001) in oocyst shedding of 83%, improved intestinal histological damage, and inhibition of the NLRP3 inflammasome pathway.

Discussion and conclusion: KPF demonstrated the potential to mitigate the consequences of cryptosporidiosis and serve as an adjuvant agent to NTZ by reducing the oocyst burden, alleviating intestinal inflammation, and facilitating mucosal repair.

Context: Moringa oleifera Lam. (Moringaceae) and Ganoderma lucidum (Curtis) P. Karst. (Ganodermataceae) are two natural resources with established neuroprotective properties. However, whether their combination is safe and has neuroprotective effects against dementia remains unexplored.

Objective: This study aimed to investigate the phytochemical composition, toxicity profile, and neuroprotective activity of fermented M. oleifera and G. lucidum mixture (FMG) in scopolamine-induced dementia model rats.

Methods: FMG was produced by fermentation with Bacillus subtilis. A state of cognitive impairment was induced in rats via daily intraperitoneal administration of scopolamine (4 mg/kg) for 28 days. Following a two-week treatment period, cognitive function was assessed using the Y-maze. Postmortem analyses included biochemical assays to measure brain acetylcholinesterase (AChE) activity and oxidative stress markers, and histological examination of the hippocampus.

Results: LC-MS analysis revealed a rich phytochemical profile. The no-observed-adverse-effect level (NOAEL) was 200 mg/kg/day, while the lowest-observed-adverse-effect level (LOAEL) was 600 mg/kg/day. Treatment at the 200 mg/kg dose significantly reversed memory deficits, restoring spontaneous alternation from 29.1% in scopolamine-treated rats to 82.6% (p < 0.05). This behavioral recovery was correlated with a significant reduction in brain AChE activity, a normalization of lipid peroxidation (TBARS) levels, and the restoration of hippocampal neuronal architecture.

Discussion and conclusions: The restorative effects of FMG are mediated by a dual mechanism involving the enhancement of central cholinergic and antioxidant systems. These results suggest that FMG possesses neuroprotective and antioxidant properties and could be a promising candidate for the management of cognitive deficits.