Journal of Pharmacy and Pharmacology最新文献

Objectives: Atherosclerosis (AS) is a chronic inflammatory disease driven by lipids that poses a serious threat to human health. Therefore, the development of drugs with both anti-inflammatory and lipid-lowering properties can provide new hope for the treatment of AS.

Methods: Previous studies have shown that the N-salicyloyl tryptamine derivative B2, formed by combining salicylic acid derivatives and the melatonin skeleton, exhibits strong anti-inflammatory activity and high biosafety. In this study, we used lipopolysaccharide (LPS)/ adenosine triphosphate (ATP) or LPS-stimulated macrophage-conditioned medium to establish an endothelial cell inflammation model. Apolipoprotein E-/- (ApoE-/-) mice fed a high-fat diet (HFD) were used to establish the atherosclerosis animal model.

Key findings: We found that B2 inhibited LPS/ATP-induced inflammation and apoptosis of endothelial cells, reduced monocyte-endothelial cell adhesion, decreased vascular cell adhesion molecule-1, intercellular adhesion molecule-1, monocyte chemoattractant protein-1, interleukin-6 (IL-6), and interleukin-1β, and inhibited the mitogen-activated protein kinase kinase 4/c-Jun N-terminal kinase pathway. In ApoE-/- mice fed a HFD, ELISA and lipid assay revealed that B2 reduced plasma IL-6 and triglyceride levels. Meanwhile, Oil Red O staining and Masson staining showed that B2 decreased the aortic plaque area and the degree of fibrosis.

Conclusions: These findings suggested that B2 exerts both anti-inflammatory and lipid-lowering effects, providing a new intervention approach and direction for the prevention and treatment of AS.

Objective: CGA combination consisting of Cordyceps sinensis polysaccharide, gypenosides, and amygdalin, is derived from Fuzheng Huayu capsule (a traditional Chinese medicine approved for liver fibrosis) via previous Uniform Design Experimentation. The effect of CGA on metabolic dysfunction-associated steatohepatitis (MASH) and the potential mechanism based on bile acids (BAs) alternative biosynthesis pathway-farnesoid X receptor (FXR) axis are investigated here.

Methods: Alanine aminotransferase, hepatic triglyceride, malondialdehyde (MDA), BAs, fatty acids oxidation (FAO) activity, mRNA of inflammatory cytokines, α-smooth muscle actin (α-SMA), transforming growth factor-β, collagen type I, and FAO enzymes were detected. Liver sections underwent hematoxylin-eosin, Oil Red O, and Sirius red staining, and immunohistochemistry assay of F4/80 and α-SMA. Protein expression of peroxisome proliferator-activated receptor α (PPAR-α), FXR, BAs biosynthesis enzymes, small heterodimer partner (SHP), bile salt export pump (BSEP), adenosine triphosphate-binding cassette sub-family B member 4 (ABCB4) and nuclear factor-kappa B were detected.

Key findings: CGA ameliorated MASH, restoring FAO, PPAR-α, and FXR, accompanied by increased chenodeoxycholic acid proportion in the FXR agonist BAs pool, BAs alternative biosynthesis, and the FXR targets including SHP, BSEP, and ABCB4.

Conclusion: CGA ameliorates MASH, promoting the hepatic BAs alternative biosynthesis pathway to activate FXR-PPARα restoring FAO.

Objectives: Latroeggtoxin-VI (LETX-VI) was previously shown to cross cell membrane and its C-terminal sequence is the functional peptide segment (FPS) for the transmembrane action. This proof-of-concept study aimed to confirm the promoting-effect of FPS as well as LETX-VI on nasal insulin absorption.

Methods: After FPS and LETX-VI were intranasally coadministrated with insulin to mice, respectively, the changes in hypoglycemic effect of the insulin were determined.

Results: Compared with insulin alone, the mixture of insulin and 0.5 mM LETX-VI decreased the peak blood glucose concentration by 33.14% (P < .05); coadministration of insulin and 4 mM FPS decreased the peak value of blood glucose by 19.88% (P < .05). Besides, addition of 4 mM FPS decreased the AUC0-90 min value from 1062.50 of insulin alone to 926.17, which was significantly lower than that of the blank control (P < .05); FPS made the insulin exert hypoglycemic effect earlier and did not change the end time of the hypoglycemic action.

Conclusion: Both LETX-VI and FPS are able to efficiently facilitate nasal insulin absorption and thus enhance the hopyglycemic effect of insulin. Relatively, FPS has a much smaller molecular weight and thus is more promising in the transmembrane delivery of drugs including insulin.

Objectives: Staphylococcus epidermidis is a public health concern due to its antimicrobial resistance, causing infections that can worsen in immunosuppressed patients. Geopropolis (GEO) is produced by Meliponines and contains anacardic acid (AA). This study evaluated the antibacterial action of GEO and AA, and their modulatory effects on macrophages, both with and without dexamethasone (DEX) treatment.

Methods: The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of GEO, AA, ceftaroline (CPT), and gentamicin (GEN) were evaluated. The effect of the treatments was evaluated on the bacteria's ability to produce biofilm and on THP-1 cells differentiated into macrophages with or without DEX, evaluating cell viability, TLR-2 expression, eicosanoids (PGE2 and LTB4), cytokine (TNF-α, IL-1β, IL-6, and IL-10), and the bactericidal activity against S. epidermidis.

Key findings: GEO exhibited no antibacterial activity. AA had a more efficient MIC and MBC than the antimicrobials and inhibited biofilm formation. AA did not affect TLR-2 expression. It increased the bactericidal capacity of macrophages suppressed or not by DEX, and inhibited IL-10 production. Our findings suggest AA practical applications, as antibacterial coatings, wound care formulations, and infection control.

Conclusions: AA has antibacterial and immunomodulatory properties and could be an effective adjuvant in treating S. epidermidis infection.

Objectives: Frankenia hirsuta (FH) is an underexplored halophytic plant used for managing inflammatory and metabolic disorders. However, its phytochemical composition and pharmacological mechanisms remain largely uncharacterized. Thus, this study aimed to comprehensively elucidate the phytochemical profile, molecular mechanisms, and pharmacological efficacy of FH using an integrated approach combining liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolite characterization, in vitro bioassays, in-vivo validation, and computational analyses.

Methods: Metabolite profiling was performed using LC-MS/MS, followed by molecular docking and network pharmacology analyses to predict potential targets involved in neuropathic, inflammatory, and metabolic pathways. In vitro cytotoxicity and anticoagulant activities of the aerial and root ethanolic extracts were assessed using MTT and activated partial thromboplastin time (aPTT) assays, respectively. The in vivo antidiabetic and neuroprotective effects were evaluated in streptozotocin-induced diabetic mice, using behavioral assays (hot plate and von Frey filaments), biochemical markers of oxidative stress and inflammation, and histopathological and immunohistochemical (IHC) examinations.

Key findings: LC-MS/MS analysis revealed a diverse bioactive constituents, including phenolic acids, flavonoid glycosides, and feruloyl derivatives. Network pharmacology and docking studies highlighted strong binding affinities toward key enzymes such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), cyclooxygenase-2, and AKT1, indicating multimodal anti-inflammatory and neuroprotective potential. In vitro, FH extracts exhibited significant cytoprotective effects and prolonged aPTT in a dose-dependent manner, confirming their safety and mild anticoagulant properties. In vivo, FH root extract (75 mg/kg) and its isolated feruloyl glycoside (FG) (5-10 mg/kg) significantly restored nociceptive thresholds, improved glycemic control, normalized oxidative and inflammatory biomarkers, and preserved pancreatic and sciatic nerve histoarchitecture. IHC analyses further demonstrated downregulation of TNF-α and IL-6 and upregulation of IL-10 in treated groups, confirming their anti-inflammatory and regenerative effects.

Conclusions: This study provides the first comprehensive evidence that FH exerts potent neuroprotective and antidiabetic effects mediated through antioxidant, anti-inflammatory, and cytokine-modulating pathways. The integrated LC-MS/MS, computational, and experimental validation framework highlights FH and its FG as promising candidates for developing safe, plant-derived therapeutics targeting diabetic neuropathy and related metabolic dysfunctions.

Objective: Forsythiae Fructus, the fruit of Forsythia suspensa (Thunb.) Vahl, is a traditional Chinese medicine widely used for clearing heat and detoxifying and for treating inflammatory conditions such as fever and respiratory infection. Its effective ingredients include phillyrin, a lignan component with pharmacological properties, including anti-inflammation and antioxidation. This study investigated the effects of phillyrin on epithelial barrier dysfunction caused by acute lung injury (ALI) and key signaling pathways in rats with lipopolysaccharide (LPS)-induced ALI to explore its mechanism of attenuating ALI.

Results: Analysis of the lung wet/dry weight ratio, myeloperoxidase activity, pathological sections, and proinflammatory factor levels in vivo revealed that phillyrin could alleviate LPS-induced ALI. Network pharmacology showed 125 hub targets between phillyrin and ALI and indicated that the Rho activator (RhoA) was the main target in the enriched pathway, and the RhoA/Rho-associated protein kinase (ROCK) was pivotal in phillyrin's therapeutic effects against ALI. Phillyrin improved tight junctions in the rats with LPS-induced ALI. In addition, western blot analyses revealed that phillyrin inhibited ALI-induced increments in RhoA, Rho-associated protein kinase 1, and myosin light-chain kinase proteins. Inhibitor experiments demonstrated that after fasudil inhibited the signaling pathway, phillyrin did not increase its inhibitory effect on key pathway proteins and its improvement effect on epithelial dysfunction.

Conclusions: Phillyrin inhibits pulmonary edema, suppresses inflammation and oxidative stress in ALI rats, and improves LPS-induced alveolar epithelial barrier dysfunction by inhibiting RhoA/ROCK pathways.

Objectives: To highlight recent developments in CRISPR/Cas9 genome-editing strategies for cancer therapy and to evaluate how nanocarrier-based delivery systems enable controlled, spatiotemporal manipulation of genetic information to overcome off-target effects, cytotoxicity, and limitations in clinical translation.

Key findings: CRISPR/Cas9 has emerged as a simple and programmable tool for correcting cancer-associated mutations and regulating adaptive immune responses; however, challenges such as off-target effects, unintended mutations in healthy cells, and cytotoxicity hinder its clinical application. Nanocarriers address these limitations through refined spatiotemporal delivery of Cas9 nuclease and sgRNA using internal and external stimuli-responsive functional groups. These systems improve cancer-cell specificity by engineering guide RNAs, prevent premature clearance, enhance systemic circulation and intracellular delivery, enable nuclear targeting, and regulate Cas9 activity. Stimuli such as light, heat, ultrasound, magnetic fields, pH, redox conditions, glutathione, and oxygen play key roles in controlled activation and release.

Summary: This review critically evaluates the structural design of nanocarriers, advanced spatiotemporal regulation strategies, and safety and efficacy concerns in CRISPR/Cas9-based cancer therapeutics. It discusses the role of cell-specific promoters, small-molecule stimulation, and stimuli-responsive delivery systems in improving genome-editing precision and therapeutic outcomes. The review also outlines future opportunities for exploiting CRISPR/Cas9 in advanced biomedical applications to enhance the effectiveness of next-generation cancer therapy.

Objectives: Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor. ADMA concentrations are augmented in lung, plasma samples of asthmatics. It remains unclear whether the increased concentration of ADMA in airway inflammation contributes to the pathophysiology or acts as a protective mechanism. The objective of this study was to evaluate the effects of exogenous ADMA on airway inflammation in mice.

Methods: Ex vivo/in vivo airway inflammation models were used. Tracheal tissues, isolated from female Balb/c mice were incubated with lipopolysaccharide (LPS), ADMA, or LPS + ADMA for 4 days in tissue culture. Tracheal reactivity was evaluated afterward by agonist-induced contraction responses. Female Balb/c mice were applied i.n. LPS (0,1 mg/ml) to induce in vivo airway inflammation. ADMA (30 mg/kg) was administered by i.n. route 1 h before and 24 h after LPS application.

Key findings: I.n. ADMA application augmented lung ADMA levels, reduced nitrite levels in bronchoalveolar lavage (BAL) fluid, prevented bronchial hyperreactivity and airway inflammation. ADMA also prevented bronchial hyperreactivity when applied 15 min before methacholine nebulization during the assessment of airway function.

Conclusion: Exogenously applied ADMA may have protective effects in airway inflammation by limiting excessive nitric oxide (NO) production. Targeting the DDAH/ADMA/NOS pathway may provide a therapeutic approach for airway inflammation.

Objective: Renal ischaemia reperfusion (I/R) injury is considered one of the main causes of acute kidney injury which can happen because of kidney transplantation surgeries. Renal I/R injury usually leads to activated inflammatory response, accumulating reactive oxygen species, and eventually, leading to apoptosis.

Methods: The rats were randomly divided into five groups (n = 6), sham, I/R, where the rats were subjected to a surgery performing bilateral renal I/R, two different does were given of Quercetin (Q), 50 mg and 100 mg, for 10 days before I/R surgery; however, EX527, a selective silent information regulator 1 (SIRT-1) inhibitor, was given with the former does in the last group, where it was administered 1 hr. after Q injection each day of the mentioned 10 days.

Key findings and conclusions: The results showed that Q preserved the kidney functions from via acting as antioxidant by upregulating the superoxide dismutase and SLC7A11 levels, downregulating the inflammatory markers, NF-κB, TNF-α, as well as suppressing ATF4/CHOP, and p53/miR34-a/p66Shc/caspase 3 apoptotic pathways. However, the use of EX527 showed a surge of the inflammatory and apoptotic responses and a depletion of renal antioxidant capacity; thus, reversing the observed protective actions to suggest the significant role of SIRT-1 activation by Q, still potential off-targets actions of the former cannot be excluded.

Objectives: Conventional pharmacotherapies afford only modest renoprotection in diabetic nephropathy (DN). Oleanolic acid (OA), a pentacyclic triterpenoid abundant in Traditional Chinese Medicine (TCM), mitigates DN, but its mechanism remains unclear. This study aimed to verify the hypothesis that OA protects podocytes by modulating autophagy, thereby exploring the potential therapeutic mechanism of OA in attenuating DN.

Methods: High glucose-injured MPC5 podocytes were treated with OA to evaluate its impact on autophagy. Podocytes were further treated with graded concentrations of OA, rapamycin (an autophagy inducer), or 3-methyladenine (an autophagy inhibitor). Cell viability was quantified using the Cell Counting Kit-8 assay. Nuclear morphology was visualized by DAPI staining, autophagosomes were enumerated by transmission electron microscopy, and the expression of autophagy-related genes was determined by quantitative reverse transcription polymerase chain reaction. These complementary approaches were used to assess high-glucose-induced podocyte injury and the capacity of OA to enhance autophagy and attenuate cellular damage.

Key findings: The effective concentration window for OA was established at 5-10 μM. Within this concentration range, podocyte viability was significantly increased, accompanied by a higher autophagosome count and elevated expression of autophagosomal markers.

Conclusions: Oleanolic acid alleviates high glucose-induced podocyte injury by robustly activating autophagy, underscoring its potential as a sustainable therapeutic strategy for DN, along with other active compounds derived from TCM.