Current pharmaceutical design最新文献

Cholesterol transport within the brain represents a highly regulated process essential for maintaining neuronal function and central nervous system (CNS) homeostasis. Unlike peripheral tissues, the brain relies on in situ cholesterol synthesis, primarily by astrocytes and other glial cells, which supply neurons via high-density lipoprotein (HDL)-like particles, identified in the human cerebrospinal fluid (CSF). The major component of HDL-like lipoproteins is the apolipoprotein E (ApoE), whose E4 isoform represents the strongest genetic risk factor for late-onset Alzheimer's disease (AD). Growing evidence suggests that impaired cholesterol transport contributes to the pathogenesis of various neurodegenerative disorders, particularly AD, a major public health concern due to increasing prevalence and the lack of effective treatments. Indeed, the unconvincing outcomes of the amyloid-targeting monoclonal antibodies underscore the urgency of identifying alternative therapeutic strategies. This review provides a comprehensive analysis of cholesterol transport mechanisms within the brain and their dysregulation in AD by examining the astrocyte-to-neuron cholesterol supply pathways, including endogenous biosynthesis, cholesterol efflux from astrocytes, neuronal uptake, and intracellular processing. Key molecular players involved in each step are discussed, focusing on their roles in AD pathophysiology and potential as therapeutic targets. Furthermore, the review critically evaluates recent preclinical studies exploring pharmacological interventions able to modulate cerebral cholesterol homeostasis. These emerging approaches offer promising alternatives to amyloid-based treatments and may open new perspectives for preventing or mitigating neurodegeneration in AD. By providing an integrated overview of cholesterol transport in the brain, this review highlights novel directions for research and drug development targeting CNS cholesterol metabolism.

Introduction: Sepsis-induced acute lung injury (S-ALI) is one of the diseases with a very high fatality rate. However, the traditional Chinese medicine compound Buzhong Yiqi Decoction (BZYQD) has an excellent effect in the treatment of S-ALI. Nevertheless, its mechanism of action is still unclear. In this study, we explored the molecular mechanisms of S-ALI injury treated with buzhong yiqi decoction through network pharmacology, in combination with in vivo experimental validation.

Methods: Traditional Chinese medicine system pharmacology (TCMSP) database was used to screen the chemical composition of BZYQD and its action targets; Multiple databases were used to collect target genes for-S-ALI, including OMIM, TTD, GeneCards, and DrugBank; The STRING database was used for the protein- protein interaction (PPI) analysis of the common targets of the BZYQD and the S-ALI; The DAVID database was used for GO and KEGG analysis; molecular docking was used to detect the binding capacity of core components and targets. HE staining was used to visualize the pathology of lung tissue in each group; ELISA was used to detect the levels of inflammatory factors (IL-1β, IL-6, IL-8, NF-κB and TNF-α) and oxidative stressrelated factors (LDH, CK-MB, SOD, GSH-Px); The qPCR and Western blot were used to examine the mRNA and protein expression of IL-1β, IL-6, TNF-α NF-κB, p-NF-κB, PI3K, p-PI3K, AKT, and IKKα.

Results: 113 chemical components and 226 targets were screened from BZYQD; 9059 S-ALI-related genes were screened out, with a total of 228 intersecting targets between BZYQD and S-ALI. Stigmasterol, quercetin, and isorhamnetin are the core components of BZYQD, PPI analysis shows that AKT1, IL6, TNF, and IL1B are the core targets of BZYQD for treating S-ALI, and molecular docking results show that the core components have high binding activity with the target; Enrichment analysis shows that these core targets are related to the TNF signaling pathway. In vivo experimental studies have found that BZYQD can improve the degree of inflammatory infiltration and edema in lung tissue of S-ALI model mice, reduce the expression of IL-6, IL-1β, IL-8, TNF-α, LDH, CK-MB, and NF-κB in serum (P<0.05), as well as the mRNA and protein expression of IL-6, IL-1β, TNF-α, NF-κB, p-NF-κB, PI3K, p-PI3K, AKT, and IKKα in lung tissue (P<0.05), and levels of SOD and GSH-Px were increased (P<0.05).

Discussion: The action targets of the main chemical components of BZYQD are TNF, AKT, and IL6. These targets can promote the activation of PI3K and TNF pathways and mediate the occurrence of inflammation and oxidative stress, which provides inspiration for the treatment of S-ALI. However, the results of this study still need to be verified in combination with in vitro approaches.

Conclusion: This study suggests that the mechanism of BZYQD in treating S-ALI may be achieved by inhibiting the

Para-probiotics, also referred to as non-viable microbial cells or cell components that confer health benefits, are emerging as promising agents in the prevention and management of inflammation-associated diseases. Unlike traditional probiotics, which require viability for efficacy, these inactivated forms offer significant advantages in terms of safety, stability, and applicability in vulnerable populations, including immunocompromised individuals. Recent studies have highlighted their capacity to modulate immune responses, enhance mucosal defense mechanisms, and reinforce intestinal barrier integrity through interactions involving microbial-associated molecular patterns (MAMPs) and host pattern recognition receptors. Such interactions influence signaling cascades like NF-κB, MAPKs, and inflammasome pathways, contributing to antiinflammatory and immunomodulatory effects. One of the key advantages is the reduced risk of adverse effects and concerns associated with live probiotic use. In addition, their robust physicochemical stability under industrial processing conditions supports their incorporation into a range of functional foods and nutraceuticals. Despite these advantages, their mechanisms of action remain incompletely understood and require further investigation. This review synthesizes current evidence on their anti-inflammatory properties, highlights preclinical and clinical studies, and discusses technological approaches for their production. Overall, these bioactives represent a safe, stable, and efficacious alternative to traditional probiotics in managing inflammatory disorders.

Introduction: Salvianolic acid B (SAB), as one of the major water-soluble compounds of Salvia miltiorrhiza, has proved to effectively reduce elevated portal pressure in cirrhotic rats. However, the short halflife and in vivo retention time of SAB affect its pharmacodynamics. Therefore, in this study, we prepared albumin nanoparticles loaded with SAB (SAB-ALB-NPs) to improve the in vivo retention time of the drug and enhance bioavailability.

Methods: We prepared and characterized SAB-ALB-NPs, including particle size, PDI, zeta potential, stability, EE, in-vitro release, and pharmacokinetics. Subsequently, we investigated the effects and potential mechanisms of SAB-ALB-NPs in CCl4-induced portal hypertension (PHT) mice models, and it was found that angiotensin- II (Ang-II) induced proliferation and contraction in hepatic stellate cells (HSCs). The CCl4 (0.3:1 in corn oil, 1mL/kg) was injected repeatedly, leading to the PHT mice model. The effect of SAB-ALB-NPs on PHT mice was evaluated by hematoxylin-eosin, Sirius red staining, immunohistochemistry, and western blot.

Results: We successfully prepared SAB-loaded albumin nanoparticles with smaller-sized particles, lower PDI and zeta potential with stable properties, and higher EE. Importantly, the SAB-ALB-NPs notably prolonged the in vitro release of SAB. SAB-ALB-NPs significantly reduced portal pressure, inhibited inflammation (decrease the concentration of TNF-α and IL-6) and hepatotoxicity of the liver (down-regulated the level of ALT and AST) against fibrous tissue hyperplasia, and reduced collagen deposition in the liver. Afterward, we used Ang-II to facilitate the proliferation of HSCs and induce HSC cell contraction. Cotreatment of SAB-ALB-NPs markedly inhibited Ang II-induced effects on cell proliferation and contraction and improved apoptosis. Importantly, SAB-ALB-NPs were preliminarily found to inhibit the expression of RhoA and ROCK II in Ang-II- treated HSC and CCl4-induced PHT mice, suggesting that SAB-ALB-NPs may participate in the regulation of RhoA/ROCK II pathway.

Conclusion: SAB-ALB-NPs improved portal hypertension by suppressing inflammation and inhibiting HSCs activation and proliferation to attenuate liver fibrosis. This therapeutic function of SAB-ALB-NPs may be owing to SAB-ALB-NPs regulating the RhoA/ROCK2 pathway, which may be one of its molecular mechanisms for reducing portal hypertension.

Introduction: Pulmonary fibrosis (PF) is a chronic pulmonary disorder with unknown etiology and an irreversible course. Traditional Chinese medicine (TCM) possesses promising clinical benefits for PF treatment through a multi-component and multi-target approach. This study evaluates the efficacy of Yangyin Yifei Tongluo Wan (YF), a traditional formulation, in the treatment of PF, and further explores the underlying mechanism.

Methods: A bleomycin (BLM)-induced PF mouse model was established. Mice were administered with low-, medium-, and high-dose YF (1.5, 3, and 6 g/kg/d, respectively). The fibrosis degree of mouse lung tissues was evaluated by morphometric measurements and hydroxyproline (HYP) analysis. Network pharmacology-based bioinformatics were employed for constructing a network involving components, targets, and disease, and YF's potential mechanism and molecular targets for PF therapy were explored. This was further validated by TUNEL staining, Western blot, RT-qPCR, and ELISA in BLM-treated mice.

Results: YF could relieve PF in BLM-treated mice in a dose-dependent manner, evidenced by a notable decrease in collagen deposition, and collagen I and III, HYP, fibronectin, vimentin, and α-SMA expressions. Network pharmacology revealed that JAK2/STAT3 signaling pathway-mediated alveolar epithelial cell apoptosis may be a potential therapeutic target for YF in treating PF. In vivo assays confirmed that YF's antifibrosis effect on BLM-induced PF was ascribed to the suppression of alveolar epithelial cell apoptosis and disruption of the JAK2/STAT3 signaling pathway.

Discussion: YF can block alveolar epithelial cell apoptosis through inactivation of the JAK2/STAT3 signaling, subsequently enhancing the resolution of PF.

Conclusion: YF may be a promising therapeutic candidate for PF treatment.

Advancements in biotechnology have played a key role in driving the development of protein- and peptide-based therapeutics. Drug delivery systems (DDSs) designed for proteins and peptides are carefully crafted to improve drug stability, enhance bioavailability, and reduce toxic side effects by ensuring precise delivery to targeted areas. However, despite their promising therapeutic potential, protein- and peptide-based drugs face substantial challenges due to their distinct physicochemical properties and biological barriers. Ongoing developments in protein- and peptide-based DDSs present valuable solutions to address these challenges, ultimately improving drug stability, delivery accuracy, and therapeutic efficacy. Researchers are actively working on creating innovative carrier technologies to further enhance the effectiveness and precision of these therapeutics. This review examines the wide-ranging applications of protein- and peptide-based therapeutics, explores advanced drug delivery techniques, and highlights various administration routes aimed at overcoming existing obstacles. In conclusion, this review offers a comprehensive understanding of protein- and peptide- based therapeutics as a viable alternative to conventional drug delivery systems, harnessing the power of cutting-edge biotechnological advancements.

Introduction: Diabetic neuropathy (DN) is a common complication of diabetes with limited therapeutic options. Given its complex pathophysiology involving oxidative stress, inflammation, and impaired nerve function, there is increasing interest in complementary therapies. This review aims to summarize the potential use of natural oils, both as dietary supplements and topical agents, for the prevention and management of DN.

Methods: A systematic literature search was conducted using databases such as SciFinder and PubMed for studies published from 1988 to January 2024. The search employed keywords including "diabetic neuropathy," "natural oils," and "bioactive constituents." Relevant studies involving preclinical and clinical evaluation of natural oils or their active compounds in DN were selected, analyzed, and categorized based on the type of oil, mode of application, and mechanism of action.

Results: Several natural oils of plant and animal origin demonstrated protective and therapeutic effects against DN in both animal models and limited clinical settings. Their beneficial effects were attributed to antiinflammatory and antioxidant properties, enhanced nerve conduction velocity, and modulation of vascular and neurotrophic factors. Both oral and topical applications contributed to symptom improvement.

Discussion: Due to the involvement of various signalling pathways and complex pathophysiology, DN has long been a condition with few acceptable treatment options. Although several natural oils have demonstrated activity against DN, very few clinical studies have been conducted to explore their therapeutic potential fully.

Conclusion: Natural oils represent a potential complementary strategy for managing DN. However, more rigorous clinical investigations are essential to confirm their safety, efficacy, and translational value.

Introduction: Polycystic ovarian syndrome (PCOS) is a hormonal condition that affects women of reproductive age. The purpose of this study was to identify the undiscovered molecular mechanisms by which Stachys lavandulifolia treats PCOS. Although Stachys lavandulifolia has been used to treat PCOS, its exact biological mechanism of action remains unknown.

Methods: We used a multifaceted strategy that included network pharmacology, molecular docking, and molecular dynamics simulations.

Results: Network pharmacology discovered 68 gene targets shared by Stachys lavandulifolia bioactive chemicals and PCOS-associated genes. Subsequent KEGG and Reactome analysis identified 18 enhanced pathways, including steroid hormone production, glucose homeostasis, and insulin resistance. Key genes involved in ovarian steroidogenesis and the hypothalamic-pituitary-ovarian axis (CYP19A1, Kiss1, human androgen receptor, oestrogen receptor alpha, and HSD17B1) were chosen for molecular docking.

Discussion: Molecular docking indicated that bioactive substances Myrsen, Agnol, Alpha Pyogenin, and Gamma Morolen have high binding affinities for the identified target proteins. Notably, the CYP19A1- Myrsen complex has the highest binding affinity at -9.0 kcal/mol. Additional molecular dynamics simulations indicated that the CYP19A1-Myrsen complex had increased flexibility and mobility, indicating a stable and effective association.

Conclusion: Our findings identify potential gene pathways and interactions through which Stachys lavandulifolia bioactive chemicals exert their therapeutic benefits in PCOS. This study establishes a solid platform for future research into Stachys lavandulifolia as a potential PCOS therapy.

Introduction: The zebrafish (Danio rerio), which lives in tropical freshwater, is thought to be one of the best animal models for studying drugs and their effects. This model is unique for its fast growth, clear embryos, genetic similarity to humans, and low cost for experiments. Literature-based data were gathered and shared so that future researchers in the field of pharmacology could get an idea of what kind of work could be done.

Methods: Journal sources like Scopus, Springer, MDPI, and PubMed were used. Seventy-four research papers from 2000 to 2025 were reviewed, but some from before 2020 were added because they were more scientifically sound. Articles about fish that aren't zebrafish were left out.

Results: In order to perform preclinical investigations of several ailments, including diabetes, cancer, cardiovascular disease, and neurological disorders, researchers are using zebrafish as an animal model. The reason behind its use is its similar genetic pattern, similar physiology, rapid development, and optical transparency.

Discussion: Researchers have found heart-healthy phospholipids, antitumor peptides, and anti-diabetic chemicals in zebrafish models, which makes them a great way to study human pathophysiology. In vivo studies using zebrafish are also easy to expand and cost-effective.

Conclusion: The emerging zebrafish model is indispensable for translational investigation. This model works as a bridge connecting in vitro assays to mammalian models. The present article is an attempt to showcase the current perspective on the pharmacological model in view of drug discovery involving zebrafish.

Introduction: Statins are widely prescribed for cardiovascular disease prevention, but their potential to increase diabetes risk has prompted regulatory warnings. Different statin drugs have varying physicochemical properties, yet comprehensive comparative assessments of their individual diabetes-related safety profiles remain limited in post-marketing surveillance data. Therefore, this study aimed to evaluate and compare the risk of diabetes-related adverse events among different statin drugs using pharmacovigilance data.

Methods: We analyzed adverse event reports from the FDA Adverse Event Reporting System (FAERS) database from 2004 to 2022. Diabetes-related adverse events were identified using relevant MedDRA Preferred Terms. Four pharmacovigilance algorithms-Reporting Odds Ratio (ROR), Medicines and Healthcare products Regulatory Agency (MHRA) standard method, Bayesian Confidence Propagation Neural Network, and Multi-Item Gamma Poisson Shrinkage-were employed to detect signals. Positive signals were defined when all four methods showed significance. Outcome severity and time-to-event were also analyzed.

Results: Among 13,438,409 ADE reports, 63,583 identified statins as primary suspect drugs, with 11,562 reporting diabetes-related events. Positive signals were detected for atorvastatin, rosuvastatin, simvastatin, pravastatin, and pitavastatin. Signal strength ranking showed atorvastatin had the strongest association (ROR 36.70; 95% CI 35.92-37.51), followed by rosuvastatin (ROR 9.63; 95% CI 9.10-10.19), pitavastatin (ROR 5.46; 95% CI 4.03-7.41), simvastatin (ROR 2.96; 95% CI 2.54-3.45), and pravastatin (ROR 2.82; 95% CI 2.14-3.71). In patients under 45, only atorvastatin showed a positive signal. Atorvastatin was associated with a higher risk of serious adverse events (PRR=1.37; 95% CI: 1.09-1.71) with a median time to event of 1,012 days.

Discussion: Our findings revealed differences in diabetes-related risk profiles among statins, with atorvastatin demonstrating the strongest signals across different age groups. The observed risk hierarchy may be attributed to differences in lipophilicity, potency, and metabolic effects. The age-dependent patterns and extended timeto- event for diabetic events underscore the importance of long-term monitoring, complementing clinical trial data with post-marketing surveillance evidence for improved statin selection.

Conclusion: Different statins demonstrate varying associations with diabetes-related adverse events, with atorvastatin showing the strongest signal across age groups. These findings may inform clinical decisionmaking when prescribing statins, particularly for patients with pre-existing diabetes risk factors.