Archives of Pharmacal Research最新文献

While studies have highlighted the negative effects of certain antidiabetic agents, similar evidence for other antidiabetic agents remains limited. In this study, we aimed to analyze bone fractures and bone mineral densities (BMDs) across patients receiving antidiabetic treatments, considering both overall and specific sites. We comprehensively searched PubMed, Embase, and ClinicalTrials.gov up to March 2024 to determine the effect of antidiabetic agent use on bone health in patients with type 2 diabetes mellitus. The primary outcome was to reveal variations in fractures across different anti-diabetic treatment modalities. The secondary outcome was the differences in BMDs based on treatment type. The fractures were grouped based on the division of specific sites. We also performed a subgroup analysis to identify differences between treatment types by dividing the study by treatment duration. The protocol is registered (CRD42024538789). A total of 234,759 individuals were enrolled in the 242 studies. We observed a trend wherein all anti-diabetic treatments were associated with decreased risk of fracture compared with placebo; however, this was not significant in direct analysis (OR 0.92, 95% CI 0.84–1.01, I² = 0, P = 0.07). For indirect analysis, glucagon-like peptide-1 receptor agonists (GLP1RAs) demonstrated a significant effect on preventing fractures in non-vertebral fracture, hip fracture, vertebral and hip fracture, and overall fracture (odds ratio [OR] 0.62, 95% confidence interval [CI] 0.43–0.90; OR 0.67, 95% CI 0.49–0.92; OR 0.64, 95% CI 0.47–0.87; OR 0.58, 95% CI 0.48–0.69, respectively). Additionally, dipeptidyl peptidase-4 inhibitors (DPP4i) significantly reduced incidences of non-vertebral fracture, vertebral and hip fracture, and overall fracture risk (OR 0.34, 95% CI 0.25–0.45; OR 0.72, 95% CI 0.55–0.95; OR 0.67, 95% CI 0.55–0.82, respectively). Meanwhile, metformin also reduces overall fracture risk (OR 0.60, 95% CI 0.42–0.88). We observed no significant differences between the antidiabetic agents according to the specific fracture site or study time point. Most antidiabetic treatments except thiazolidinediones did not increase the risk of fractures compared with the placebo. Incretin-based therapies (GLP1RA and DPP4i) exerted beneficial effects on fracture prevention compared with other treatments. These findings underscore the need for well-conducted RCTs to provide further evidence.

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder marked by mitochondrial dysfunction and oxidative stress. Although levodopa remains the gold standard for managing PD motor symptoms, it lacks neuroprotective and disease-modifying effects, highlighting the need for new neuroprotective therapies. Mitophagy, the selective mitochondrial degradation by autophagy, is critical for neuronal health. Oleanolic acid, a natural hepatoprotective compound, shows uncertain efficacy in PD treatment. This study investigated the neuroprotective effects and underlying mechanisms of oleanolic acid using the 1-methyl-4-phenylpyridinium (MPP⁺)-induced cellular model and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. In vitro, oleanolic acid demonstrated dopaminergic neuroprotection by reducing mitochondrial dysfunction and reactive oxygen species accumulation in PD cells. It upregulated the mitophagic protein DJ-1, enhancing the sequestration of damaged mitochondria into autophagosomes by mitophagy. DJ-1 knockdown attenuated oleanolic acid’s neuroprotection, confirming DJ-1’s role in oleanolic acid’s action. In vivo, pre-treatment with oleanolic acid in MPTP-induced PD mice prevented PD-like motor symptoms, reduced neuronal death in the substantia nigra, and mitigated striatal neurodegeneration. Post-treatment with oleanolic acid not only reduced these effects but also increased Bcl-2 and DJ-1 levels in the substantia nigra and striatum. In vitro, oleanolic acid activated JNK for Sp1 upregulation and nuclear translocation, which induced DJ-1 expression. Computational modeling predicted that oleanolic acid likely interacts with JNK, suggesting this binding might be necessary for JNK-Sp1-DJ-1 axis activation for mitophagy-driven neuroprotection. These results highlight oleanolic acid’s potential as a therapeutic agent in PD prevention and treatment via the JNK-Sp1-DJ-1 pathway. Further studies are required to validate its efficacy.

Saccharopolyspora spinosa, a member of the Pseudonocardiaceae family, was originally isolated from soil in the Virgin Islands and is renowned for producing spinosad, a broad-spectrum insecticidal secondary metabolite. While research on S. spinosa has historically focused on spinosad production, little is known about the broader spectrum of secondary metabolites encoded by its genome. Like Streptomyces, S. spinosa harbors numerous biosynthetic gene clusters (BGCs), many of which remain cryptic under standard laboratory conditions. In this study, the spinosyn gene cluster was deleted using the heat-sensitive vector pKC1139, generating the mutant strain S. spinosaΔSPN. The fermentation products of both the wild-type S. spinosa (B1) and S. spinosaΔSPN (B2) were analyzed through HPLC coupled with high-resolution tandem mass spectrometry (HRMS/MS). Data analysis was conducted using GNPS-based molecular networking and MestReNova. A total of seven metabolites were putatively annotated in the wild-type strain (B1), with spinosyns being the predominant compounds. In contrast, the mutant strain (B2) produced putatively linear and cyclic lipopeptides, including gageostatins and gageopeptins as the major metabolites. Additionally, the crude extract from S. spinosaΔSPN (B2) exhibited antibacterial activity, likely due to the production of lipopeptides, which are known for their antimicrobial properties. These findings indicate that deletion of the spinosyn gene cluster can activate cryptic biosynthetic pathways, leading to the discovery of novel bioactive compounds with potential applications in medicine.

The use of tacrolimus (TAC), a critical immunosuppressant post transplantation, is complicated by its high pharmacokinetic variability. While the gut microbiota has gained attention as a potential contributor, few studies have assessed its role in TAC metabolism variability. This study investigated the associations between the gut microbiota and TAC metabolism rates in kidney transplant recipients during the first month post transplantation—a crucial period for adjusting TAC to achieve therapeutic levels. We recruited 20 kidney transplant recipients and profiled their gut microbiota diversity and composition from stool samples collected before transplantation and at weeks 1 and 4 post transplantation via 16S rRNA sequencing. The TAC pharmacokinetic parameters were also collected. Associations between TAC metabolism status or pharmacokinetic parameters and gut microbiota diversity and composition were evaluated. Recipients with a fast TAC metabolism rate (C₀/D ratio < 1.05 ng/mL × 1/mg) presented significantly greater changes in both bacterial alpha and beta diversity metrics at 1 week post transplantation than did those with a slow metabolism rate (C₀/D ratio ≥ 1.05 ng/mL × 1/mg). Compared with slow metabolizers, fast metabolizers were associated with a significant increase in the abundance of three bacterial genera (Faecalibacterium, Clostridia vadinBB60, and Ruminococcus) and a significant decrease in the abundance of two bacterial species (Bacteroides plebeius and Parabacteroides goldsteinii). This study revealed links between gut microbiota diversity and composition and TAC metabolism rates in kidney transplant recipients during the early posttransplant period, underscoring the importance of investigating the gut microbiota as a contributor to TAC pharmacokinetic variability. Clarifying this causal relationship could better predict inter- and intraindividual TAC pharmacokinetic variability.

Chitinase 3-like 1 (CHI3L1) has been implicated in the pathogenesis of various diseases, including cancer. In our previous study, we found that anti-CHIL1 antibody inhibited lung tumorigenesis. It has been reported that CHI3L1 is highly overexpressed in colon cancer tissue compared with normal tissue, and high levels of serum CHI3L1 have been associated with worse colon cancer prognosis. We investigated the anticancer effect of an anti-CHI3L1 antibody on colon cancer cells. The anti-CHI3L1 antibody inhibited the cell growth of colon cancer cells in a concentration-dependent manner. The anti-CHI3L1 antibody also reduced the migration but increased apoptotic cell death in colon cancer cells. Using STRING (Search Tool for the Retrieval of Interacting Genes/Proteins), we identified an association between VEGFA and CHI3L1 in colon cancer. We confirmed interaction between VEGFA and CHI3L1 through immunoprecipitation. Furthermore, the combination treatment of the anti-CHI3L1 antibody and VEGFA siRNA inhibited cell growth but increased apoptotic cell death. Additionally, using the Human Base database, we found that CHI3L1 and VEGFA are associated with nicotinamide phosphoribosyltransferase (NAMPT). Furthermore, combining the anti-CHI3L1 antibody and NAMPT siRNA more effectively reduced cell growth and the expression of CHI3L1, VEGFA, and cell growth-related proteins, but significantly increased apoptosis-related proteins. The combination of VEGFA siRNA and NAMPT siRNA more effectively inhibited cell growth. Anti-CHI3L1 antibody inhibited the production of ATP and NADH in colon cancer and had a higher inhibitory effect on these levels when combined with NAMPT siRNA These data demonstrated that anti-CHI3L1 antibody is useful as a potential therapy for colon cancer by inhibiting NAMPT-dependent VEGFA expression and ATP and NADH levels.

Bruton’s tyrosine kinase (BTK) is a therapeutically validated drug target. Small-molecule inhibitors of BTK have changed the treatment paradigms of multiple B-cell malignancies and evolved over three generations to overcome clinical challenges. Four drugs are now approved by the FDA, including the first-in-class drug ibrutinib and successively approved acalabrutinib, zanubrutinib, and pirtobrutinib. The third-generation drug pirtobrutinib, which binds non-covalently to BTK, is expected to overcome resistance mutations at the covalent binding Cys481 residue of the first and second-generation drugs that covalently bind to BTK. However, some newly identified non-Cys481 resistance mutations to pirtobrutinib have shown their co-resistance to some of the covalent inhibitors, and this leaves a major unmet need that is promoting the development of next-generation BTK-targeted therapeutics. More non-covalent BTK inhibitors with differentiated binding modes are under development, and the ongoing development focus of next-generation therapeutics involves new and alternative directions to target BTK using dual-binding inhibitors and degraders of BTK, as well as its allosteric inhibitors. Recent exploration of the differentiated features of BTK inhibitors in various aspects has shown the possible link between their different features and different functional and therapeutic consequences. This review summarizes the key differentiated features of the BTK inhibitors approved by the FDA and others under development to add knowledge for their therapeutic application and future development. Long-term follow-up updates of clinical outcomes of the earlier developed drugs are also included, together with direct and indirect comparisons of efficacy and safety between the different generations of drugs. The ongoing development status of next-generation BTK-targeted therapeutics is described, with a discussion on their therapeutic potential and some limitations.

Angiogenesis, the process of new blood vessel formation, is a fundamental physiological process implicated in several pathological disorders. The vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are crucial for angiogenesis and vasculogenesis. Among them, the tyrosine kinase receptor VEGFR-2 is primarily expressed in endothelial cells (ECs). These cells regulate various physiological responses, including differentiation, cell proliferation, migration, and survival, by binding to VEGF mitogens. Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) is a key regulator of this process, making it a prime target for therapeutic intervention. Several drugs targeting VEGFR-2 have been approved and are currently utilized to halt the pathological axis of VEGF-VEGFR. This review will focus on the recent developments in the molecular structure and function of VEGFR-2, the molecular mechanism of VEGFR-2 activation, and its downstream signaling pathway. It will also discuss therapies and experimental drugs approved to inhibit the function of VEGFR-2 and the resistance mechanism.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a liver manifestation of metabolic syndrome characterized by excessive hepatic lipid accumulation and lipid metabolism disorders. It has become the most common chronic liver disease worldwide. β-arrestin2 is a multifunctional scaffold protein that is among the most important regulatory molecules, and it exerts key roles in regulating various cellular processes, such as immune response, cellular collagen production, and inflammation. In the current study, we aimed to explore the function of β-arrestin2 in the development and progression of MASLD. Firstly, we observed that the expression of β-arrestin2 was upregulated in liver samples from patients with MASLD. Then, the western diet (WD) combined with CCl₄ injection-induced MASLD was established in wild-type mice, and showed that liver β-arrestin2 expression was also gradually increased, and positively correlated with the degree of lipid metabolism disorder during MASLD progression. Ulteriorly, β-arrestin2 knockout (Arrb2 KO) mice were utilized to induce the MASLD model and found that β-arrestin2 deficiency significantly ameliorated lipid accumulation and inflammatory response in the liver of MASLD mice. Furthermore, the in vitro depletion and overexpression experiments showed that increased β-arrestin2 aggravated lipid accumulation via inhibiting the activation of the TAK1/AMPK pathway, which may be mediated by competitively binding to TAB1 with TAK1. These findings suggest that β-arrestin2 is essential to regulate intrahepatic lipid metabolism. Here, we provide a novel insight in understanding of the expression and function of β-arrestin2 in MASLD, demonstrating that it may be a potential therapeutic target for MASLD treatment.

Microneedles (MN) have emerged as a promising transdermal drug delivery technology that offers advantages such as minimal invasiveness, high biocompatibility, and biodegradability. Gelatin methacryloyl (GelMA)-based MNs have gained attention because of their flexibility, mechanical strength, and modification capabilities, which support controlled drug release. The synthesis process of GelMA involves crosslinking using UV light, resulting in a stable hydrogel structure that supports therapeutic applications, such as wound healing, cancer therapy, and glucose monitoring. However, challenges such as skin penetration strength, drug-loading capacity, and regulatory standards still require solutions. Material and design innovations, particularly the combination of GelMA with nanomaterials and natural polymers, have the potential to enhance the MN efficiency and expand its applications in various medical fields. This review explores the latest developments in GelMA-based MN design and their future potential as reliable therapeutic devices.

The growth factor-mediated mitogen-activated protein kinase (MAPK) signaling pathways in cancer development have become increasingly important in the discovery of therapeutic agents for the treatment of cancer. RSK2 has been historically overlooked in studies regarding its involvement in physiology and signaling pathways related to human diseases, except for Coffin-Lowry syndrome, because it is located downstream of ERKs. For the last 25 years, the authors’ laboratory has made groundbreaking discoveries regarding the role of RSK2, especially by elucidating its binding partners, signaling network, and crosstalk. RSK2 is an important emerging target for developing anticancer drugs. Nevertheless, further studies on the detailed mechanism and signaling network are necessary to avoid the unexpected effects of RSK2 inhibitors. This paper describes a new paradigm of RSK2, where it works as a signaling node to modulate diverse cellular processes, including cell proliferation and transformation, cell cycle regulation, chromatin remodeling, and immune response and inflammation regulation.