Pakistan Journal of Pharmaceutical Sciences

Abstract: Background: Bergenin (BN), a C-glucoside of 4-O-methyl gallic acid, exhibits a broad spectrum of pharmacological activities, including notable antioxidant, anti-inflammatory and anticancer effects. Objectives: This study aimed to explore the impact of polydopamine nanoparticles loaded with bergenin (PDANPs-BN) on glioma and their mechanisms of action. Methods: PDANPs-BN nanocomposites were prepared and U251 cells were cultured and divided into the BN group and the PDANPs-BN group. The biological processes of U251 cells were observed by using CASC11 mimic, si-CASC11 and agonists and inhibitors of AKT3. Results: Compared to free BN, PDANPs-BN significantly inhibited the malignant biological behavior of U251 cells, reducing the cell proliferation rate by approximately 45% and suppressing migration capacity by about 60% (P<0.05). Mechanistic studies revealed that PDANPs-BN downregulated CASC11 expression levels by 2.1-fold, thereby inhibiting AKT3 signaling pathway activity. The strongest antitumor effect was observed when combined with si-CASC11 and an AKT3 inhibitor. While the addition of an AKT3 agonist partially reversed this effect, cell proliferation remained suppressedand colony-forming ability was altered. Conclusion: PDANPs-BN acts by targeting the CASC11/AKT3 axis, resulting in downregulation of CASC11 and consequent inhibition of AKT3 signaling, which ultimately curbs the malignant progression of glioma.

Abstract: Background: Sepsis-induced acute lung injury (ALI) is a critical illness with a high mortality rate. Madecassic acid (MA), a pentacyclic triterpenoid extracted from Centella asiatica, exhibits multiple biological activities, but its role in sepsis-associated ALI remains poorly elucidated. Objectives: The aim of this study was to investigate the protective effect of MA on lipopolysaccharide (LPS)-induced ALI in mice and to elucidate its potential mechanisms in regulating inflammation, oxidative stress, apoptosis and the PI3K/AKT/mTOR signaling pathway. Methods: An ALI mouse model was established by intraperitoneal LPS injection. The mice were randomly divided into a sham operation group, an MA alone group, an LPS model group and an LPS combined with MA treatment group. The degree of lung injury was assessed via histopathological examination of the lungs and the lung wet/dry weight ratio; the levels of inflammatory factors (TNF-α and IL-6) and oxidative stress markers (MPO, MDA, SOD and GSH-Px) in the bronchoalveolar lavage fluid (BALF) were measured; and the expression of apoptosis-related proteins and PI3K/AKT/mTOR pathway activation in the lung tissues were detected via Western blotting. Results: MA treatment significantly reduced LPS-induced lung tissue injury, edema and inflammatory cell infiltration; decreased the levels of proinflammatory factors (TNF-α and IL-6); improved oxidative stress parameters (decreased MPO and MDA levels and increased SOD and GSH-Px levels); inhibited apoptosis (downregulated Bax and cleaved caspase-3 expression and upregulated Bcl-2 expression); and inhibited the phosphorylation of PI3K, AKT and mTOR. Conclusion: MA attenuates sepsis-associated ALI through anti-inflammatory, antioxidant and anti-apoptotic effects and this mechanism is related to inhibiting the activation of the PI3K/AKT/mTOR signaling pathway. MA has the potential to be a therapeutic agent for sepsis-associated ALI.

Abstract: Background: Chemotherapy-induced alopecia negatively impacts the mental health of cancer patients. Topical minoxidil, a widely recommended drug for hair regrowth, causes scalp irritation and contact dermatitis. Oral minoxidil causes multiple cardiovascular and neurological side effects. Cetirizine hydrochloride, an antihistamine with a better safety profile than minoxidil, may stimulate hair follicle activity by modulating prostaglandin levels. Objectives: The present study aimed to develop a cetirizine hydrochloride-loaded emulgel and evaluate its potential, in combination with microneedling, for the treatment of chemotherapy-induced alopecia. Methods: Different emulgel formulations comprising cetirizine HCl, liquid paraffin, carbopol 940, propylene glycol, oleic acid, Tween 20, Span 20 and propylparaben were optimized using central composite design and response surface methodology. Physicochemical evaluation of the prepared emulgel included physical examination, determination of pH, viscosity, spreadability, drug content and stability. Interactions and compatibility among formulation constituents were assessed using In-silico analysis and Fourier transform infrared spectroscopy. In-vitro drug release, ex-vivo permeation and in-vivo hair growth studies were carried out to evaluate the performance efficiency of emulgel. Results: The prepared emulgels exhibited acceptable physicochemical properties and remained stable for 3 months. Constituents were found to be compatible with each other. The optimized formulation F4 released >95% drug at pH 5.5 within 360 minutes. During an ex-vivo study, ~94% of the drug permeated across rat skin within 6 hours following application of emulgel on the microneedle-pretreated skin. In cyclophosphamide-induced alopecia in rats, application of emulgel to microneedle-pierced skin for 15 days promoted hair growth. Conclusion: The prepared cetirizine HCl-loaded emulgel and microneedle combination may be a promising approach to treating chemotherapy-induced alopecia.

Abstract: Background: The pharmaceutical industry is a strategic emerging sector in China, yet its scientific and technological innovation network remains poorly characterized in terms of structural dynamics and evolutionary pathways. Objectives: In the field of scientific and technological innovation in China's pharmaceutical industry, this study systematically sorts out the context of research, reveals the structural characteristics and evolutionary laws of the innovation network and provides references for industrial policy formulation and enterprise strategic layout. Methods: Based on 602 relevant papers collected from the China National Knowledge Infrastructure (CNKI) from 1996 to 2024, VOSviewer and CiteSpace software were comprehensively used to conduct co-occurrence analysis, cluster analysis and burst term detection, so as to construct a multi-dimensional dynamic network model. Results: The number of published papers on scientific and technological innovation in China’s pharmaceutical industry increased, with accelerated growth and greater volatility after 2010. A core author group has initially taken shape, but the participation rate of enterprises is only 8.3%, indicating insufficient industry-university-research collaboration. Research hotspots have expanded from traditional biomedicine to emerging technologies such as artificial intelligence-assisted drug design and mRNA vaccines, with industrial clusters and factor collaboration becoming new focuses. Conclusion: The innovation of the pharmaceutical industry follows a phased evolutionary path of "technology-driven – cluster development – factor collaboration". At present, it is confronted with structural constraints such as inadequate data sharing, unbalanced resource allocation and a shortage of interdisciplinary talents. It is suggested that enterprises’ dominant position in innovation be strengthened, a cross-regional public R and D data platform for the pharmaceutical industry be established, policy incentives shift from project funding to performance-based rewards for innovation alliances and the industry evolve into an adaptive innovation ecosystem.

Abstract: Background: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease for which targeted therapies remain limited. The Notch signaling pathway has been implicated in T cell differentiation and autoimmune inflammation. Objectives: This study aimed to investigate the therapeutic effects of the Notch signaling antagonist DAPT on autoimmune arthritis in mice and to explore its underlying immunological mechanisms. Methods: A collagen-induced arthritis (CIA) mouse model was established. DAPT (100 ng/kg) or PBS was administered intraperitoneally every other day from day 0 to day 36. Notch pathway activation in CD4+ T cells and synovial tissues was assessed by Western blot and immunohistochemistry. Arthritis severity was evaluated by clinical scoring, radiological examination and histopathology. Th1, Th17 and Treg cell frequencies and absolute numbers in spleen and lymph nodes (LNs) were analyzed by flow cytometry. Plasma cytokine levels were measured by multiplex assay. In-vitro Th17 differentiation assays were performed with DAPT or a Notch agonist. Results: Compared with normal mice, CIA mice showed significant upregulation of NICD expression in CD4+ T cells and synovial tissues. DAPT treatment significantly reduced clinical arthritis scores, joint erosion and cartilage destruction. DAPT also decreased the frequencies and absolute numbers of Th1 and Th17 cells in the spleen and LNs, alongwith reduced plasma levels of IFN-γ and IL-17. In-vitro, DAPT suppressed Th17 differentiation, while Notch agonist enhanced it. Treg cells were not significantly altered by DAPT. Conclusion: The Notch signaling antagonist DAPT ameliorates autoimmune arthritis in mice by suppressing Th1 and Th17 immune responses, highlighting Notch signaling as a potential therapeutic target for RA.