Pakistan Journal of Pharmaceutical Sciences

Abstract: Background: Fracture healing is a dynamic biological process involving inflammation, callus formation, mineralization and remodeling. Osteogenic and apoptosis-related markers may reflect changes during repair, but tissue-level marker expression alone does not establish a causal apoptotic mechanism. Objectives: To evaluate whether Compound Miao medicine Jiuxian Luohan bone-setting decoction is associated with improved femoral fracture healing in rats and with altered expression of runt-related transcription factor 2 (Runx2), Osterix, procollagen type I N-terminal propeptide (PINP), Bcl-2-associated X protein (Bax) and Caspase-3 at the fracture site. Methods: Twenty-five male specific-pathogen-free (SPF) Sprague-Dawley rats were used to establish a right femoral fracture model and were randomized into five groups (n=5/group): model, low-, medium- and high-dose decoction and orthopedic bone-setting tablet groups. Treatments were initiated 24 h after modeling and administered by gavage twice daily for 30 days. Anteroposterior and lateral radiographs were obtained on day 15 and scored using the Lane-Sandhu system. Fracture-site tissues were collected on day 30 for reverse transcription quantitative polymerase chain reaction (RT-qPCR), Western blotting, immunohistochemistry and Alizarin Red staining. Results: Compared with the model group, the high-dose decoction group showed a higher Lane-Sandhu score at week 2 and greater callus formation. Runx2, Osterix and PINP mRNA/protein levels increased, whereas Bax and Caspase-3 mRNA/protein levels decreased in treated groups, particularly in the high-dose group. Alizarin Red staining indicated greater deposition of mineralized matrix in treated tissues. Conclusion: Compound Miao medicine Jiuxian Luohan bone-setting decoction was associated with improved radiographic healing and favorable changes in osteogenic and apoptosis-related markers in this rat femoral fracture model.

Abstract: Macrophage functional states are increasingly viewed as a dynamic spectrum rather than a fixed M1/M2 dichotomy. Astragalus polysaccharides (APS) are structurally heterogeneous natural polysaccharides with reported immunomodulatory, anti-inflammatory, antioxidant, antitumor and tissue-repair activities; however, their structure-activity relationships, receptor-recognition mechanisms and translational readiness remain incompletely defined. This review summarizes mechanistic and translational evidence for APS-mediated regulation of macrophage functional states, with emphasis on structural heterogeneity, innate immune recognition, pathway crosstalk, disease-context dependence and current barriers to clinical development. A narrative literature review was conducted using PubMed, Web of Science, Scopus, Google Scholar and selected publisher databases. The literature search focused on studies published between 2020 and 2026, with priority given to recent mechanistic, preclinical and translational studies addressing APS, macrophage activation, macrophage polarization, immunometabolism, oxidative stress and disease-specific immune remodeling. Predominantly preclinical evidence suggests that APS do not act as simple unidirectional inducers of M1- or M2-like polarization. Instead, APS appear to modulate macrophage functional states according to structural features, receptor engagement and disease context. TLR4/MyD88/NF-kappaB, MAPK, Notch, PI3K/Akt/Nrf2/HO-1, JAK/STAT, cGAS-STING, NLRP3 inflammasome and immunometabolic pathways form interconnected regulatory networks. Preclinical studies suggest that APS may promote antitumor inflammatory and antigen-presenting programs in tumors while attenuating excessive inflammatory activation and supporting reparative programs in diabetic vascular injury, acute kidney injury and chronic wounds. This review integrates APS structure-activity relationships with macrophage plasticity and translational limitations. Further progress toward clinical development would depend on high-purity fractionation, rigorous quality control, glycomics-based receptor mapping, single-cell and spatial validation, pharmacokinetic and safety studies and well-designed clinical investigations.

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.