Pakistan Journal of Pharmaceutical Sciences

Abstract: Background: Prostate cancer progression is influenced by the tumor microenvironment. Bone marrow mesenchymal stem cells (BMSCs) can modulate tumor behavior, but the role of their lncRNA PVT1 is unclear. Objective: To investigate whether lncRNA PVT1 in BMSCs regulates the malignant phenotype of prostate cancer cells through miR-122 and elucidate its mechanism of action in the tumor microenvironment. Method: Rat BMSCs were isolated and cultured and a Transwell co-culture system was established with human prostate cancer cell lines (PC-3). RT-qPCR was used to detect the expression of PVT1 and miR-122 in BMSCs and cancer cells. PVT1 was overexpressed and knocked down in BMSCs to observe its effects on cancer cell proliferation (CCK-8), apoptosis (flow cytometry) and cell cycle (PI staining) in the co-culture system. The targeting relationship between PVT1 and miR-122 was validated using a dual-luciferase reporter assay. Rescue experiments were performed by simultaneously manipulating PVT1 and miR-122 in BMSCs. Results: In prostate cancer patient tissues and cell lines, PVT1 expression was downregulated while miR-122 expression was upregulated. In the co-culture system, overexpression of PVT1 in BMSCs significantly inhibited cancer cell proliferation, arrested the cell cycle at the G0/G1 phase and promoted apoptosis. Conversely, knockdown of PVT1 in BMSCs promoted the malignant phenotype of cancer cells. Mechanistically, PVT1 directly targeted and negatively regulated miR-122. Overexpression of miR-122 reversed the inhibitory effect of PVT1 overexpression in BMSCs on cancer cells. Conclusion: BMSCs exert a tumor-suppressive effect in the prostate cancer microenvironment through the PVT1/miR-122 axis, which may serve as a novel therapeutic target for prostate cancer.

Abstract: Background: Intrauterine adhesion (IUA) is a common complication of endometrial injury. Bone marrow mesenchymal stem cells (BMSCs) have been implicated in endometrial repair, but strategies to enhance their therapeutic efficacy remain to be optimized. The C-X-C chemokine receptor type 4 (CXCR4)/C-X-C motif chemokine ligand 12 (CXCL12) axis plays a pivotal role in BMSC homing. Objective: This study aimed to test the hypothesis that ATI-2341, a functionally selective allosteric regulator of CXCR4, enhances the therapeutic efficacy of BMSCs in a rat IUA model. Methods: After establishing the endometrial injury model, rat BMSCs were extracted and treated with ATI-2341 TFA (100 ng/mL). IUA model rats were randomly divided into model control group, BMSCs group, BMSCs+ATI-2341 TFA group, BMSCs+PBS group and Positive control group (n=10 each). Endometrial thickness was assessed by hematoxylin and eosin (HE) staining; cell proliferation by the methyl thiazolyl tetrazolium (MTT) assay; matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinase-1 (TIMP-1) protein expression by Western blot; and cytokeratin and vimentin expression by immunohistochemistry. Results: ATI-2341 TFA-pre-treated BMSCs significantly increased endometrial thickness compared to untreated BMSCs (P < 0.05) or estrogen (P < 0.05). ATI-2341 TFA enhanced BMSC proliferation at 48 h (P < 0.05) and 72 h (P < 0.05). BMSCs exposed to ATI-2341 TFA or estrogen exhibited strong cytokeratin positivity and vimentin negativity. MMP-9 was downregulated (P < 0.05) and TIMP-1 upregulated (P < 0.05) in the ATI-2341 TFA group relative to controls. Conclusion: ATI-2341 TFA promotes acquisition of epithelial-like immunophenotype in BMSCs within the injured endometrial microenvironment and is associated with improved endometrial morphology in IUA rats. These findings provide preliminary evidence for the functional modulation of BMSCs by CXCR4-targeted therapy in endometrial repair.

Abstract: Background: Given the high incidence of apnea of prematurity (AOP) and the repeated hypoxia-induced nerve damage, treatment optimization from the dosing perspective is critical. Caffeine is the current first-line therapeutic drug for AOP. However, the conventional dose results in low blood concentration compliance, with significant variation among individuals. Objectives: To explore the clinical efficacy and safety of a therapeutic drug monitoring (TDM)-guided individualized caffeine dosage regimen and its association with early neurobehavioral development and weight gain in preterm infants (PTIs). Methods: In this retrospective propensity score-matched cohort study, 130 PTIs with AOP were included after 1:1 matching, with 65 infants in the TDM-guided individualized dosing group and 65 in the conventional fixed-dose group. Inter-group comparative assessments were conducted from the perspectives of blood drug concentration compliance rates, apnea control, adverse reactions, neurobehavioral development scores, clinical outcomes and weight gain rates. Results: Compared with the conventional fixed-dose group, the TDM-guided individualized dosing group had a significantly higher target attainment rate of blood caffeine concentration (92.31% vs 70.77%; OR=5.22, 95% CI 1.68-12.74, P=0.002), lower apnea episode frequency at 4 weeks (MD -1.40 times/day, 95% CI -2.13 to -0.67, P<0.001), lower overall incidence of adverse reactions (6.15% vs 20.00%; OR=0.26, 95% CI 0.09-0.87, P=0.035), higher NBNA score at 40 weeks of corrected gestational age (MD 1.74, 95% CI 1.23-2.25, P<0.001), shorter hospital stay (MD -4.11 days, 95% CI -6.51 to -1.71, P=0.001) and faster weight gain rate (MD 7.88 g/day, 95% CI 3.21-12.55, P=0.001). Conclusion: The TDM-guided individualized caffeine dosing regimen was associated with improved precision of AOP treatment, better short-term therapeutic efficacy and safety, and higher early neurobehavioral assessment scores and weight gain in preterm infants within 6 months of corrected gestational age. Multicenter studies with longer follow-up are needed to further verify its long-term clinical benefits.

Abstract: Background: Postoperative chemotherapy for breast cancer often leads to intestinal dysbiosis and immune suppression. Traditional Chinese medicine shows potential in regulating gut microbiota and enhancing immune function, offering a promising adjunctive therapeutic strategy. Objectives: To explore the effects of a traditional Chinese medicine compound on the recovery of intestinal bifidobacteria and CD4+ T-cell activation in breast cancer patients undergoing postoperative chemotherapy. Methods: Female patients with newly diagnosed breast cancer were randomly assigned to a control group (triamcinolone tablets) and an observation group (control treatment plus kidney-tonifying and compound traditional Chinese medicine soup). Intestinal flora and immune indices were measured and analyzed using SPSS 22.0. Results: After chemotherapy, the observation group showed significant increases in bifidobacteria to 9.01±1.49 lg (CFU/g) and in CD4+ T-cell counts to 969/μL. The expression levels of peripheral blood CD4+ T cells and the differences in S2, nm23 and Her-2 indices were significant between the groups, with the observation group showing greater CD4+ T cell activation. The incidence of adverse reactions was significantly lower in the observation group (P-values: 0.002, 0.006 and 0.030). The observation group also demonstrated better control of gastrointestinal conditions and disease progression (P<0.001). Conclusion: The traditional Chinese medicine compound effectively maintained intestinal flora balance, promoted beneficial bacterial growth, reduced adverse reactions and offered better therapeutic prospects for breast cancer patients.

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.