Advanced pharmaceutical bulletin最新文献

Purpose: Acne vulgaris is a chronic inflammatory condition affecting the pilosebaceous units. With the rise of antibiotic resistance and the potential side effects associated with conventional treatments, there is increasing interest in exploring natural alternatives for treating acne. This study aimed to formulate and clinically evaluate a topical gel containing clove oil and curcumin in patients with mild to moderate acne vulgaris, using topical clindamycin as a standard comparator.

Methods: The antibacterial activity of clove oil and curcumin against Propionibacterium acnes and Staphylococcus epidermidis was assessed by determining their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). Based on these findings, semisolid gel formulations were developed and subjected to in vitro evaluations. Subsequently, a single-blind, randomized, comparative clinical study was conducted in 31 participants diagnosed with mild to moderate acne. Volunteers applied clindamycin gel in the morning and the clove oil-curcumin gel in the evening, or vice versa, over a 4-week period. Clinical outcomes, including acne lesion counts, Acne Severity Index (ASI), and patient satisfaction, were assessed.

Results: The clove oil-curcumin gel demonstrated comparable efficacy to clindamycin in reducing acne lesions, papules, and ASI. While no significant differences were observed between the two groups in comedone reduction, patient satisfaction increased in clove oil-curcumin gel group.

Conclusion: Topical application of a gel containing clove oil and curcumin demonstrated promising results as an effective and well-tolerated alternative or adjunctive therapy for acne vulgaris. These findings support the potential of plant-based formulations in acne management.

Purpose: Chimeric antigen receptor (CAR) T cell therapy has emerged as a promising cancer treatment. Nevertheless, the tumor microenvironment (TME) of solid tumors provides substantial challenges to CAR T cell efficacy. Tumor growth factor-beta (TGF-β), a potent immunosuppressive cytokine in the TME, impedes T cell activation, proliferation, and cytotoxicity, diminishing the anti-tumor potency of CAR T cells. This study investigates whether TGF-βRII CAR T cells can overcome these barriers and remain functional in TGF-β-rich environments.

Methods: We developed a novel TGF-βRII CAR T cell (TGF-βRII-CD28CD3z) and a dominant-negative TGF-β receptor (dnTβRII) T cell utilizing Jurkat cells. Transduction efficiency and surface expression were confirmed using flow cytometry. T cell activation and proliferation were assessed by CD69 and Ki-67 expression, respectively. IL-2 and IFN-γ secretion were quantified using ELISA kits.

Results: Flow cytometry confirmed the successful cell surface expression of the designed receptors: 62% and 24% for TGF-βRII CAR and dnTβRII, respectively. TGF-βRII CAR T cells were markedly activated in a dose-dependent manner, with optimal responses at 10 ng/mL TGF-β. The Ki-67 expression of CAR T cells, used as a proliferation marker, increased 1.21-fold (from 79.5% to 96%) upon exposure to 10 ng/mL TGF-β. At 5 ng/mL TGF-β, the cells' proliferation was maintained at a 1.04-fold increase. Cytokine analysis revealed a 1.9-fold increase in IL-2 (130±4 pg/mL) and a 2.7-fold increase in IFN-γ (146±21.9 pg/mL) secretion at 10 ng/mL TGF-β. Additionally, at 5 ng/mL TGF-β, IL-2 secretion increased 1.6-fold (110±10.7 pg/mL), and IFN-γ secretion increased 1.7-fold (94.3±10.2 pg/mL). In contrast, dnTβRII T cells also produced IL-2 (95 pg/mL±22, 2.7-fold increase) but failed to sustain proliferation or IFN-γ production at 10 ng/mL TGF-β.

Conclusion: Our findings demonstrate that the TGF-βRII CAR T cells not only resist TGF-β-mediated suppression but also promote activation, proliferation, and cytokine release in the presence of TGF-β. This underscores their therapeutic potential as an innovative approach to overcome TGF-β-driven immunosuppression and improve the CAR T cell therapy efficacy in solid tumors.

Purpose: The aim of this study was to elucidate the mechanisms underlying the formation and maintenance of drug resistance in cancer cells. Previously, we demonstrated that prolonged treatment of estrogen-dependent MCF-7 breast cancer cells with exosomes derived from estrogen-resistant MCF-7/T cells leads to a partial loss of estrogen sensitivity in MCF-7 cells. Moreover, repeated transfection with one of the exosomal microRNAs-microRNA-181a-2-induced an irreversible decrease in hormonal sensitivity in the recipient cells. In the present work, to further investigate the possible mechanism of miR-181a-2-induced acquired resistance, we analyzed the effect of multiple miR-181a-2 transfections on the expression of cellular miR-181a-2 and related signaling proteins.

Methods: miR-181a-2 was ectopically expressed by mimetic transfection or suppressed by antisense oligonucleotides. miR-181a-2 precursor/MIR181A2HG expression (qRT-PCR) and MIR181A2 locus copy number (qPCR) were assessed. wtSnail was expressed via transient transfection. Tamoxifen sensitivity was measured by MTT assay. Protein expression was studied by immunoblotting, estrogen receptor α/Snail transcriptional activity was evaluated by reporter analysis.

Results: We found that multiple transfections with miR-181a-2 resulted in a marked increase in cellular miR-181a-2 precursor levels, whereas single transfection had no such effect. Similarly, stable transfection with miR-181a-2 led to increased levels of cellular miR-181a-2 and its host gene, MIR181A2HG, which was associated with partial resistance to tamoxifen. Analysis of the genomic DNA encoding miR-181a-2 revealed no changes in copy number in transfected cells. Furthermore, we identified the transcription factor Snail as a key mediator of miR-181a-2-induced resistance and demonstrated its role in the formation of an autoregulatory loop of miR181a-2 and the maintenance of cell resistance.

Conclusion: Overall, these results reveal a novel mechanism of resistance-associated signaling pathway rearrangement based on the formation of a miR-181a-2 autoregulatory loop.

Purpose: Chronic stress usually causes immunosuppression, activates tyrosine kinase (TK), and increases inflammatory responses. Based on Persian medicine, the spleen is crucial for the immune system and stress response. Cuscuta epithymum (CE) contains antioxidant properties and is beneficial to the immune system.

Methods: In this experimental study, 28 male and 56 female rats were randomly divided into four groups and exposed to stress from restraint. Simultaneously, Cuscuta's extract was given to the other two groups while normal saline was given to the control and stressed rats. Four different coupling combinations were created by mating control and experimental rats: McFc, MsFs, McFc+EX, and MsFs+EX (M: male, F: female, C: control, S: stress, and EX: extract). The TK level, megakaryocyte, and macrophage cell number in the liver and spleen were then assessed after certain parents and male pups were dissected on postnatal day (PND) 25. Western blot analysis was used to measure the brain's quantitative levels of TNF-α and IL-1β protein expression.

Results: Rats under stress had much higher levels of TK and macrophage cells in their liver and spleen tissues than the other rats, while the stress+CE group had significantly lower levels. While megakaryocyte cells increased in CE-treated animals, they dramatically declined in the stress group. The brain homogenate's TNF-α and IL-1β levels were considerably lowered by Cuscuta extract.

Conclusion: Our study showed the significant role of the Cuscuta in decreasing the adverse effects of stress on the liver and spleen immune system, as well as a remarkable anti-neuroinflammatory effect.

Purpose: Breast cancer remains the most prevalent malignancy among women worldwide, with a strikingly high incidence in Egypt, particularly in familial cases. This study aims to comprehensively elucidate the pathological and molecular significance of ERBB2 (HER2/neu) overexpression in Egyptian familial breast cancer, highlighting its role in tumor aggressiveness, immune evasion, and precision oncology.

Methods: We enrolled 44 Egyptian breast cancer patients along with 35 daughters and 24 sisters (2013-2015, Mansoura University Hospital). Comprehensive analyses included serum biochemical assays, histopathological evaluation, immunohistochemical staining for ERBB2, and molecular detection of ERBB2 amplification using first-round and nested PCR. Associations with clinical, hormonal, and metabolic variables were also explored.

Results: Serum biochemical profiling revealed significantly elevated ALT (6.6±0.55 U/mL), LDH (16.8±1.4 U/mL), and CA15 3 (160±13.33 U/mL), with reduced AST (2.6±0.22 U/mL) compared to controls (P≤0.05). Histopathology confirmed invasive ductal carcinoma with dense stromal desmoplasia. Immunohistochemistry demonstrated ERBB2 overexpression in>10% of tumor cells. Nested PCR detected ERBB2 amplification in 72% of patients, and in daughters (17%) and sisters (20%). Notably, higher ERBB2 expression was observed in unmarried patients (100%), pre-menopausal women (73-72%), and those with diabetes or hypertension, suggesting hormonal and metabolic modulation via PI3K/AKT/mTOR and MAPK/ERK pathways. ERBB2 mutations were identified in 14% of patients, 2.1% of daughters, and 1.2% of sisters. Furthermore, ERBB2 may upregulate PD-L1, contributing to immune evasion.

Conclusion: Our findings highlight ERBB2 as a pivotal diagnostic and prognostic biomarker in Egyptian familial breast cancer and support integrating HER2-targeted therapies with immune checkpoint inhibitors and metabolic interventions. This approach could transform outcomes in high-risk familial cohorts. The study emphasizes the importance of genetic screening and precision medicine strategies that consider molecular, hormonal, and metabolic contexts in breast cancer care.

Human papillomavirus (HPV), specifically types 16 and 18, is the main cause of cervical cancer and a significant cause of death among women. Specifically, HPV E6 and E7 oncogenes hinder the normal cell cycle regulation, resulting in uncontrolled cell growth and cervical cancer. The available therapy options include surgery, radiotherapy, and chemotherapy, which show success but also demonstrate notable complications. SiRNA (small interfering RNA) and mRNA (messenger RNA) therapies have emerged as precise and effective tools to silence the HPV E6 and E7 oncogenes and stimulate the immune system to fight against HPV infection, respectively, presenting a targeted therapy approach and overcoming the available therapy challenges. Nanoparticles and Pegylated liposomes are the delivery systems that increase the efficacy and safety of siRNA and mRNA therapies. This review critically appreciates the effective targeting of siRNA and mRNA-based therapies by highlighting their key advantages and limitations. Despite being a target-specific and effective approach, there are certain challenges like scale-up, cost-effectiveness, and developing stable delivery systems, which are required to be discussed. In addition, other precision medicine approaches, such as CRISPR/CAS-9, antisense oligonucleotides, or immunotherapy, have also been included as compared to siRNA/mRNA therapies. Their preclinical, patent, and clinical translations have also been discussed exhaustively.

Purpose: This study explores the use of glass microspheres doped with rare earth elements, specifically samarium (Sm) and neodymium (Nd), and graphene quantum dots (GQDs) in biological applications, particularly cancer therapy.

Methods: Glass microspheres were synthesized using an eco-friendly approach with recycled glass and subsequently doped with Sm, Nd, or GQDs. The samples were characterized by scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS). In vitro cytotoxicity was assessed in MCF-7 (breast cancer) and DU-145 (prostate cancer) cell lines.

Results: In vitro assays demonstrated that these doped microspheres significantly reduced cell viability in breast (MCF-7) and prostate (DU-145) cancer cell lines. The GQD microspheres showed a marked reduction in cell proliferation, attributed to mechanisms involving apoptosis and reactive oxygen species (ROS) production. Sm and Nd microspheres also decreased cell survival, with Nd microspheres showing the highest efficacy.

Conclusion: The study highlights the potential of rare earth elements and GQDs in developing advanced nanotherapeutic agents for cancer treatment, emphasizing their role in disrupting cellular functions and promoting cytotoxic effects in tumor cells.

Purpose: Melanoma arises from the malignant transformation of melanocytes, a serious health problem in high UV-exposure countries. Ineffective treatments and metastasis have led to poor prognosis and high mortality among melanoma patients. Several underlying mechanisms are suspected. The splicing-error in many genes has been frequently reported in melanoma, therefore, targeting splicing regulator Serine/Arginine protein kinases (SRPKs) is promising.

Methods: SRPKs expression in the TCGA dataset was analyzed by GEPIA. A375 and MNT-1 were comparatively treated by SRPK inhibitors, SRPIN340 and SPHINX31. Effects on viability and growth were measured by MTT and hanging drop assay. Apoptotic death was examined by flow cytometry and western blotting. Invasive ability was determined by transwell assay. Invasive-associated genes, proteins, and enzymes were tracked by RT-PCR, western blotting, immunofluorescence, and gelatin zymography.

Results: SRPIN340 exhibited higher inhibitory effects on the viability and growth of melanoma cells than SPHINX31. Apoptotic induction was found with downregulated Bcl-2 and upregulated cytochrome c, especially in A375 cells. For metastatic inhibition in A375, lower numbers of invaded cells were counted. Downregulated vimentin mRNA and transcription factors-snail, as well as altered vimentin protein expression and localization were marked. Remarkably, the activities of MMP2 and MMP9 were suppressed.

Conclusion: SRPK inhibitors potentially suppressed melanoma cell survivability and metastasis through the triggering of apoptotic proteins and dysregulating vimentin. These collected data serve as a basis for utilizing new alternative therapeutic strategies by targeting splicing regulator SRPK, for melanoma treatment.

Circular RNAs (circRNAs) are a novel class of non-coding RNAs primarily generated through a back-splicing processes. These molecules exhibit extensive expression across various tissues, indicating their significant role in numerous biological processes, particularly in complex diseases such as cancer. Based on their origin, structure, and biogenesis, circular RNAs are categorized into exonic circRNAs (ecirc-RNAs), circular intronic RNAs (ci-RNAs), or exonic-intronic circRNAs (EIci-RNAs). Due to their covalently closed-loop configuration, it is necessary to develop specialized techniques to study them. CircRNAs are known to function as protein and microRNA sponges, regulate transcription, interact with RNA-binding proteins (RBPs), and, in rare cases, serve as templates for translation. In this review, we provide an overview of circRNA features, biogenesis, and functions. In addition, we summarize molecular methods for studying them and explain their significant roles in malignancies.

This review explores the synergistic effects of exosomes and autophagy in mitigating spinal cord injury (SCI) while elucidating the underlying molecular mechanisms. We evaluate current literature on the roles of exosomes and autophagy in SCI, highlighting key findings from both in vitro and in vivo studies. Previous research has demonstrated the contributions of these processes to cellular responses under SCI-related conditions. Additionally, animal models have provided insights into the therapeutic potential of modulating exosome and autophagy pathways. The overview discusses the activation of mTOR signaling and autophagy-related proteins, emphasizing their impacts on inflammation and axonal integrity. We identify a synergistic mechanism in which exosome-mediated cargo delivery and autophagy modulation work together to mitigate the effects of SCI. The regulation of the mTOR pathway and autophagy-related proteins is crucial for reducing inflammation and preserving axonal integrity. These findings underscore the therapeutic potential of targeting exosomes and autophagy for SCI treatment. The collaborative actions of these cellular processes present promising therapeutic avenues for SCI and possibly other neurological disorders. This review underscores the necessity for further studies to unravel the molecular intricacies and to translate these findings into clinical applications for SCI patients.