The effectiveness of ruxolitinib and cyclophosphamide combination on T helper 17 and regulatory T cells in rat experimental membranous glomerulonephritis.

The progression and pathogenesis of membranous glomerulonephritis (MGN) are inextricably linked to chronic inflammation. Despite improving clinical remission rates due to the application of cyclophosphamide (CYC), treatment of MGN still requires further exploration. Ruxolitinib (Ruxo) negatively affects the signaling pathways participating in the production of pro-inflammatory cytokines. Hence, we investigated whether the combination of CYC and Ruxo can modulate inflammation through influencing T helper 17 (Th17) lineages and regulatory T cells (Tregs). Passive Heymann nephritis (PHN), an experimental model of MGN, was induced in a population of rats. Then, the animals were divided into five groups: PHN, CYC-receiving, Ruxo-receiving, CYC-Ruxo-receiving PHN rats, and healthy controls. After 28 days of treatment, biochemistry analysis was performed and splenocytes were isolated for flowcytometry investigation of Th17 cells and Tregs. The correlative transcription factors of the cells, alongside their downstream cytokine gene expressions, were also assessed using real-time PCR. Furthermore, serum cytokine signatures for the lymphocytes were determined through ELISA. The combination of CYC and Ruxo significantly reduced the serum values of urea in rats versus the PHN group (24.62 ± 7.970 vs. 40.60 ± 10.81 mg/dL). In contrast to Treg's activities, the functionality of Th17 cells noticeably increased not only in PHN rats but also in CYC or Ruxo-receiving PHN animals when compared with the control (10.60 ± 2.236, 8.800 ± 1.465, 8.680 ± 1.314 vs. 4.420 ± 1.551 %). However, in comparison to the PHN group, the incidence of Th17 cells notably fell in rats receiving CYC and Ruxo (10.60 ± 2.236 vs. 6.000 ± 1.373 %) in favor of the Treg's percentage (5.020 ± 1.761 vs. 8.980 ± 1.178 %), which was verified by the gene expressions and cytokine productions correlative to these lymphocytes. The combination of CYC and Ruxo was able to decline Th17 cells in favor of Tregs improvement in PHN rats, suggesting an innovative combination therapy in MGN treatment approaches.

The efficacy of topical sodium pentaborate formulation on hemorrhoid disease: A randomized, double-blind, placebo-controlled trial.

Background: The topical application of boron has been significantly associated with intensifying wound healing. Using 3% boric acid in deep wounds significantly contributes to wound healing and reduces the duration of hospitalization in the intensive care. The objective of this study was to assess the therapeutic impact of a topical gel containing sodium pentaborate pentahydrate on the management of wounds resulting from grade 1 to 3 hemorrhoids. Methods: In this randomized double-blind placebo-controlled trial, we applied a topical gel consisting of sodium pentaborate pentahydrate 3% on 206 eligible patients with the diagnosis of grade 1, 2, and 3 hemorrhoid diseases. Then patients were randomly allocated to two groups of sodium pentaborate pentahydrate or placebo gel with a ratio of 1:1 and received the allocated gel for four weeks. Patient hemorrhoid symptoms severity, hemorrhoid degree, and anoscopy findings were compared before and after the trial. Results: Before the intervention, symptom severity (p > 0.05) and anoscopy findings (p = 0.815) were similar between the two groups. Subsequent to the intervention, a majority of patients in the intervention group experienced a reduction in anal itching compared to the placebo group [adjusted mean difference (aMD) 95% CI: -1.98 (-2.2 to -1.8), p = 0.007]. Moreover, resting pain [aMD (95% CI): -1.37 (-1.6 to -1.1), p = 0.015], pain during defecation [aMD (95% CI): -2.19 (-2.4 to -2.0), p = 0.005], feeling a lump in the anus (aMD (95% CI): -0.71 (-1.2 to -0.2), p = 0.011), bleeding during defecation (41.7% vs. 66.9%, p = 0.027), and hemorrhoid degree (p < 0.001) in the intervention group was less than the placebo group. Conclusion: Our findings indicate the effectiveness of the study gel on hemorrhoid symptoms and anoscopy findings in patients.

Harnessing tumor-derived exosomes: A promising approach for the expansion of clinical diagnosis, prognosis, and therapeutic outcome of prostate cancer.

Prostate cancer is the second leading cause of men's death worldwide. Although early diagnosis and therapy for localized prostate cancer have improved, the majority of men with metastatic disease die from prostate cancer annually. Therefore, identification of the cellular-molecular mechanisms underlying the progression of prostate cancer is essential for overcoming controlled proliferation, invasion, and metastasis. Exosomes are small extracellular vesicles that mediate most cells' interactions and contain membrane proteins, cytosolic and nuclear proteins, extracellular matrix proteins, lipids, metabolites, and nucleic acids. Exosomes play an essential role in paracrine pathways, potentially influencing Prostate cancer progression through a wide variety of mechanisms. In the present review, we outline and discuss recent progress in our understanding of the role of exosomes in the Prostate cancer microenvironment, like their involvement in prostate cancer occurrence, progression, angiogenesis, epithelial-mesenchymal transition, metastasis, and drug resistance. We also present the latest findings regarding the function of exosomes as biomarkers, direct therapeutic targets in prostate cancer, and the challenges and advantages associated with using exosomes as natural carriers and in exosome-based immunotherapy. These findings are a promising avenue for the expansion of potential clinical approaches.

Sensitization of A-549 lung cancer cells to Cisplatin by Quinacrine-loaded lipidic nanoparticles via suppressing Nrf2 mediated defense mechanism.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is believed to be responsible for the control mechanisms of cellular defense response and master regulator of antioxidant system by adjustment of endogenous antioxidants, phase II detoxifying enzymes and transporters, so inhibition of Nrf2 could be considered molecule target to overcome drug resistance and cancer progression. By harnessing liposome as an advanced nanoparticles transporter, we formulated Quinacrine known as nrf2 inhibitor into nano-carrier, and sensitized A-549 lung tumor cells to Cisplatin. The aim of this work was to prepare liposome nano-carriers to enhance the bioavailability of Quinacrine and to improve passive targeting in A549 cells. Quinacrine formulation into liposome exposed a mean particle size of 80±5 nm in passive targeting and 110±3 after decoration with chitosan oligosaccharides (COS), respectively. The highest amount of cell death (p<0.05) occurred with the co-incubation of the A549 cells with new formulation and Cisplatin. Additionally, Quinacrine-loaded liposomes declined Nrf2 expression more than Quinacrine alone (p<0.05). Correspondingly, the expression of Nrf2 downstream genes, MRP1, Trx, and bcl2 decreased significantly. Taking all the data into consideration, liposomes containing Quinacrine could ameliorate the effectiveness of Cisplatin by raising the permeability of cancer cells to the abovementioned chemical treatment and might be then given as a candidate to boost the therapeutic protocols in cancer patients.

Luteolin-loaded phytosomes sensitize human breast carcinoma MDA-MB 231 cells to doxorubicin by suppressing Nrf2 mediated signalling.

Nuclear factor erythroid 2-related factor 2 (Nrf2) has been recognized as a transcription factor that controls mechanisms of cellular defense response by regulation of three classes of genes, including endogenous antioxidants, phase II detoxifying enzymes and transporters. Previous studies have revealed roles of Nrf2 in resistance to chemotherapeutic agents and high level expression of Nrf2 has been found in many types of cancer. At physiological concentrations, luteolin as a flavonoid compound can inhibit Nrf2 and sensitize cancer cells to chemotherapeutic agents. We reported luteolin loaded in phytosomes as an advanced nanoparticle carrier sensitized MDA-MB 231 cells to doxorubicin. In this study, we prepared nano phytosomes of luteolin to enhance the bioavailability of luteolin and improve passive targeting in breast cancer cells. Our results showed that co- treatment of cells with nano particles containing luteolin and doxorubicin resulted in the highest percentage cell death in MDA-MB 231 cells (p<0.05). Furthermore, luteolin-loaded nanoparticles reduced Nrf2 gene expression at the mRNA level in cells to a greater extent than luteolin alone (p<0.05). Similarly, expression of downstream genes for Nrf2 including Ho1 and MDR1 were reduced significantly (p<0.05). Inhibition of Nrf-2 expression caused a marked increase in cancer cell death (p<0.05). Taken together, these results suggest that phytosome technology can improve the efficacy of chemotherapy by overcoming resistance and enhancing permeability of cancer cells to chemical agents and may thus be considered as a potential delivery system to improve therapeutic protocols for cancer patients.