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Purpose: To investigate the effect of cyclosporine A 2% eye drop following trabeculectomy on intraocular pressure (IOP) and surgical success compared to postoperative steroid drop. Study Design: Prospective, randomized clinical trial in an institutional setting. Methods: Patients: Forty patients with primary open-angle glaucoma and candidates for trabeculectomy were included in this study. Standard fornix-based trabeculectomy augmented with mitomycin C was performed for all patients. None of the included subjects had a history of prior laser or intraocular surgery in that eye. Intervention: All included subjects were randomly assigned to either postoperative cyclosporine A 2% or betamethasone 0.1% eye drops. Main Outcome Measures: IOP measured by applanation tonometer and surgical success rate. Results: Seventy-five potentially eligible POAG patients were seen during the study period, and 40 met the study criteria and were randomly assigned to one of the study groups. Patients in the cyclosporine A 2% group had consistently lower IOP, fewer glaucoma medications, and higher success rates for at least 24 months after surgery (P < 0.0001). Complete success was more frequent in the cyclosporine group. Moreover, the cyclosporine A group had more diffuse and elevated bleb with less vascularity in the first 3 months after surgery (P ≤ 0.01). This was paralleled with fewer dry eye signs and symptoms in the cyclosporine group in the first 3 months (P < 0.03). Conclusion: Postoperative cyclosporine A 2% eye drop can be used instead of steroid drops and is associated with improved surgical success and decreased dry eye manifestations. [ABSTRACT FROM AUTHOR] more...

Purpose: Methotrexate is one of the most essential single agents in patients with primary central nervous system lymphoma (PCNSL). However, 25–50% result in relapse with a poor prognosis. Therefore, studies on methotrexate resistance are warranted to explore salvage chemotherapy for recurrent PCNSL. Single-cell sequence analysis enables the characterization of novel cell types and provides a precise understanding of cancer biology. Methods: Single-cell sequence analysis of parental and methotrexate-resistant PCNSL cells was performed. We used a Weighted Gene Co-expression Network Analysis to identify groups of significantly connected genes. Results: We identified consensus modules in both the HKBML and TK datasets. HLA-DRβ1, HLA-DQβ1,and SNRPG were hub genes those detected in both datasets revealed by network analysis. Cyclosporine A was selected as the candidate drug for treating methotrexate-resistant cells. Conclusion: The results of the present study characterized the methotrexate resistance-related signaling pathways in cultured PCNSL cells. Overall, these results may account for variations in treatment responses and lead potential novel therapeutic strategies for patients with PCNSL. [ABSTRACT FROM AUTHOR] more...

Background: The potential nephrotoxicity of cyclosporine A (CsA) has been a problem for treating graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the relationship between CsA blood concentration and acute kidney injury (AKI) in pediatric patients after allo-HSCT remains unclear. Methods: We performed a retrospective study including pediatric patients who received allo-HSCT in West China Second Hospital of Sichuan University from 2000 to 2022 and collected their clinical data. Included patients' CsA blood concentration were divided into three cohorts according to the guideline. Multivariate logistic regression was used to estimate the relationship between AKI and CsA blood concentration and other factors. And the maximum cut-off value for the safe blood concentration range of CsA was obtained by the receiver operating characteristic (ROC) curve. Results: Seventy-nine patients (average age 6.75 ± 4.25) were included. The incidence of kidney injury for three CsA blood concentration cohorts (< 200 ng/ml, 200–300 ng/ml, > 300 ng/ml) were 21.30%, 23.50%, and 66.70%, respectively. A multivariate logistic regression identified CsA blood concentration (> 300 ng/ml) and infection were risk factors for AKI (OR <200 ng/ml: 0.115, 95% CI: 0.029–0.458; OR 200–300 ng/ml: 0.184, 95% CI: 0.036–0.929; OR infection: 5.006, 95% CI: 1.491–16.810). Meanwhile, the maximum cut-off value for the safe blood concentration range of CsA is 276.85 ng/ml with an AUC value of 0.684 (P = 0.010). Conclusion: In conclusion, clinical treatment for the pediatric patients after allo-HSCT may be considered to control the blood concentration of CsA in 200–276.85 ng/ml and closely monitoring patients who have infections. [ABSTRACT FROM AUTHOR] more...

Simple Summary: Coccidiosis is a disease caused by various Eimeria species that parasitize the intestinal tract of chickens. Eimeria infections cause significant economic losses in the poultry industry due to reduced weight gain, increased feed conversion ratios, and high mortality rates. Among the known Eimeria species, Eimeria tenella is considered the most pathogenic, although its prevalence can vary across different regions. Eimeria tenella induces apoptosis in host cells. This study systematically investigated the mechanisms by which E. tenella induces host cell apoptosis via the mitochondrial permeability transition pore (MPTP) and cytochrome c. Using inhibitors, this study demonstrated that the inhibition of mitochondrial pathways significantly reduces host cell apoptosis following infection. Unraveling the mechanisms of Eimeria tenella-induced apoptosis can contribute to the development of targeted therapies, novel vaccines, and enhanced disease control measures to effectively control infection and mitigate economic losses. Coccidiosis in chickens is a parasitic disease caused by Eimeria species, resulting in significant economic losses to the poultry industry. Among these species, Eimeria tenella is considered the most virulent pathogen, with its infection strongly associated with the apoptotic response of host cells. Eimeria tenella modulates host cell apoptosis in a stage-specific manner, suppressing apoptosis in the early phase to promote its intracellular development and triggering apoptosis in later stages to facilitate parasite egress and disease progression. This study established an in vitro infection model using 60 fifteen-day-old chick embryo cecal epithelial cells and infecting the cells with Eimeria tenella sporozoites at a 1:1 ratio of host cells to sporozoites. The aim was to examine the relationship between parasitic infection and the apoptotic response of host cells in the chick embryo cecal epithelial cells infected with E. tenella. The roles of the mitochondrial permeability transition pore (MPTP) and cytochrome c in intrinsic apoptosis were examined through the application of cyclosporine A (CsA), N, N, N', N'-tetramethyl-1,4-phenylenediamine (TMPD), and ascorbate (Asc). TUNEL staining, ELISA, and flow cytometry were performed to evaluate apoptotic rates. CsA, TMPD, and Asc significantly (p < 0.01) decreased cytochrome c release, caspase-9 activation, and apoptotic rates from 24 to 120 h post-E. tenella infection. These findings highlight the significance of cytochrome c-mediated, mitochondria-dependent apoptotic pathways in parasitized chick embryo cecal epithelial cells. [ABSTRACT FROM AUTHOR] more...

Oxidative stress, inflammation and renin-angiotensin system (RAS) activation play an important role in the nephrotoxicity which is caused by the long-term use of the immunosuppressive drug cyclosporine (CsA). This study investigates whether chenodeoxycholic acid (CDCA), an endogenous farnesoid X receptor (FXR) agonist with antioxidant and anti-inflammatory effects, modulates CsA nephrotoxicity. CsA (25 mg/kg/day; s.c.) was administered to rats for 12 days. CDCA (20 mg/kg/day; i.p.) injection was started 3 days before CsA and continued for 15 days. CDCA improved renal damage and function in CsA-administered rats. Renal function markers in serum, renal histology, oxidative stress, inflammation and RAS components were determined in kidney. CDCA reduced CsA-induced renal increases in NADPH oxidase 4 and NADPH oxidase 2 mRNA expressions, oxidative stress and inflammation. CDCA elevated renal FXR, small heterodimer partner-1, hypoxia-inducible factor and vascular endothelial growth factor and nuclear factor erythroid 2-related factor mRNA expressions in CsA rats. It prevents renin angiotensin system activation by reducing angiotensin II (Ang-II) levels in serum and upregulating renal mRNA expressions of Ang II type-II receptor (AT2R) and angiotensin converting enzyme 2 (ACE2), but not AT1R and ACE in CsA rats. Our results indicate that CDCA may be a protective agent against CsA-nephrotoxicity by decreasing inflammation, oxidative stress and RAS activation via AT2R and ACE2 upregulations. [ABSTRACT FROM AUTHOR] more...

Invasive candidiasis is a common fungal infection associated with multiple risk factors, such as cancer, neutropenia, corticosteroid therapy, catheterization, and the use of broad-spectrum antibiotic treatment. Candida albicans is the predominant causative agent, although other Candida species have been emerging in the last years, together with a rise in a number of strains resistant to the currently available antifungal drugs, which poses a challenge when treating these infections. Drug repurposing and drug combinations are promising strategies for the treatment of invasive mycoses. In this study, we evaluated the effect of the combination of fluconazole (FLZ) and cyclosporine A (CsA) against 39 clinical isolates and reference strains of Candida. Two methods, the Loewe additivity model and Bliss independence model, were used to assess the antifungal activity of the drug combination according to CLSI and EUCAST guidelines. The results demonstrated a synergistic effect between fluconazole (FLZ) and cyclosporine A (CsA) against 15–17 Candida isolates, depending on the evaluation model used, including FLZ-resistant strains of C. albicans, C. glabrata, C. parapsilosis, and C. tropicalis. Notably, the combination significantly reduced the minimum inhibitory concentration (MIC) of FLZ in a substantial number of isolates, including those with resistance to FLZ. Additionally, time–kill curve studies confirmed the synergistic interaction, further validating the potential of this combination as an alternative therapeutic strategy for candidiasis treatment. These findings emphasize the importance of investigating innovative drug combinations to address the challenges posed by antifungal resistance and improve treatment options for invasive fungal infections. [ABSTRACT FROM AUTHOR] more...

Purpose: To assess the clinical efficacy of 0.1% cyclosporine A (CsA) in dry eye patients who have shown inadequate responses to previous treatment with 0.05% CsA. Design: This study was designed as a switching, prospective, multicenter, 12-week, open-label study. Methods: Patients with dry eye disease (DED), who experienced inadequate responses to at least 3 months of treatment with 0.05% cyclosporine, were enrolled in this study. Clinical evaluations included the National Eye Institute (NEI) corneal and conjunctival staining scores, tear film break-up time (TF-BUT), Symptom Assessment in Dry Eye (SANDE), ocular discomfort scale (ODS), and tear volume. These parameters were assessed at baseline, and again at 4, 8, and 12 weeks after switching to 0.1% CsA. Results: Ninety-one patients were enrolled in the study, and 70 patients completed the trial. Statistical analysis was performed on the full analysis set (FAS) using the Markov Chain Monte Carlo (MCMC) method to account for missing data. After switching to 0.1% CsA, subjective symptoms assessed by the Symptom Assessment in Dry Eye (SANDE) and Ocular Discomfort Scale (ODS) showed improvement (p < 0.0001). Objective signs of dry eye, including the National Eye Institute (NEI) score, tear film break-up time (TF-BUT), and tear volume also improved (p < 0.0001). Conclusions: In patients with dry eye disease (DED) who exhibited inadequate responses to 0.05% cyclosporine A (CsA), switching to 0.1% CsA resulted in significant improvements in both subjective symptoms and objective clinical signs. This finding suggests that higher concentrations of CsA may be more effective in treating individuals with moderate to severe DED. [ABSTRACT FROM AUTHOR] more...

Purpose: Supersaturated formulations have been widely explored for improving the oral bioavailability of drugs by using mesoporous silica (MS) to generate supersaturation via molecular adsorption; however, this is followed by precipitation. Several precipitation inhibitors (PI) have been explored to prevent precipitation and maintain the drug in solution for a longer period. However, the combined approach of MS and PIs, the impact of MS and Silica, and the loading of high-molecular-weight neutral molecules such as Cyclosporine A (CsA) have not yet been explored. The present study aimed to explore the impact of MS and a hydroxypropyl methylcellulose (HPMC) matrix on the supersaturation and bioavailability of the neutral drug CsA. Methods: A CsA-loaded mesoporous silica/HPMC ternary matrix and CsA-HPMC and CsA-MS controls were prepared, and physicochemical characterization was carried out. The ternary matrix and controls were investigated for the Non-sink Mini FaSSIF dissolution and biorelevant transfer studies. Furthermore, drug release modeling was performed using DDSolver, and pharmacokinetic studies were performed to assess the impact on oral bioavailability compared with the marketed formulation. Results: The study suggested that the co-loaded CsA, HPMC, and MS demonstrated higher supersaturation than CsA-loaded silica and CsA-HPMC controls. A significant improvement in FaSSIF single medium (2-fold) and biorelevant transfer (3.37-fold) increase in the dissolution profile was observed for the co-loaded CsA-MS-HPMC samples. The in vitro dissolution profile was corroborated by pharmacokinetic studies, which showed a 1.19-fold higher oral bioavailability of CsA-MS-HPMC compared to that of CsA-MS and CsA-HPMC. Conclusion: The pharmacokinetics indicated that CsA-MS-HPMC co-loaded samples demonstrated supersaturation and improved bioavailability compared with the physical mixture. [ABSTRACT FROM AUTHOR] more...

Aims: Skin allotransplantation often results in graft rejection, necessitating the use of immunosuppressants. Tacrolimus (Tac) and cyclosporine A (CsA) are two commonly used immunosuppressants in this context. However, the efficacies of both agents in various formulations remain unclear. In this regard, this study was conducted to evaluate the efficacies of using topical Tac and intraperitoneal CsA, stand-alone and in combination, in preventing acute rejection following rat skin allotransplantation. Setting and Design: This study was designed as a double-blind experimental animal study. It was conducted under veterinary control in accordance with EU Directive 2010/63/EU for animal experiments and national regulations at the Animal Experimentation Research Laboratory of Bezmialem Foundation University in Turkey. Materials and Methods: The study material consisted of 20 female albino Wistar (WIS) rats that underwent skin allograft transplantation. These rats were randomly divided into four groups according to the treatment they were administered: the Tac group, the CsA group, the Tac and CsA group, and the control group. Rejection symptoms were monitored over a month, followed by macroscopic and histopathological evaluations of the grafts. Statistical Analysis Used: Qualitative data were analysed using the Chi-square test, and in cases where Chi-square analysis was not appropriate, Fisher's exact test was used. The efficacies of the treatment drugs were compared between treatment groups using a nonparametric analysis of variance test followed by Dunn's post hoc test. Results: The most severe (Grade 4) symptoms associated with rejection, both in terms of clinical and histopathological scale scores (P < 0.001), were observed in the control group. The mildest rejection-associated symptoms, i.e. mainly (80%) Grade 0 symptoms, were observed in the Tac group, followed by the Tac and CsA group, where Grade 0, 1, and 2 symptoms were observed in 60%, 20%, and 20% of the rats, respectively, and the CsA group, where Grade 1, 2, and 3 symptoms were observed in 20%, 40%, and 40% of the rats, respectively. Conclusions: Stand-alone topical Tac was found to be more effective in mitigating acute rejection than stand-alone CsA and Tac and CsA in combination, suggesting its potential as a superior treatment modality in skin allotransplantation. [ABSTRACT FROM AUTHOR] more...

This study aims to investigate the effect and mechanism of cyclosporine A (CsA) on paclitaxel-resistant prostate cancer cells. Paclitaxel-resistant prostate cancer cell lines were established by gradual increment method. The proliferation of cells was tested using MTT and colony formation assay. Western blot was used to detect protein expression. Expression levels of gene mRNA were detected using real-time polymerase chain reaction (RT-PCR). Xenografts in nude mice were used to validate the conclusion in vitro. The results showed that CsA could increase the sensitivity of prostate cancer cells to paclitaxel. Treatment of paclitaxel-resistant prostate cancer cell lines with CsA gradients decreased metadherin (MTDH) protein expression. RT-PCR showed that CsA could decrease the mRNA level of MTDH. Overexpression of MTDH in prostate cancer cells increases paclitaxel resistance in prostate cancer cells. Conversely, knockdown of MTDH reduced paclitaxel resistance in prostate cancer cells. Treating cells with CsA failed to reduce paclitaxel resistance in prostate cancer cells when MTDH was overexpressed. Xenografts in nude mice yielded consistent conclusions with the in vitro results. In conclusion, CsA can reduce the resistance of prostate cancer cells to paclitaxel. In vitro and in vivo experiments have shown that CsA can reduce paclitaxel resistance in prostate cancer cells by decreasing MTDH expression. In clinical practice, CsA can be used in combination with paclitaxel to improve the therapeutic effect on prostate cancer. MTDH may serve as a novel target for treating paclitaxel resistance in prostate cancer. [ABSTRACT FROM AUTHOR] more...

Background: Cyclosporine A (CsA) and regular doses of recombinant human thrombopoietin (rhTPO) can accelerate platelet recovery in patients with non-severe aplastic anemia (NSAA). However, it is unclear whether CsA plus rhTPO at a higher dose can further increase the efficacy. Methods: Data from patients with newly diagnosed NSAA, who had been treated with CsA in combination with different doses of rhTPO between February 2021 and August 2021 at Peking Union Medical College Hospital, were reviewed. All the enrolled patients had been treated with CsA at 3–5 mg/(kg/d), and patients were further classified into high-dose (with rhTPO 30000U qd × 14 days for 2 months) group or regular-dose (with rhTPO 15000U qd × 7days for 3 months) group. The treatment response and therapy-related adverse events were compared. Results: 36 patients including 16 (44.4%) in the high-dose and 20 (55.6%) in the regular-dose group were enrolled. The baseline characteristics were compatible between the two groups. The platelet counts were significantly higher at 1/3/6 months in the high-dose group (p = 0.028, 0.0063 and p = 0.040, respectively). The high-dose group had a significantly shorter time to platelet transfusion independence ([1 (0.5–6) months vs 2.5 (1–12) months, p = 0.040]). There was no significant difference in overall response and complete response rate between the two groups at 1/3/6/12 months (p > 0.05). Treatment-related morbidities were similar between the two groups (p > 0.05). Conclusions: Adding a higher dose of rhTPO can further accelerate platelet recovery and platelet transfusion independence in patients with newly diagnosed NSAA. [ABSTRACT FROM AUTHOR] more...

Objectives: Cyclosporine A promotes gingival fibrosis by enhancing the proliferation of gingival fibroblasts, leading to gingival overgrowth. The population of gingival fibroblasts is regulated by cell cycle machinery, which balances cell growth and inhibition. Cells that detect DNA damage pause at the G1/S checkpoint to repair the damage instead of progressing to the S phase. Previous studies have linked drug-induced gingival overgrowth to the response of fibroblasts to lipopolysaccharide (LPS) and cyclosporine A. This research investigates the effects of cyclosporine A on the G1/S checkpoint and its mediators in LPS-treated gingival fibroblasts to clarify the mechanisms behind cyclosporine-A-induced gingival overgrowth. Methods: Semi-confluent human gingival fibroblasts were treated with LPS or cyclosporine A in DMEM. Cell proliferation was evaluated by counting the total number of cells. The distribution of the cell cycle phases was analyzed using flow cytometry. Additionally, the expression levels of mRNAs and proteins related to cell cycle regulators were quantified by reverse-transcription quantitative PCR and Western blotting, respectively. Results: Cyclosporine A treatment significantly enhanced cell proliferation and the G1-S cell cycle transition. It increased the mRNA levels of CDC25A and CYCLIN D while decreasing those of RB1, SMAD3, and SMAD4. Additionally, it upregulated the protein levels of CDC25A, CYCLIN D, CDK4, CDK6, and pRB and downregulated the protein levels of SMAD3 and SMAD4. Conclusions: Gingival overgrowth induced by cyclosporine A could be attributed to these alterations. [ABSTRACT FROM AUTHOR] more...

Objective: IgA vasculitis (IgAV), previously named as Henoch–Schönlein purpura, is the most frequent systemic vasculitis in children. In adults, IgAV is less common although it is associated with more severe disease. In fact, the frequency of glomerulonephritis (referred to as IgAV nephritis) in adults is higher than in children and tends to present more severely, with around 10–30% of those affected eventually progressing to end-stage renal disease. In this review, we describe the pathophysiology, main clinical features, diagnosis of the disease, and latest clinical data regarding IgAV therapy. Methods: A narrative literature review, primarily based on articles published in PubMed, was conducted. In addition to discussing the main aspects of glucocorticoids and conventional disease-modifying drugs used in the management of IgAV, this review focuses on the latest information reported regarding biologics and potential future therapies. Results: Glucocorticoids are the first-line therapy for IgAV, especially in adults with severe manifestations. Colchicine, dapsone, and methotrexate can be useful for controlling minor manifestations. Several immunomodulatory agents, such as cyclosporine A, tacrolimus, and mycophenolate mofetil, have shown favorable results as glucocorticoid-sparing agents. Leflunomide has shown promising results but requires further study. The use of rituximab has demonstrated efficacy in reducing relapse frequency, lowering the cumulative glucocorticoid burden, and achieving long-term remission of the disease in children and adults with IgAV. Immunoglobulins and plasma exchange therapy can also be useful in difficult and life-threatening situations. Other potential therapies with encouraging results include TRF-budesonide, B-cell-directed therapy, B-cell-depleting agents, sodium–glucose cotransporter-2 inhibitors, endothelin receptor antagonists, and complement pathway inhibitors. Conclusions: Glucocorticoids are the first-line therapy for IgAV, especially in adults with severe manifestations. The role of various immunomodulatory therapies, such as calcineurin inhibitors and mycophenolate mofetil, remains promising, while rituximab reduces the long-term side effects of glucocorticoids and can help achieve disease remission. Other potential therapies with encouraging results require further research. [ABSTRACT FROM AUTHOR] more...

Background/Objectives: Meibomian gland dysfunction (MGD) and dry eye syndrome (DES) are common eye diseases characterized by altered tear film stability and inflammation of the ocular surface, causing significant discomfort and possible visual impairment. This study aimed to investigate the efficacy of curcumin-loaded liposomes (Lipo@Cur) compared to cyclosporine A-loaded liposomes (Lipo@CycA) in experimental rabbit models of MGD and DES, with a focus on their ability to improve tear film stability and reduce ocular surface inflammation. Methods: MGD and DES were induced using complete Freund's adjuvant (CFA) and treated to evaluate the effect of liposomal formulations on tear break-up time (TBUT), clinical signs of inflammation (telangiectasia, conjunctival hyperemia, meibomian foramen occlusion), and corneal as well as conjunctival histological cells. Results: Lipo@Cur increased TBUT and reduced the signs of ocular surface inflammation, potentially approaching the effectiveness of clinically approved cyclosporine A encapsulated in liposomes (Lipo@CycA). Histological analysis suggested improvements in corneal epithelial thickness and goblet cell density in the treated groups, which may indicate a reversal of DES-induced damage to the ocular surface. Conclusions: Plant-originated curcumin encapsulated in liposomes offers a promising therapeutic strategy for the management of MGD and DES that may improve patient outcomes by addressing the underlying inflammatory mechanisms of these conditions. [ABSTRACT FROM AUTHOR] more...

Objectives: This study aimed to assess the effectiveness and safety of intense pulsed light (IPL) therapy plus topical 0.05% cyclosporine A (CsA) eye drops to treat Sjögren's Syndrome-related dry eyes (SS-DE). Research design and methods: In this prospective, randomized trial included, 60 individuals with SS-DE symptoms were randomized to receive topical eye drops containing either 0.1% sodium hyaluronate (Group S) or 0.05% CsA (Group C) plus IPL therapy. Before the first treatment (baseline), and at 12, 16, and 20 weeks after treatment commencement, we assessed the best corrected visual acuity (BCVA), the Ocular Surface Disease Index (OSDI) score, the Schirmer I test (SIT), noninvasive tear breakup time (NBUT), corneal fluorescein staining (CFS), meibomian gland (MG) dropout, lid margin abnormality, MG expressibility, and meibum quality. Results: Both groups showed significant improvements in the OSDI, NBUT, CFS, MG expressibility, and meibum quality (all p < 0.05). Group C showed a greater increase in OSDI, NBUT, MG expressibility, and meibum quality (all p < 0.05). Moreover, SIT and lid margin abnormalities significantly improved in Group C (both p < 0.05), but not in Group S. Conclusion: Treatment with 0.05% CsA eyedrops plus IPL therapy could significantly reduce the issues and physical discomfort of patients with SS-DE. Clinical Trial: Registered on 20 July 2021, with the registration number ChiCTR2100049059. [ABSTRACT FROM AUTHOR] more...

Objectives: This study aimed to develop nanosuspensions (NSs) of cyclosporine A (CycA) using a top-down technology [high-pressure homogenization-(HPH)] for oral administration. Materials and Methods: Formulas were prepared using different ratios of hydroxypropyl methylcellulose (HPMC) (1% and 0.5%) and sodium dodecyl sulfate (SDS) (1%) to improve the solubility of CycA. The HPH method was optimized by investigating the effects of critical formulation parameters (stabilizer ratio) and critical process parameters (number of homogenization cycles) on the particle size (PS), polydispersity index (PDI), and zeta potential (ZP) of NS using the Design of Experiment (DoE). After lyophilization, differential scanning calorimetry, X-ray diffraction, fourier-transform infrared spectroscopy, and morphological evaluation with scanning electron microscopy were performed. Stability studies were conducted at 4°C and 25°C storage conditions. The solubility of the optimum CycA NS was investigated by comparing it with a coarse CycA powder and a physical mixture (PM). In vitro dissolution studies were conducted in four media using United States Pharmacopeia apparatus I. Results: PS, PDI, and ZP values for the NS were approximately 250 nm, 0.6, and 35 mV, respectively. Under storage conditions, the CycA NS exhibited significant physical stability at both 4°C and 25°C for 9 months. The solubility of CycA was improved 1.9 and 1.4 times by NS in the presence of CycA powder and PM, respectively. CycA NS exhibited higher dissolution than CycA coarse powder in 0.1 N HCl, fasted simulated intestinal fluid, and fed simulated intestinal fluid. Conclusion: CycA NS was successfully developed using the DoE approach with the HPH method with HPMC:SDS combination in a 1:0.5 ratio, and the solubility and dissolution of CycA in the NS were improved. [ABSTRACT FROM AUTHOR] more...

Cyclosporine A (CsA) is widely used as an immunosuppressant in organ transplantation to improve graft survival and prevent tissue rejection. The impact of CsA on cancer progression is highly complex, influenced by the intricate relationship between immunosuppression and malignancy. While individuals with compromised immune systems, notably organ transplant recipients, face an elevated risk of cancer invasion and progression due to immunosuppressive regimens, CsA's role in either promoting or inhibiting cancer remains elusive. Divergent outcomes from in vitro and in vivo studies suggest suppression of cancer progression under CsA treatment and complicate the translation of findings to clinical scenarios. Despite promising in vitro and in vivo results, the clinical application of CsA in oncology necessitates careful consideration of its toxicity profile in in vivo models, starting at 50–200 mg/kg/d. The divergence between preclinical and clinical findings highlights the need for further research to elucidate the true nature of CsA's impact on cancer, providing a foundation for more informed and targeted therapeutic approaches. [ABSTRACT FROM AUTHOR] more...

Aim: The binding of integrin αvβ3 with endometrial fibronectin (FN) promotes the migration of preimplantation embryos in mice. We have previously shown that cyclosporine A (CsA) improves the adhesion and invasion of mouse preimplantation embryos. In this study, we evaluated the roles of calcium ions and downstream signaling factors in the binding of integrin αvβ3 to FN. Methods: Female Institute of Cancer Research (ICR) mice were superovulated and mated, and two‐cell embryos were harvested from the oviducts and cultured to the blastocyst stage The adhesion and stretching growth of hatched embryos in laminin‐coated dishes were evaluated, and integrinβ3 expression was determined using qPCR. Blastocytes were cultured with 0 or 1 μM cyclosporine A (CsA) and the attachment of embryonic integrin αvβ3 to FN120 was observed using a fluorescent bead. To further determine the mechanism, the cells were also incubated with calcium ions and protein kinase C and calmodulin antagonists. The binding of integrin αvβ3 to FN120 was examined via confocal laser scanning microscopy. Results: The adhesion and stretching growth of peri‐implantation embryos were greater and integrinβ3 expression was higher in the 1 μM CsA group than in the 0 μM CsA group (p < 0.05). When incubated with calcium ions and protein kinase C and calmodulin antagonists, the ability of peri‐implantation embryos to bind to FN decreased; CsA treatment promoted this binding. Conclusion: This study revealed that CsA up − regulates integrinβ3 expression in peri − implantation embryos and promotes binding to FN via calcium ions, and protein kinase C, and calmodulin. These findings provide evidence supporting the beneficial effect of CsA on the peri − implantation embryo adhesion. [ABSTRACT FROM AUTHOR] more...

Background: Mooren's ulcer (MU) is a rare and debilitating form of peripheral ulcerative keratitis (PUK), characterized by a crescent-shaped ulcer with a distinctive overhanging edge at the corneal periphery. If left untreated, MU can lead to severe complications such as corneal perforation and blindness. Despite various treatment approaches, including anti-inflammatory and cytotoxic drugs, as well as surgical interventions, there is no clear evidence of the most effective treatment due to the lack of randomized controlled trials. AS-OCT is a non-invasive imaging technique that provides high-resolution cross-sectional images of the anterior segment, allowing for accurate evaluation of corneal ulcer characteristics, including depth, extent, and disease progression. Methods: We present the case of a 20-year-old male patient with MU managed using a stepladder approach, which included local and systemic corticosteroids, limbal conjunctival resection, and Cyclosporine A 1% eye drops. The patient underwent consecutive AS-OCT examinations and strict follow-up to tailor systemic and topical therapy. Results: Complete healing of the corneal ulcer with resolution of the inflammatory process was achieved. There was no recurrence of the disease at the 7-month follow-up. AS-OCT demonstrated progressive reorganization and thickening of the stromal tissue until the complete recovery of stromal thickness. Conclusions: The AS-OCT imaging modality allowed for the accurate evaluation of corneal ulcer characteristics, facilitating informed decision-making regarding the use of systemic immunosuppression, surgical interventions, and local immunomodulation and providing detailed and precise assessment of disease progression. This approach enabled a tailored and effective treatment strategy for the patient and played a critical role in guiding the therapeutic approach. [ABSTRACT FROM AUTHOR] more...

Background and Objectives: Systemic Lupus Erythematosus (SLE) often causes damage to small nerve fibers, leading to distressing painful and autonomic symptoms. Despite this, Small Fiber Neuropathy (SFN) remains an underrecognized complication for SLE patients. In this cross‐sectional study, we aimed to assess SFN in patients with SLE and to explore its correlations with immunologic disease features and clinical manifestations. Methods: We recruited 50 SLE patients (1 male to 12.5 females, aged 20–80 years) reporting painful disturbances. We conducted a comprehensive clinical and neurophysiological evaluation, using Nerve Conduction Studies and Quantitative Sensory Testing. Additionally, we carried out an extensive laboratory assessment of disease‐related serological parameters. We also performed a thorough skin biopsy analysis, investigating somatic and autonomic innervation while detecting complement and inflammatory cell infiltrates within the skin. Results: Out of 50 patients, 19 were diagnosed with SFN, primarily characterized by a non‐length‐dependent distribution; 7 had a mixed neuropathy, with both large and small fiber involvement. Patients with SFN were younger than patients with a mixed neuropathy (p =.0143); furthermore, they were more likely to have a history of hypocomplementemia (p =.0058) and to be treated with cyclosporine A (p =.0053) compared to patients without neuropathy. However, there were no significant differences in painful and autonomic symptoms between patients with and without SFN. Discussion: This study highlights the relevant frequency of SFN with a non‐length‐dependent distribution among SLE patients experiencing painful symptoms. Indeed, SFN emerges as an early manifestation of SLE‐related neuropathy and is closely associated with hypocomplementemia, suggesting a potential pathogenic role of the complement system. Moreover, SFN may be influenced by disease‐modifying therapies. However, the precise role of SFN in shaping painful and autonomic symptoms in patients with SLE remains to be fully elucidated. [ABSTRACT FROM AUTHOR] more...

Hepatic ischemia‐reperfusion injury (HIRI) is a prevalent issue during liver resection and transplantation, with currently no cure or FDA‐approved therapy. A promising drug, Cyclosporin A (CsA), ameliorates HIRI by maintaining mitochondrial homeostasis but has systemic side effects due to its low bioavailability and high dosage requirements. This study introduces a biomimetic CsA delivery system that directly targets hepatic lesions using mesenchymal stem cell (MSC) membrane‐camouflaged liposomes. These hybrid nanovesicles (NVs), leveraging MSC‐derived proteins, demonstrate efficient inflammatory chemotaxis, transendothelial migration, and drug‐loading capacity. In a HIRI mouse model, the biomimetic NVs accumulated at liver injury sites entered hepatocytes, and significantly reduced liver damage and restore function using only one‐tenth of the CsA dose typically required. Proteomic analysis verifies the protection mechanism, which includes reactive oxygen species inhibition, preservation of mitochondrial integrity, and reduced cellular apoptosis, suggesting potential for this biomimetic strategy in HIRI intervention. [ABSTRACT FROM AUTHOR] more...

Dry eye disease (DED) is caused by inflammation and damage to the corneal surface due to tear film instability and hyperosmolarity. Various eye drops are used to treat this condition. Each eye drop has different properties and mechanisms of action, so the appropriate drug should be used according to clinical phenotypes. This study aims to compare the therapeutic mechanisms of cyclosporine A (CsA) and diquafosol tetrasodium (DQS). An experimental in vivo/in vitro model of DED using hyperosmolarity showed decreased cell viability, inhibited wound healing, and corneal damage compared to controls. Treatment with cyclosporine or diquafosol restored cell viability and wound healing and reduced corneal damage by hyperosmolarity. The expression of the inflammation-related genes il-1β, il-1α, and il-6 was reduced by cyclosporine and diquafosol, and the expression of Tnf-α, c1q, and il-17a was reduced by cyclosporine. Increased apoptosis in the DED model was confirmed by increased Bax and decreased Bcl-2 and Bcl-xl expression, but treatment with cyclosporine or diquafosol resulted in decreased apoptosis. Diquafosol increased NGF expression and translocation into the extracellular space. DED has different damage patterns depending on the progression of the lesion. Thus, depending on the type of lesion, eye drops should be selected according to the therapeutic target, focusing on repairing cellular damage when cellular repair is needed or reducing inflammation when inflammation is high and cellular damage is severe. [ABSTRACT FROM AUTHOR] more...

Cyclosporine A (CP) inclusion complex using cyclodextrin (binary) and cyclodextrin with TPGS (ternary) was prepared by the freeze-drying method. The phase solubility study was performed to calculate the solubility parameters. The prepared formulations were evaluated for saturation solubility and drug release studies. The spectroscopy and molecular docking studies were performed to confirm the formation of inclusion complex. The phase solubility results revealed a high stability constant for both binary and ternary samples. A significant enhancement in saturation solubility and dissolution was found in the prepared inclusion complexes. The spectroscopy studies revealed no interaction between the drug and carrier. The molecular docking study displayed the formation of a stable complex with a good docking score. The diffraction pattern showed the conversion of crystalline CP into an amorphous form after the formation of the inclusion complex. The findings were also supported by the saturation solubility study, which showed a significant enhancement in solubility. From the results, it can be concluded that Cyclosporine A inclusion complex using HP βCD with TPGS is an excellent delivery system. Therefore, the prepared delivery systems may be an alternative to the conventional delivery system for enhanced solubility of highly lipophilic drugs. [ABSTRACT FROM AUTHOR] more...

This article presents a case report of a 17-year-old boy with Kikuchi-Fujimoto disease (KFD), a condition characterized by fever and swollen lymph nodes in the neck. The boy experienced low body temperature, slow heart rate, and low blood pressure while being treated with glucocorticoids or cyclosporine A. These side effects resolved after stopping the medications and providing fluids. The article suggests that using a low dose of cyclosporine A may be a viable alternative for KFD patients who experience these adverse effects. It also mentions that caution should be exercised when using nonsteroidal anti-inflammatory drugs (NSAIDs) alongside this treatment. [Extracted from the article] more...

This study aimed to investigate the effect of cyclosporine A (CsA) on secretion of Th1 and Th2 cytokines by decidual stromal cells (DSCs) mediated by galectin (Gal)-9.HTR8/SVneo cells and primary trophoblasts were used for in vitro studies. Gal-9 expression was measured using quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay, CsA was used to regulate Gal-9 expression in trophoblasts. DSCs were treated with trophoblast supernatant and changes in Th1 and Th2 cytokine levels were analyzed. Changes in DSC levels of the T-cell immunoglobulin mucin receptor 3 (TIM-3) levels in DSCs after treatment with Gal-9 were assessed. Western blotting and ERK and AKT inhibitors were used to assess the involvement of the corresponding signaling pathways. Gal-9 was expressed by both primary trophoblasts and HTR8/SVneo cells. CsA treatment increased Gal-9 secretion by trophoblasts, which in turn increased IL-6 (Th2 cytokine) and decreased TNF-α and IFN-γ (Th1 cytokines) secretion in DSCs. Upon downregulation of trophoblast Gal-9 secretion, DSCs secreted lower levels of Th2 cytokines and higher levels of Th1 cytokines, and the effect was reversed by addition of CsA. TIM-3 expression changed in parallel with Gal-9 secretion. CsA treatment upregulated expression of Gal-9 in trophoblasts, promoted secretion of Th2 cytokines, and inhibited secretion of Th1 cytokines via ERK signaling. [ABSTRACT FROM AUTHOR] more...

Purpose: Dry eye syndrome (DES), arising from various etiologic factors, leads to tear film instability and ocular surface damage. Given its anti-inflammatory effects, cyclosporine A (CsA) has been widely used as a short-term treatment option for DES. However, poor bioavailability and solubility of CsA in aqueous phase make the development of a cyclosporine A-based eye drop for ocular topical application a huge challenge. Methods: In this study, a novel strategy for preparing cyclosporine A-loaded silk fibroin nanoemulsion gel (CsA NBGs) was proposed to address these barriers. Additionally, the rheological properties, ocular irritation potential, tear elimination kinetics, and pharmacodynamics based on a rabbit dry eye model were investigated for the prepared CsA NBGs. Furthermore, the transcorneal mechanism across the ocular barrier was also investigated. Results: The pharmacodynamics and pharmacokinetics of CsA NBGs exhibited superior performance compared to cyclosporine eye drops, leading to a significant enhancement in the bioavailability of CsA NBGs. Furthermore, our investigation into the transcorneal mechanism of CsA NBGs revealed their ability to be absorbed by corneal epithelial cells via the paracellular pathway. Conclusion: The CsA NBG formulation exhibits promising potential for intraocular drug delivery, enabling safe, effective, and controlled administration of hydrophobic drugs into the eye. Moreover, it enhances drug retention within the ocular tissues and improves systemic bioavailability, thereby demonstrating significant clinical translational prospects. [ABSTRACT FROM AUTHOR] more...

This study aimed to control the oral absorption of cyclosporine A (CsA) with the use of a mucosal drug delivery system (mDDS). Mucopenetrating nanocarriers (MP/NCs) and mucoadhesive nanocarriers (MA/NCs) were prepared by flash nanoprecipitation employing polystyrene‐block‐poly(ethylene glycol) and polystyrene‐block‐poly(N,N‐dimethyl aminoethyl methacrylate), respectively. Their particle distribution in the rat gastrointestinal tract were visualized by fluorescent imaging. Plasma concentrations were monitored after oral administration of CsA‐loaded MP/NCs (MP/CsA) and MA/NCs (MA/CsA) to rats. MP/NCs and MA/NCs had a particle size below 200 nm and ζ‐potentials of 4 and 40 mV, respectively. The results from in vitro experiments demonstrated mucopenetration of MP/NCs and mucoadhesion of MA/NCs. Confocal laser scanning microscopic images showed diffusion of MP/NCs in the gastrointestinal mucus towards epithelial cells and localization of MA/NCs on the surface of the gastrointestinal mucus layer. In a pH 6.8 solution, rapid and sustained release of CsA were observed for MP/CsA and MA/CsA, respectively. After oral dosing (10 mg‐CsA/kg) to rats, amorphous CsA powder exhibited a time to maximum plasma concentration (Tmax) of 3.4 h, maximum plasma concentration (Cmax) of 0.12 μg/mL, and bioavailability of 0.7%. Compared with amorphous CsA powder, MP/CsA shortened Tmax by 1.1 to 2.3 h and increased the bioavailability by 43‐fold to 30.1%, while MA/CsA prolonged Tmax by 3.4 to 6.8 h with Cmax and bioavailability of 0.65 μg/mL and 11.7%, respectively. These pharmacokinetic behaviors would be explained by their diffusion and release properties modulated by polymeric surface modification. The mDDS approach is a promising strategy for the pharmacokinetic control of orally administered CsA. [ABSTRACT FROM AUTHOR] more...

Introduction: To evaluate the short-term efficacy of cyclosporine A (CsA)-0.1% cationic emulsion (CE) in patients with dry eye disease (DED) and mitigation of the inflammatory flares triggered by desiccating stress environments. Methods: A single-center non-randomized clinical trial was performed at a tertiary care setting. Twenty patients with DED treated with CsA 0.1% CE were exposed to a normal controlled environment (NCE) (23 °C, 50% relative humidity) and an adverse controlled environment (ACE) (23 °C, 10% relative humidity, 0.43 m/s localized airflow) during baseline and the 1- and 3-month visits. Patients underwent the following evaluations: conjunctival hyperemia and staining, corneal fluorescein staining (CFS) using the Oxford and Cornea and Contact Lens Research Unit (CCLRU) scale, meibomian gland (MG) secretion quality, Dry Eye Questionnaire-5, Symptom Assessment in Dry Eye (SANDE II), and Change in Dry Eye Symptoms Questionnaire. Multivariate models were adjusted for statistical analysis. Results: Nineteen women and one man (mean age, 58.9 ± 12.3 years) completed the study. All symptom questionnaires, CFS, conjunctival hyperemia and staining, and MG secretion quality improved (p ≤ 0.003) with 1 month of treatment; improvements were maintained after 3 months (p ≤ 0.02), except for SANDE II (p ≥ 0.07). The CFS worsening (total CCLRU) after baseline ACE exposure (from 8.6 to 10.1) was higher, although not significant (p = 0.64), compared with 1 month (from 5.4 to 5.8) and 3 months (from 5.0 to 5.9) after treatment. Conclusion: Topical CsA-0.1% CE improved DED signs and symptoms after 1 month of treatment under controlled environmental conditions. Future studies should confirm the benefit of CsA-0.1% CE in desiccating stress environments. Trial Registration: ClinicalTrials.gov identifier, NCT04492878. [ABSTRACT FROM AUTHOR] more...

Purpose To compare the effectiveness of using Cyclosporine A (CsA) eye drops with a concentration of 0.05% alone versus using eye drops containing both CsA of 0.05% concentration combined with autologous serum (AS) of 20% used together for treating vernal keratoconjunctivitis (VKC) which were moderate to severe. Methods A prospective comparative noninterventional case series was carried out at the Ophthalmology Department at Kafrelsheik University, involving 40 individual patients with moderate to severe VKC sorted into two groups; 20 patients using CsA 0.05% eye drops as group A and 20 patients in group B using eye drops of CsA 0.05% combined with AS eye drop of 20% concentration for treating VKC for 12 weeks, 4 times daily. Results According to the scores recorded for symptoms and signs, the difference detected statistically was of no significance among the two involved study groups as regards the baseline score (P=0.783, and 0.137, respectively). While the scores reported for the symptoms and signs were statistically lower significantly among group B other than observed among group A as determined at the 4th week (P=0.015, and 0.004, respectively), 8th week (P<0.001, for both), and 12th week (P=0.001, and 0.002, respectively). Regarding side effects of treatment, 12 patients had a burning sensation, eight of them in group A and four patients in group B, with not reach to significant level between the studied groups during the follow-up visits (P=0.382) Conclusions We concluded a higher efficacy of using combined eye drops of CsA 0.05% and AS 20% for treating VKC than CsA 0.05% eye drops alone. [ABSTRACT FROM AUTHOR] more...

Reversing the multiple drug resistance (MDR) arising from the overexpression of the efflux transporters often fails mainly due to the high toxicity or the poor water solubility of the inhibitors of these transporters. Here, we demonstrate the delivery of an inhibitor targeting three ABC transporters (ABCB1, ABCC1 and ABCG2) directly to the cell membrane using membrane-fusing vehicles (MFVs). Three different transfected MDCK II cell lines, along with parental cells, were used to investigate the inhibitory effect of cyclosporine A (CsA) in solution versus direct delivery to the cell membrane. CsA-loaded MFVs successfully reversed MDR for all three investigated efflux transporters at significantly lower concentrations compared with CsA in solution. Results showed a 15-fold decrease in the IC50 value for ABCB1, a 7-fold decrease for ABCC1 and an 11-fold decrease for ABCG2. We observed binding site specificity for ABCB1 and ABCG2 transporters. Lower concentrations of empty MFVs along with CsA contribute to the inhibition of Hoechst 33342 efflux. However, higher concentrations of CsA along with the high amount of MFVs activated transport via the H-binding site. This supports the conclusion that MFVs can be useful beyond their role as delivery systems and also help to elucidate differences between these transporters and their binding sites. [ABSTRACT FROM AUTHOR] more...

Objective(s): Selenium Nanoparticles can modulate the function of the immune system and improve immunity. We investigate the expression of toll-like receptor-7 (TLR-7), myeloid differentiation primary response 88 (MyD88), Nuclear factor kappa B (NF-κB), and TNF receptor associated factor 6 (TRAF6) genes in thymus of Wistar rats following treatment with cyclosporine A (CsA) and Nano-selenium (Nano-Se) supplementation. Materials and Methods: Twenty-four male Wistar rats (200-220 grams) were divided into 3 groups of control (n=8), CsA (n=8), and CsA+Nano-Se (n=8). Rats in CsA and CsA+Nano-Se group's received cyclosporine A and olive oil solution by subcutaneous injection for 10 days at a dose of 5 mg/kg/day. Nano-Se with a dose of 2.5 mg/kg of body weight was gavaged to the CsA+Nano-Se group once a day and 3 times a week. Real-time PCR were used for gene expression of TLR-7, MyD88, NF-kB, and TRAF6 at thymus. Results: The result of this study show that CsA significantly decreased expressions of TLR-7, MyD88, NF-kB, and TRAF6 at thymus compared to control group (P<0.05). However, expressions of TLR-7, MyD88, NF-kB, and TRAF6 at thymus in CsA+ Nano-Se group was significantly increased compared to CsA group (P<0.05). Conclusion: Nano-Se supplementation significantly regulated the expression of TLR-7, MyD88, NF-kB and TRAF6 genes in the thymus of rats treated with cyclosporine A. Therefore, Nano-Se supplementation can be recommended to boost immune function after using immunosuppressive drugs. However, more research is needed in the future. [ABSTRACT FROM AUTHOR] more...

Ferroptosis has been characterized as a form of iron-dependent regulated cell death accompanied by an accumulation of reactive oxygen species and lipid oxidation products along with typical morphological alterations in mitochondria. Ferroptosis is activated by diverse triggers and inhibited by ferrostatin-1 and liproxstatin-1, apart from iron chelators and several antioxidants, and the process is implicated in multiple pathological conditions. There are, however, certain ambiguities about ferroptosis, especially regarding the final executioner of cell death subsequent to the accumulation of ROS. This study uses a typical inducer of ferroptosis such as erastin on SH-SY5Y cells, and shows clearly that ferroptotic death of cells is accompanied by the loss of mitochondrial membrane potential and intracellular ATP content along with an accumulation of oxidative stress markers. All these are prevented by ferrostatin-1 and liproxstatin-1. Additionally, cyclosporine A prevents mitochondrial alterations and cell death induced by erastin implying the crucial role of mitochondrial permeability transition pore (mPTP) activation in ferroptotic death. Furthermore, an accumulation of α-synuclein occurs during erastin induced ferroptosis which can be inhibited by ferrostatin-1 and liproxstatin-1. When the knock-down of α-synuclein expression is performed by specific siRNA treatment of SH-SY5Y cells, the mitochondrial impairment and ferroptotic death of the cells induced by erastin are markedly prevented. Thus, α-synuclein through the involvement of mPTP appears to be the key executioner protein of ferroptosis induced by erastin, but it needs to be verified if it is a generalized mechanism of ferroptosis by using other inducers and cell lines. [ABSTRACT FROM AUTHOR] more...

Copyright of Die Ophthalmologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) more...

Background and Purpose: Atherosclerosis induced by cyclosporine A (CsA), an inhibitor of the calcineurin/nuclear factor of activated T cells (NFAT) pathway, is a major concern after organ transplantation. However, the atherosclerotic mechanisms of CsA remain obscure. We previously demonstrated that calcineurin/NFAT signalling inhibition contributes to atherogenesis via suppressing microRNA‐204 (miR‐204) transcription. We therefore hypothesised that miR‐204 is involved in the development of CsA‐induced atherosclerosis. Experimental Approach: ApoE−/− mice with macrophage‐miR‐204 overexpression were generated to determine the effects of miR‐204 on CsA‐induced atherosclerosis. Luciferase reporter assays and chromatin immunoprecipitation sequencing were performed to explore the targets mediating miR‐204 effects. Key Results: CsA alone did not significantly affect atherosclerotic lesions or serum lipid levels. However, it exacerbated high‐fat diet‐induced atherosclerosis and hyperlipidemia in C57BL/6J and ApoE−/− mice, respectively. miR‐204 levels decreased in circulating monocytes and plaque lesions during CsA‐induced atherosclerosis. The upregulation of miR‐204 in macrophages inhibited CsA‐induced atherosclerotic plaque formation but did not affect serum lipid levels. miR‐204 limited the CsA‐induced foam cell formation by reducing the expression of the scavenger receptors SR‐BII and CD36. SR‐BII was post‐transcriptionally regulated by mature miR‐204‐5p via 3′‐UTR targeting. Additionally, nuclear‐localised miR‐204‐3p prevented the CsA‐induced binding of Ago2 to the CD36 promoter, suppressing CD36 transcription. SR‐BII or CD36 expression restoration dampened the beneficial effects of miR‐204 on CsA‐induced atherosclerosis. Conclusion and Implications: Macrophage miR‐204 ameliorates CsA‐induced atherosclerosis, suggesting that miR‐204 may be a potential target for the prevention and treatment of CsA‐related atherosclerotic side effects. [ABSTRACT FROM AUTHOR] more...

Studies indicate that mitogen-activated protein kinases (MAPKs) are activated and overexpressed in psoriatic lesions. The aim of the study was to assess changes in the expression pattern of genes encoding MAPKs and microRNA (miRNA) molecules potentially regulating their expression in human adult low-calcium high-temperature (HaCaT) keratinocytes exposed to bacterial lipopolysaccharide A (LPS) and cyclosporine A (CsA). HaCaT cells were treated with 1 µg/mL LPS for 8 h, followed by treatment with 100 ng/mL cyclosporine A for 2, 8, or 24 h. Untreated cells served as controls. The molecular analysis consists of microarray, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay analyses. The statistical analysis of the obtained results was performed using Transcriptome Analysis Console and STATISTICA 13.5 PL with the statistical significance threshold of p < 0.05. Changes in the expression profile of six mRNAs: dual-specificity phosphatase 1 (DUSP1), dual-specificity phosphatase 4 (DUSP4), mitogen-activated protein kinase kinase 2 (MAP2K2), mitogen-activated protein kinase kinase 7 (MAP2K7), mitogen-activated protein kinase kinase kinase 2 (MAP3K2) and mitogen-activated protein kinase 9 (MAPK9) in cell culture exposed to LPS or LPS and the drug compared to the control. We observed that under the LPS and cyclosporine treatment, the expression o/ miR-34a, miR-1275, miR-3188, and miR-382 changed significantly (p < 0.05). We demonstrated a potential relationship between DUSP1 and miR-34a; DUSP4 and miR-34a, miR-382, and miR-3188; MAPK9 and miR-1275, MAP2K7 and mir-200-5p; MAP3K2 and mir-200-5p, which may be the subject of further research in the context of psoriasis. [ABSTRACT FROM AUTHOR] more...

Copyright of Journal of Pharmaceutical Practice & Service is the property of Journal of Pharmaceutical Practice Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) more...

Cyclosporine A (CsA) is a cyclic peptide immunosuppressant drug that is beneficial in the treatment of various ocular diseases. However, its ocular bioavailability in the posterior eye is limited due to its poor aqueous solubility. Conventional CsA formulations such as a solution or emulsion permeate poorly across the eye due to various static and dynamic barriers of the eye. Dissolvable microneedle (MN)-based patches can be used to overcome barrier properties and, thus, enhance the ocular bioavailability of CsA in the posterior eye. CsA-loaded dissolvable MN patches were fabricated using polyvinylpyrrolidone (PVP) and characterized for MN uniformity and sharpness using SEM. Further characterization for its failure force, penetration force, and depth of penetration were analyzed using a texture analyzer. Finally, the dissolution time, ex vivo permeation, and ocular distribution of cyclosporine were determined in isolated porcine eyes. PVP MNs were sharp, uniform with good mechanical properties, and dissolved within 5 min. Ocular distribution of CsA in a whole porcine eye perfusion model showed a significant increase of CsA levels in various posterior segment ocular tissues as compared to a topically applied ophthalmic emulsion (Restasis®) (P < 0.001). Dissolving MNs of CsA were prepared, and the MN arrays can deliver CsA to the back of the eye offering potential for treating various inflammatory diseases. [ABSTRACT FROM AUTHOR] more...

Summary: During the early stages of human pregnancy, successful implantation of embryonic trophoblast cells into the endometrium depends on good communication between trophoblast cells and the endometrium. Abnormal trophoblast cell function can cause embryo implantation failure. In this study, we added cyclosporine A (CsA) to the culture medium to observe the effect of CsA on embryonic trophoblast cells and the related mechanism. We observed that CsA promoted the migration and invasion of embryonic trophoblast cells. CsA promoted the expression of leukaemic inhibitory factor (LIF) and fibroblast growth factor (FGF). In addition, CsA promoted the secretion and volume increase in vesicles in the CsA-treated group compared with the control group. Therefore, CsA may promote the adhesion and invasion of trophoblast cells through LIF and FGF and promote the vesicle dynamic process, which is conducive to embryo implantation. [ABSTRACT FROM AUTHOR] more...

Background: The management of post-refractive surgery dry eye disease (DED) can be challenging in clinical practice, and patients usually show an incomplete response to traditional artificial tears, especially when it is complicated with ocular pain. Therefore, we aim to investigate the efficacy of combined topical 0.05% cyclosporine A and 0.1% sodium hyaluronate treatment in post-refractive surgery DED patients with ocular pain unresponsive to traditional artificial tears. Methods: We enrolled 30 patients with post-refractive surgery DED with ocular pain who were unresponsive to traditional artificial tears. Topical 0.05% cyclosporine A and 0.1% sodium hyaluronate were used for 3 months. They were evaluated at baseline and 1 and 3 months for dry eye and ocular pain symptoms and objective parameters, including Numerical Rating Scale (NRS), Neuropathic Pain Symptom Inventory modified for the Eye (NPSI-Eye), tear break-up time (TBUT), Schirmer I test (SIt), corneal fluorescein staining (CFS), corneal sensitivity, and corneal nerve morphology. In addition, tear levels of inflammatory cytokines and neuropeptides were measured using the Luminex assay. Results: After 3 months of treatment, patients showed a statistically significant improvement in the ocular surface disease index (OSDI), TBUT, SIt, CFS, and corneal sensitivity (all P < 0.01) using linear mixed models. As for ocular pain parameters, the NRS and NPSI-Eye scores were significantly reduced (both P < 0.05) and positively correlated with the OSDI and CFS scores. Additionally, tear IL-1β, IL-6, and TNF-α levels were improved better than pre-treatment (P = 0.01, 0.03, 0.02, respectively). Conclusion: In patients with post-refractive surgery DED with ocular pain, combined topical 0.05% cyclosporine A and 0.1% sodium hyaluronate treatment improved tear film stability, dry eye discomfort, and ocular pain, effectively controlling ocular inflammation. Trial registration: Registration number: NCT06043908. [ABSTRACT FROM AUTHOR] more...

Background: Acute graft-versus-host disease (aGvHD) is a major cause of death for patientsfollowing allogeneic hematopoietic stem cell transplantation (HSCT). Effective management of moderate to severe aGvHD remains challenging despite recent advances in HSCT, emphasizing the importance of prophylaxis and risk factor identification. Methods: In this study, we analyzed data from 1479 adults who underwent HSCT between 2005 and 2017 to investigate the effects of aGvHD prophylaxis and time-dependent risk factors on the development of grades II–IV aGvHD within 100days post-HSCT. Results: Using a dynamic longitudinal time-to-event model, we observed a nonmonotonic baseline hazard overtime with a low hazard during the first few days and a maximum hazard at day 17, described by Bateman function with a mean transit time of approximately 11days. Multivariable analysis revealed significant time-dependent effects of white blood cell counts and cyclosporine A exposure as well as static effects of female donors for male recipients, patients with matched related donors, conditioning regimen consisting of fludarabine plus total body irradiation, and patient age in recipients of grafts from related donors on the risk to develop grades II–IV aGvHD. Additionally, we found that higher cumulative hazard on day 7 after allo-HSCT are associated with an increased incidence of grades II–IV aGvHD within 100days indicating that an individual assessment of the cumulative hazard on day 7 could potentially serve as valuable predictor for ater grades II–IV aGvHD development. Using the final model, stochastic simulations were performed to explore covariate effects on the cumulative incidence over time and to estimate risk ratios. Conclusion: Overall, the presented model showed good descriptive and predictive performance and provides valuable insights into the interplay of multiple static and time-dependent risk factors for the prediction of aGvHD. [ABSTRACT FROM AUTHOR] more...

Background: Inflammatory bowel diseases (IBDs) have several treatment modalities including immunoregulators, like cyclosporine A, an immunosuppressant that interacts with cytoplasmic cyclophilin A, and probiotics. Aims: This study explored and compared the possible role of syndecan-1 in the IBD pathogenic process as well as the effectiveness of cyclophilin A, cyclosporine A, and their combination in the management of IBDs in the presence of probiotics. Methodology: IBD was induced in a total of 112 mice equally divided between syndecan-1 knock-out (KO) and Balb/c wild-type mice, using 2% dextran sulfate sodium (DSS) followed by intraperitoneal treatment with cyclosporine A, cyclophilin A, or a combination of both. In addition, a daily dose of probiotics was given in their drinking water. The animals were monitored for clinical signs and symptoms and checked for gross pathologies in the abdomen after 3 weeks. Descending and sigmoid colon biopsies were collected and fixed for routine microscopy or frozen for protein extraction and molecular testing for IL-6, CD3, CD147, and beta 1 integrins as well as pAkt expression. Results: The data showed that the induction of IBD in the syndecan-1 KO mice was more severe at the clinical, histological, and molecular levels than in the wild type. The combined CypA-CyA treatment showed no added inhibitory effect compared to single-drug treatment in both strains. Probiotics added to the combination was more effective in the wild type and, when used alone, its inhibition of IL-6 was the highest. As for the CD147 marker, there were more suppressions across the various groups in the KO mice except for the probiotics-alone group. Concerning CD3, it was significantly increased by the CypA-CyA complex, which led to more inflammation in the KO mice. Probiotics had little effect with the combination. In relation to beta 1 integrins, the CypA-CyA combination made no significant difference from CyA alone, and adding probiotics to the combination resulted in higher beta 1 integrin expression in the KO mice. As for pAkt, it was very well expressed and upregulated in both strains treated with DSS, but the effect was much larger in the KO mice. In brief, the CypA-CyA complex showed a decrease in the expression of pAkt, but there was no added effect of both drugs. Probiotics along with the complex had a similar reduction effects in both strains, with a greater effect in the wild-type mice, while probiotics alone led to a similar reduction in pAkt expressions in both strains. Conclusions: The differential effects of CyA, CypA, probiotics, and their combinations on the various inflammatory markers, as well as the histological alterations and clinical signs and symptoms, speak in favor of a clear role of syndecan-1 in reducing inflammation. However, probiotics need to be considered after more explorations into the mechanisms involved in the presence of CypA and CyA especially since pAkt is less active in their presence. [ABSTRACT FROM AUTHOR] more...

Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are key determinants of drug–drug interactions (DDIs). Various drugs including the calcineurin inhibitor (CNI) cyclosporine A (CsA) exert preincubation-induced trans-inhibitory effects upon OATP1B1 and/or OATP1B3 (abbreviated as OATP1B1/3) by unknown mechanism(s). OATP1B1/3 are phosphoproteins; calcineurin, which dephosphorylates and regulates numerous phosphoproteins, has not previously been investigated in the context of preincubation-induced trans-inhibition of OATP1B1/3. Herein, we compare the trans-inhibitory effects exerted on OATP1B1 and OATP1B3 by CsA, the non-analogous CNI tacrolimus, and the non-CNI CsA analogue SCY-635 in transporter-overexpressing human embryonic kidney (HEK) 293 stable cell lines. Preincubation (10–60 min) with tacrolimus (1–10 µM) rapidly and significantly reduces OATP1B1- and OATP1B3-mediated transport up to 0.18 ± 0.03- and 0.20 ± 0.02-fold compared to the control, respectively. Both CsA and SCY-635 can trans-inhibit OATP1B1, with the inhibitory effects progressively increasing over a 60 min preincubation time. At each equivalent preincubation time, CsA has greater trans-inhibitory effects toward OATP1B1 than SCY-635. Preincubation with SCY-635 for 60 min yielded IC50 of 2.2 ± 1.4 µM against OATP1B1, which is ~18 fold greater than that of CsA (0.12 ± 0.04 µM). Furthermore, a proteomics-based screening for protein interactors was used to examine possible proteins and processes contributing to OATP1B1/3 regulation and preincubation-induced inhibition by CNIs and other drugs. A total of 861 and 357 proteins were identified as specifically associated with OATP1B1 and OATP1B3, respectively, including various protein kinases, ubiquitin-related enzymes, the tacrolimus (FK506)-binding proteins FKBP5 and FKBP8, and several known regulatory targets of calcineurin. The current study reports several novel findings that expand our understanding of impaired OATP1B1/3 function; these include preincubation-induced trans-inhibition of OATP1B1/3 by the CNI tacrolimus, greater preincubation-induced inhibition by CsA compared to its non-CNI analogue SCY-635, and association of OATP1B1/3 with various proteins relevant to established and candidate OATP1B1/3 regulatory processes. [ABSTRACT FROM AUTHOR] more...

Background: Mitochondrial permeability transition pore (mPTP) opening plays a crucial role in cell death during ischemia-reperfusion injury (IRI). Cyclosporine A (CsA) inhibits mPTP opening. This study aimed to investigate the effects of CsA treatment during cardioplegia on the mitochondrial function and cardiac IRI. Methods: Landrace pigs (52.9 ± 3.7 kg) were subjected to midline sternotomy, cardiopulmonary bypass at 34°C and 90 minutes of cardiac arrest. They received either a single shot of standard 4°C cold histidine-tryptophan-α-ketoglutarate (HTK)-Bretschneider solution (n = 11) or HTK-Bretschneider plus 1.2 mg/L CsA (histidine-tryptophan-α-ketoglutarate plus cyclosporine A (HTK/CsA); n = 11). During reperfusion global left-ventricular function was assessed and myocardial biopsies were harvested at baseline, during ischemia and 45 minutes following reperfusion. High-resolution respirometry and hydrogen peroxide production were measured. Immunohistochemical stainings for apoptosis-inducing factor and hypoxia-inducible factor-1α as well as a flow cytometry-based JC-1 mitochondrial membrane potential assay were performed. Results: Hemodynamic parameters were comparable between both groups. The cytochrome C release (HTK: 930.3 ± 804.4 pg/mg, HTK/CsA: 699.7 ± 394.0 pg/mg, p = 0.457) as well as PGC1α content (HTK: 66.7%, HTK/CsA: 33.3%, p = 0.284) was lower in the HTK/CsA group. Respiratory measurements revealed that the oxygen flux under basal respiration was higher in the HTK/CsA group (8.2 ± 1.3 pmol·O2·s−1·mg−1·ww) than in the HTK group (3.8 ± 1.4 pmol·O2·s−1·mg−1·ww, p = 0.045). There were no significant differences regarding histological surrogates of apoptosis and necrosis. Conclusions: Supplementing cardioplegic solutions with CsA enhances the basal mitochondrial respiration thereby exerting a cardioprotective effect and diminishing IRI-induced damage. CsA seems to preserve mitochondrial function via non-ROS related pathways. [ABSTRACT FROM AUTHOR] more...

Background: Pharmaceutical companies do not sell formulations for all diseases; thus, healthcare workers have to treat some diseases by concocting in-hospital preparations. An example is the high-concentration 2% cyclosporine A (CyA) ophthalmic solution. Utilizing a filter in sterility operations is a general practice for concocting in-hospital preparations, as is the case for preparing a 2% CyA ophthalmic solution. However, whether filtering is appropriate concerning the active ingredient content and bacterial contamination according to the post-preparing quality control of a 2% CyA ophthalmic solution is yet to be verified. Methods: We conducted particle size, preparation concentration, and bacterial contamination studies to clarify aforementioned questions. First, we measured the particle size of CyA through a laser diffraction particle size distribution. Next, we measured the concentration after preparation with or without a 0.45-µm filter operation using an electrochemiluminescence immunoassay. Finally, bacterial contamination tests were conducted using an automated blood culture system to prepare a 2% CyA ophthalmic solution without a 0.45 μm filtering. Regarding the pore size of the filter in this study, it was set to 0.45 μm with reference to the book (the 6th edition) with recipes for the preparation of in-hospital preparations edited by the Japanese Society of Hospital Pharmacists. Results: CyA had various particle sizes; approximately 30% of the total particles exceeded 0.45 μm. The mean ± standard deviation of filtered and non-filtered CyA concentrations in ophthalmic solutions were 346.51 ± 170.76 and 499.74 ± 76.95ng/mL, respectively (p = 0.011). Regarding bacterial contamination tests, aerobes and anaerobes microorganisms were not detected in 14 days of culture. Conclusions: Due to the results of this study, the concentration of CyA may be reduced by using a 0.45-µm filter during the preparation of CyA ophthalmic solutions, and furthermore that the use of a 0.45-µm filter may not contribute to sterility when preparing CyA ophthalmic solutions. [ABSTRACT FROM AUTHOR] more...

Glycyrol (GC) is one natural active product. Imiquimod-induced psoriasis-like Balb/c mouse models were established. The model mice were intraperitoneally injected with cyclosporine A (CsA) and GC for 8 days followed by a series of biological detections. GC had little toxicity according to the levels of peripheral blood cells, hemoglobin, blood urea nitrogen (BUN), and serum creatinine (CRE), while CsA significantly increased the levels of BUN and CRE. GC decreased the splenic index and reduced the expressions of IL-6, IL-23, and CXCL-3 in the model mice and IL-6, CXCL-1, and CXCL-2 in the inflammatory HaCaT cells. The half inhibition concentration (IC50) of GC on HaCaT cells was 29.72 μmol/L, resulting in improved apoptosis, enhanced expressions of p21, BAX, and BIK, and reduced expressions of BCL-2. GC is an immunosuppressive agent against psoriasis-like symptoms by anti-inflammatory effects, which provides a strategy for the discovery of anti-psoriatic natural products. [ABSTRACT FROM AUTHOR] more...

Objective: This study was to assess the safety and effectiveness of immunosuppressive agents, specifically Voclosporin, when used in conjunction with mycophenolate mofetil (MMF) induction therapy for the management of lupus nephritis (LN). Methods: A systematic review and network meta-analysis (NMA) was conducted on randomized controlled trials investigating the efficacy of immunosuppressant-induced therapy for LN. The random effects model was used in the analysis. I² was used to evaluate the heterogeneity of the model. Odds ratios (OR) and 95% credible intervals (CrI) were computed to assess and compare the relative effectiveness and safety of various treatment protocols. Results: The study included a total of 16 randomized controlled trials (RCTs) involving 2444 patients with LN. The analysis results indicated that there was no significant difference in terms of partial remission (PR) between the drugs. However, when considering complete remission (CR), the combination of Voclosporin with MMF showed the highest remission rate, followed by Tacrolimus (TAC). Unfortunately, Voclosporin in combination with MMF had the highest risk of infection and serious infection, indicating a lower safety profile. Conclusions: Voclosporin in combination with MMF demonstrated the highest efficacy as an induction therapy for LN. However, it should be noted that the risk of infection and serious infection was found to be high with this regimen. On the other hand, TAC not only showed efficacy but also had a lower risk of infection and serious infection, making it a favorable option in terms of safety. This study did' not include results on other adverse events. [ABSTRACT FROM AUTHOR] more...

In order to facilitate therapeutic drug monitoring of tacrolimus and cyclosporine A in clinical practice, a simple, rapid, robust, sensitive and specific LC–MS/MS assay was developed and validated for the simultaneous determination of tacrolimus and cyclosporine A in human whole blood. Erythrocytes were destroyed using internal standard solution with 10% (w/v) zinc sulfate in water. The analytes were extracted from 100 μl of whole blood by protein precipitation with acetonitrile. Chromatographic separation was conducted on a Kinetex PFP column (60°C) by a gradient elution with a flow rate of 0.450 ml/min in 2.5 min. Quantitative analysis was performed using electrospray ionization and multiple reaction monitoring in positive ionization mode. The method was fully validated as per current guidelines on bioanalytical methodologies of the US Food and Drug Administration and European Medicines Agency. The method developed was applied successfully in analyzing clinical samples from patients administered tacrolimus or cyclosporine A. The sample treatment procedure was rationalized and improved to fulfill the complete target extraction. The chromatography conditions were optimized to achieve rapid and accurate quantification of both analytes. This method may be beneficial as a constructive input for the therapeutic drug monitoring of tacrolimus and cyclosporine A in obtaining individualized therapy. [ABSTRACT FROM AUTHOR] more...

Background: Dry eye disease (DED) is a disorder characterized by loss of tear film homeostasis that causes ocular surface inflammation and damage. The incidence of DED increases with age. Cyclosporine ophthalmic solution 0.09% (CEQUA®; OTX-101), cyclosporine ophthalmic emulsion 0.05% (Restasis®; CsA), and lifitegrast ophthalmic solution 5% (Xiidra®; LFT) are anti-inflammatory agents indicated for DED. This analysis compared treatment patterns in patients with DED receiving OTX-101, CsA, or LFT. Methods: This real-world, retrospective, longitudinal cohort study utilized Symphony Health Integrated Dataverse claims from July 2019 to June 2021. The dataset included all patients with OTX-101 claims and patients with CsA or LFT claims randomly selected 2:1 to OTX-101. Patients were sorted into 3 cohorts based on index treatment. Index date was that of first treatment claim, and follow-up period was from index date to end of clinical activity or data availability. Time to treatment discontinuation (TTD), probability of discontinuation, and treatment persistence were assessed for OTX-101 vs. CsA, then OTX-101 vs. LFT. Subgroup analysis was performed based on age and prior DED treatment. Kaplan-Meier analysis and log-rank test were used to examine TTD. A logistic model evaluated association between index treatment and discontinuation. Unadjusted and adjusted odds ratios, 95% confidence intervals, and P-values were reported, with statistically significant associations based on P-values < 0.05. Results: Overall, 7102 patients (OTX-101 n = 1846; CsA n = 2248; LFT n = 3008) were eligible. Median TTD was 354 days for patients receiving OTX-101 vs. 241 days for CsA and 269 days for LFT. Log-rank test indicated TTD was significantly longer for patients on OTX-101 vs. CsA (P = 0.033). Patients on CsA were 35% more likely to discontinue treatment than patients on OTX-101; OTX-101 and LFT groups had similar discontinuation rates. After 360 days, 49.8% of patients receiving OTX-101 remained on treatment vs. 39.4% of patients on CsA (P = 0.036) and 44.0% of patients on LFT (P = 0.854). Conclusions: Patients receiving OTX-101 remained on treatment significantly longer and were significantly less likely to discontinue treatment than patients on CsA. Older patients remained on OTX-101 significantly longer than CsA. These findings highlight treatment pattern differences in patients with DED receiving these anti-inflammatory agents. [ABSTRACT FROM AUTHOR] more...

Ulcerative colitis (UC) is an idiopathic, chronic, relapsing disease. In most cases, only the distal colon is affected, and the colonic stasis or fast colonic transit through the inflamed colon usually results in reduced exposure of the distal inflamed colon. Although the immunosuppressant cyclosporine A (CsA) has been used in patients with severe colitis who do not respond to corticosteroids, the clinical application of CsA remains limited due to the systemic toxicities and insufficient accumulation at the site of action for the intravenous and oral routes. In this study, we loaded CsA into the amphipathic poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) micelles and then embedded them in hydrogels consisting of chitosan, poloxamer 188, and poloxamer 407 to construct a thermosensitive and mucoadhesive hydrogel drug delivery system (PLCP). The PLCP presented a high drug-loading capacity and showed a stable and rapid gelation rate after rectal administration into the body. Compared to CsA-loaded micelles and Sandimmun (Neoral®), the developed thermosensitive gel exhibited prolonged retention on the inflamed colon, as seen from in vitro adhesion and in vivo distribution experiments. It also fast mitigated colitis symptoms in TNBS-treated mice by regulating the expression levels of proinflammatory cytokines (TNF-α, IL-1β, COX-2, and iNOS2), anti-inflammatory cytokines (IL-10, Nrf2, NQO1, and HO-1), and other relevant biochemical factors. Our results suggested that CsA-loaded micelle thermal hydrogel system could be a promising strategy by enhancing the retention in the diseased colon and promoting the relief and recovery of UC. [ABSTRACT FROM AUTHOR] more...

Pachymaran (PCP), the major medicinal constituent of Poria cocos, has a regulatory effect on immunosuppressive lung injury, but its mechanism of action with respect to gut microorganisms and their metabolites is not clear. The aim of this study was to investigate the protective effect of PCP against immunosuppressive lung injury caused by cyclosporine A (CsA), and to reveal its possible mechanism of action via the comprehensive analysis of 16S rRNA and LC-MS. We demonstrated that PCP was effective at alleviating CsA-induced immunosuppressive lung injury by restoring the organ indices and lung tissue morphology and structure. PCP significantly altered the composition of the gut and lung microbiota in mice with CsA-induced immunosuppressive lung injury by increasing the number of beneficial bacteria from the Eubacterium nodatum group, Eubacterium ventriosum group, Akkermansia, and Ruminococcus, and reducing the pathogenic Rikenellaceae RC9 gut group to fulfill its immunomodulatory role. In lung tissue microecology, PCP intervention significantly reduced the abundance of Chryseobacterium, Lawsonella, Paracoccus, and Sediminibacterium and increased the abundance of Alloprevotella. The LC-MS results showed that PCP alleviated the CsA-induced immunosuppression of lung tissue injury. The model serum metabolite Americine decreased the expression of PC(O-18:1(4Z)/0:0). Our results suggest that PCP may be involved in regulating the composition, function, and metabolism of the gut and lung microbiota to reverse CsA-induced immunosuppressive lung injury. [ABSTRACT FROM AUTHOR] more...