Protective effects of methylprednisolone-cyclophosphamide treatment on bleomycin-induced pulmonary fibrosis.

BACKGROUND: Methylprednisolone (MP) and cyclophosphamide (CTX) combination treatment has shown great benefits in improving pulmonary fibrosis (PF) and high safety. Currently, the mechanism underlying the effects of MP-CTX on improving PF remains unclear. This study determined the effects of MP-CTX combination treatment on the modulation of inflammation, oxidative stress, and T-cell immunity in PF. METHODS: PF rat models were induced by bleomycin stimulation. MP (3 mg/kg) and MP-CTX (MP: 3 mg/kg; CTX: 8 mg/kg) combination were administered in the PF + MP and PF + MP + CTX groups, respectively. Transmission electron microscopy, hematoxylin and eosin staining, Ashcroft score, and Masson trichrome staining were performed to measure lung morphology in PF. Enzyme-linked immunosorbent assay and quantitative polymerase chain reaction assay were performed to quantify inflammatory factors. Malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-PX) levels were determined using commercial kits. α-Smooth muscle actin (SMA) and collagen I levels were determined using western blotting and immunohistochemistry. The T-cell count was evaluated using flow cytometry. RESULTS: MP-CTX reduced lung injury, collagen deposition, and α-SMA and collagen I levels in a bleomycin-induced PF rat model. Additionally, MP-CTX decreased the levels of MDA and inflammatory factors (tumor necrosis factor-α, interleukin-1ß, and interleukin-6) but increased the activities of SOD and GSH-PX. Furthermore, MP-CTX changed T-cell types in lung tissues, such as increasing CD4+CD25+Foxp3+ cell count. CONCLUSIONS: MP-CTX combination treatment improved the degree of PF by reducing inflammation and oxidative stress and improving T-cell immunity. These findings provide novel insights into the mechanisms underlying the effects of MP-CTX on PF.

Cyanidin-3-O-glucoside and protocatechuic acid alleviate heat stress-induced testicular damage.

Testicular hyperthermia induced by unhealthy living habits and pathological or occupational factors can cause spermatogenic dysfunction with an outcome of sub-fertility or even infertility. Cyanidin-3-O-glucoside (C3G) is the most typical anthocyanin in foods that has been recognized as an antioxidant with promising protection for male reproduction. However, its specific effect against testicular hyperthermia and the mechanisms involving its primary gastrointestinal metabolite protocatechuic acid (PCA) are still unexplored. In the present study, testicular hyperthermia in mice was established by employing a single hot water bath at 43 °C for 30 min. C3G and PCA were intragastrically given to investigate their prevention ability against heat stress-induced testicular damage. It was found that C3G and PCA restored the external diameter and thickness, and alleviated atrophy and vacuolation of seminiferous tubules. Simultaneously, C3G and PCA enhanced testicular heat stress tolerance through reducing superfluous eIF2α phosphorylation and stress granule formation. C3G and PCA effectively improved the testicular antioxidant system and regulated the IRE1α-XBP1 pathway, contributing to mitigatory spermatogenesis dysfunction and testicular damage. This finding revealed that anthocyanins were the novel compounds for alleviating testicular damage, and provided a reliable theoretical basis for improving male fertility disturbed by heat stress.

The consequence and mechanism of dietary flavonoids on androgen profiles and disorders amelioration.

Androgen is a kind of steroid hormone that plays a vital role in reproductive system and homeostasis of the body. Disrupted androgen balance serves as the causal contributor to a series of physiological disorders and even diseases. Flavonoids, as an extremely frequent family of natural polyphenols, exist widely in plants and foods and have received great attention when considering their inevitable consumption and estrogen-like effects. Mounting evidence illustrates that flavonoids have a propensity to interfere with androgen synthesis and metabolism, and also have a designated improvement effect on androgen disorders. Therefore, flavonoids were divided into six subclasses based on the structural feature in this paper, and the literature about their effects on androgens published in the past ten years was summarized. It could be concluded that flavonoids have the potential to regulate androgen levels and biological effects, mainly by interfering with the hypothalamic-pituitary-gonadal axis, androgen synthesis and metabolism, androgen binding with its receptors and membrane receptors, and antioxidant effects. The faced challenges about androgen regulation by flavonoids masterly include target mechanism exploration, individual heterogeneity, food matrixes interaction, and lack of clinical study. This review also provides a scientific basis for nutritional intervention using flavonoids to improve androgen disorder symptoms.

Appropriate empirical antifungal therapy is associated with a reduced mortality rate in intensive care unit patients with invasive fungal infection: A real-world retrospective study based on the MIMIC-IV database.

Objective: The study aimed to determine the prevalence and pathogens of invasive fungal infection (IFI) among intensive care unit (ICU) patients. The next goal was to investigate the association between empirical antifungal treatment and mortality in ICU patients. Methods: Using microbiological events, we identified all ICU patients with IFI and then retrieved electronic clinical data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. The data were statistically analyzed using t-tests, chi-square tests, log-rank tests, and Cox regression. Results: The most commonly reported fungi were Candida (72.64%) and Aspergillus (19.08%). The most frequently prescribed antifungal medication was fluconazole (37.57%), followed by micafungin (26.47%). In the survival study of ICU patients and patients with sepsis, survivors were more likely to receive empirical antifungal treatment. In contrast, non-empirical antifungal therapy was significantly associated with poor survival in patients with positive blood cultures. We found that the current predictive score makes an accurate prediction of patients with fungal infections challenging. Conclusions: Our study demonstrated that empirical antifungal treatment is associated with decreased mortality in ICU patients. To avoid treatment delays, novel diagnostic techniques should be implemented in the clinic. Until such tests are available, appropriate empirical antifungal therapy could be administered based on a model that predicts the optimal time to initiate antifungal therapy. Additional studies should be conducted to establish more accurate predictive models in the future.

Circ-PRKCI Alleviates Lipopolysaccharide-induced Human Kidney 2 Cell Injury by Regulating miR-106b-5p/GAB1 Axis.

ABSTRACT: Circular RNAs act as vital regulators in diverse diseases. However, the investigation of circular RNAs in sepsis-engendered acute kidney injury remains dismal. We aimed to explore the effects of circular RNA protein kinase C iota (circ-PRKCI) in lipopolysaccharide (LPS)-mediated HK2 cell injury. Sepsis in vitro model was established by LPS treatment. Quantitative real-time polymerase chain reaction assay was conducted for determining the levels of circ-PRKCI, microRNA-106b-5p (miR-106b-5p), and growth factor receptor binding 2-associated binding protein 1 (GAB1). Cell viability and apoptosis were evaluated using Cell Counting Kit-8 assay and flow cytometry analysis, respectively. The concentrations of interleukin-6, interleukin-1ß, and tumor necrosis factor-α were measured with enzyme-linked immunosorbent assay kits. The levels of oxidative stress markers were determined using relevant commercial kits. Western blot assay was conducted for B-cell lymphoma-2 (Bcl-2), BCL2-Associated X (Bax), and GAB1 protein levels. Dual-luciferase reporter assay and RNA immunoprecipitation assay were used to verify the association between miR-106b-5p and circ-PRKCI or GAB1. We found the Circ-PRKCI level was decreased in sepsis patients and LPS-induced human kidney 2 (HK-2) cells. LPS exposure inhibited cell viability and facilitated apoptosis, inflammation, and oxidative stress in HK-2 cells. Circ-PRKCI overexpression abrogated the effects of LPS on cell apoptosis, inflammation, and oxidative stress in HK-2 cells. Furthermore, circ-PRKCI was identified as the sponge for miR-106b-5p to positively regulate GAB1 expression. Overexpression of circ-PRKCI relieved LPS-mediated HK-2 cell damage by sponging miR-106b-5p. MiR-106b-5p inhibition ameliorated the injury of HK-2 cells mediated by LPS, whereas GAB1 knockdown reversed the effect. Collectively, Circ-PRKCI overexpression attenuated LPS-induced HK-2 cell injury by regulating miR-106b-5p/GAB1 axis.