Rapamycin Attenuates H2O2-Induced Oxidative Stress-Related Senescence in Human Skin Fibroblasts.

BACKGROUND: Oxidative stress plays an important role in the skin aging process. Rapamycin has been shown to have anti-aging effects, but its role in oxidative senescence of skin cells remains unclear. The aim of this study was to explore the effect of rapamycin on oxidative stress-induced skin cell senescence and to illustrate the mechanism. METHODS: Primary human skin fibroblasts (HSFs) were extracted and a model of H2O2-induced oxidative senescence was constructed, and the effects of rapamycin on their value-added and migratory capacities were detected by CCK-8 and scratch assays. SA-ß-gal was utilized to detect senescence, oxidatively closely related factors were also assessed. Gene and protein expressions of senescence, oxidative, and autophagy were detected by western blotting and quantitative-PCR. The data were analyzed by one-way analysis of variance. RESULTS: Rapamycin (0.1 nmol/L for 48 h) promoted the proliferative and migration of H2O2-treated HSFs (p < 0.05), decreased senescent phenotypes SA-ß-gal staining and the expression of P53, and MMP-1 proteins, and increased the expression level of COL1A-1 (p < 0.001). Rapamycin also enhanced the activities of SOD and HO-1, and effectively removed intracellular ROS, MDA levels (p < 0.05), in addition, autophagy-related proteins and genes were significantly elevated after rapamycin pretreatment (p < 0.001). Rapamycin upregulated the autophagy pathway to exert its protective effects. CONCLUSION: Our findings indicate that rapamycin shields HSFs from H2O2-induced oxidative damage, the mechanism is related to the reduction of intracellular peroxidation and upregulation of autophagy pathway. Therefore, rapamycin has the potential to be useful in the investigation and prevention of signs of aging and oxidative stress.

Serological and molecular survey of Toxoplasma gondii infection and associated risk factors in urban cats in Kunming, Southwest China.

Toxoplasma gondii (T. gondii) is a worldwide zoonotic parasite that can infect almost warm-blood animals, including humans, which seriously affect the health of host. Cats are known to be the only definitive host of T. gondii and continuously excrete highly infectious oocysts. This parasite carried by the companion animals leads to a great public health risk. However, there is little information on epidemiology of T. gondii in urban cats in Kunming, Southwest China. In the present study, a total of 231 serum and fecal samples were collected in Kunming aera, and then seroprevalence of T. gondii IgG antibodies in serum and molecular investigation in feces were analyzed to elucidate T. gondii infection in urban cats. The results revealed that 168 of 231 cats (72.7%) were positive for T. gondii antibodies, and 1 of 74 cat feces (1.4%) also showed a positive PCR for T. gondii DNA. The positive fecal sample was sequenced and then phylogenetically analyzed, and the isolate of T. gondii in the present study was closely related to T. gondii strain CN. In addition, the food, water and age of cats were identified as the risk factor for seropositivity. Overall, our findings indicate the widespread occurrence of T. gondii infection in urban cats in Kunming, Southwest China and identify food, water and age are the risk factors associated with T. gondii infection, which can provide effective information for developing strategies to prevent and control this zoonosis.

Hyalinizing clear cell carcinoma of the sublingual gland: A case report and literature review.

RATIONALE: Hyalinizing clear cell carcinoma (HCCC) of the salivary glands is a rare low-grade malignant tumor. This type of tumor is particularly uncommon in the sublingual glands. PATIENT CONCERNS: A 57-year-old female with a mass on the left side of the floor of the mouth that had been present for 2 months. The computed tomography scan of the neck revealed a nodular abnormal density shadow in the left sublingual area, measuring approximately 2.6 cm × 1.9 cm. DIAGNOSES: Primary HCCC of the sublingual gland. INTERVENTIONS: The patient underwent surgical treatment and reconstruction using a left anterolateral femoral free flap, which showed immunohistochemical positivity for CK 5/6, CK 7, CK (AE1/AE3), and Ki-67 (<5%), but negative for SMA and S-100. OUTCOMES: No recurrence was observed during the 12-month postoperative follow-up period. LESSONS: The absence of characteristic clinical manifestations makes HCCC highly susceptible to misdiagnoses. This case presents a rare instance of HCCC in the sublingual gland, providing a reference for the clinical diagnosis and treatment of the disease.

Association of urinary bisphenol A with hyperlipidemia and all-cause mortality: NHANES 2003-2016.

BACKGROUND: The connection between urinary bisphenol A (BPA) and hyperlipidemia is still unclear, and few studies have evaluated whether urinary BPA affects mortality among individuals with hyperlipidemia. Therefore, we aimed to investigate the link between urinary BPA and hyperlipidemia and assess the impact of urinary BPA on mortality risk in subjects with hyperlipidemia. METHODS: We analyzed data of the National Health and Nutrition Examination Survey from 2003 to 2016. Multivariable logistic analysis was performed to examine the relationship between urinary BPA and hyperlipidemia. Cox regression analysis was carried out to investigate the relationship between urinary BPA and all-cause mortality in subjects with hyperlipidemia. RESULTS: This study included 8,983 participants, of whom 6,317 (70.3%) were diagnosed with hyperlipidemia. The results showed that urinary BPA was higher in participants with hyperlipidemia group than those without hyperlipidemia (3.87 ± 0.32 vs. 2.98 ± 0.14, P = 0.01). Urinary BPA levels were analyzed in tertiles. Compared with tertile 1 of BPA (reference), the odds ratio (95% confidence interval) of hyperlipidemia related to tertile 3 of BPA was 1.28 (1.11-1.48). The hazard ratio for all-cause death associated with the highest versus lowest tertile of urinary BPA was 1.20 (95% confidence interval: 1.01-1.44; P = 0.04) among participants with hyperlipidemia. CONCLUSIONS: The study indicated a positive relationship between urinary BPA and the risk of hyperlipidemia. Urinary BPA was associated with a significantly higher risk of all-cause mortality in adults with hyperlipidemia.

Higher Dietary Inflammatory Index and Systemic Immune-Inflammation Index Score are Associated With Higher Risk of Chronic Kidney Disease: Analysis of the National Health and Nutrition Examination Survey From 1999 to 2018.

OBJECTIVE: Chronic kidney disease (CKD) is characterized by a gradual decline in kidney function over time. The role of dietary inflammatory index (DII) and systemic immune-inflammation index (SII) in individuals with CKD remains uncertain. We aimed to explore the potential correlation between DII and SII with the prevalence of CKD in adult Americans. METHODS: This cross-sectional study used data from the National Health and Nutrition Examination Study between 1999 and 2018. The DII was calculated based on the 24-hour dietary history interview, while the SII was calculated as the product of platelet count multiplied by neutrophil count and divided by lymphocyte count. CKD was diagnosed based on impaired glomerular filtration rate (<60 mL/min per 1.73 m2) or urinary albumin-creatinine ratio ≥30 mg/g. Multivariable logistic regression analyses and subgroup analyses were performed to examine the association between DII/SII and CKD. RESULTS: In total, this study included 40,388 participants, of whom 7443 (18.4%) had CKD. The prevalence of CKD changed from 14.84% (95% confidence interval (CI): 13.20-16.48%) in 1999-2000 to 12.76% (95% CI: 11.10-14.43%) in 2017-2018. According to adjusted multivariate logistic regression models, individuals with higher DII scores had a higher likelihood of having CKD (odds ratio = 1.24; 95% CI: 1.12-1.37). Similarly, higher SII scores were associated with a higher risk of CKD (odds ratio = 1.37; 95% CI: 1.25-1.50). Subgroup analyses further demonstrated relatively stronger associations between DII/SII and CKD among individuals with other factors such as sex, age, body mass index, smoking status, drinking status, hypertension, and diabetes. CONCLUSIONS: The DII and SII scores were significantly positively associated with higher risks of CKD. Anti-inflammatory diet might have the potential to prevent CKD. The SII may serve as a cost-effective and straightforward approach for detecting CKD. Further prospective longitudinal studies are needed to verify the causality.

Evaluation of fetal cerebral microvascular status and its relationship with fetal growth and development using microvascular imaging technique.

The study conducted retrospective analysis design, aiming to explore the use of Microvascular Imaging Technique (MVFI) to assess fetal cerebral microcirculation and analyze the relationship between Microvascular Index (MVI) and fetal growth and development. 100 pregnant women who met the criteria for fetal growth restriction (FGR) provided in the Expert Consensus on Fetal Growth Restriction (2019 Edition) and underwent routine prenatal examinations at the Obstetrics and Gynecology Department of Peking University Third Hospital from January 2021 to June 2023 were selected as the study subjects. A normal fetus with a fetal weight less than 10 % can be classified as FGR, Pregnant women with fetal umbilical artery (UA) systolic and diastolic (S/D) values ≥3 were included in the observation group, while 200 pregnant women with normal fetuses were selected as the control group during the same period. The fetuses' change in both groups were measured using color Doppler ultrasound, including bi-parietal diameter (BPD), head circumference (HC), abdominal circumference (AC), and femur length (FL). The cerebral microcirculation of the fetuses in both groups was evaluated using MVFI, and the MVI values were compared. The clinical characteristics of FGR fetuses with umbilical artery S/D ratio ≥ 3 were summarized, and the correlation between fetal cerebral microvascular status and fetal growth and development was analyzed using Pearson correlation analysis. The outcomes told that the BPD, HC, AC, and FL values of the fetuses in the control group were lower the other's value (P < 0.05), and the MVI and peak systolic velocity of the middle cerebral artery (MCA-PSV) values were also lower in the control group (P < 0.05). Pearson correlation analysis revealed a positive correlation between fetal growth and development and MVI and MCA-PSV values in FGR fetuses. In conclusion, MVFI can monitor and quantitatively analyze fetal intracranial microcirculation, visualize slow blood flow in microvascular structures, and this study provides preliminary evidence of the close relationship between fetal cerebral microcirculation and intrauterine growth and development.

Relationship between neutrophil lymphocyte ratio and red blood cell distribution width and respiratory failure in COPD patients.

The neutrophil lymphocyte ratio (NLR) and red blood cell distribution width (RDW) have been repeatedly demonstrated to be associated with risk of severity, progression, and prognosis of chronic obstructive pulmonary disease (COPD), but data on respiratory failure (RF) in patients with COPD are very limited. This study aimed to examine the relationship between NLR and RDW and the incident RF in patients with COPD. This is a retrospective study that reviewed data by examining the hospitalization medical records to identify those who were admitted with a diagnosis of COPD. Based on whether RF occurred during index hospitalization, patients were classified as COPD group and COPD combined with RF group. Also, healthy controls of the same age and sex were enrolled in a 1:1 ratio as the COPD group. Univariate comparisons were performed between three groups to examine differences. With the COPD group as reference, multivariable logistic regression was formed to identify the relationship between NLR and RDW and RF, with adjustment for multiple covariates. There were 136 healthy controls, 136 COPD patients and 62 patients with COPD combined with RF included for analysis. There was a significant difference for eight variables, including age, WBC, neutrophil, NLR, RDW, platelet, PLR, and CRP. The Spearman test showed the significant correlation between NLR and WBC (correlation coefficient, 0.38; P = .008), NLR and RDW (correlation coefficient, 0.32; P = .013), and NLR and CRP level (correlation coefficient, 0.54; P < .001). The multivariable logistic regression showed that age (every additional 10 years) (OR, 1.785), NLR (OR, 1.716), RDW (OR, 2.266), and CRP (OR, 1.163) were independently associated with an increased risk of RF. This study demonstrated the independent associative effect of NLR and RDW with RF in patients with COPD, exhibiting the potential clinical role in evaluating the progress of COPD to RF.

Neural Network Classification Algorithm Based on Self-attention Mechanism and Ensemble Learning for MASLD Ultrasound Images.

BACKGROUND: Ultrasound image examination has become the preferred choice for diagnosing metabolic dysfunction-associated steatotic liver disease (MASLD) due to its non-invasive nature. Computer-aided diagnosis (CAD) technology can assist doctors in avoiding deviations in the detection and classification of MASLD. METHOD: We propose a hybrid model that integrates the pre-trained VGG16 network with an attention mechanism and a stacking ensemble learning model, which is capable of multi-scale feature aggregation based on the self-attention mechanism and multi-classification model fusion (Logistic regression, random forest, support vector machine) based on stacking ensemble learning. The proposed hybrid method achieves four classifications of normal, mild, moderate, and severe fatty liver based on ultrasound images. RESULT AND CONCLUSION: Our proposed hybrid model reaches an accuracy of 91.34% and exhibits superior robustness against interference, which is better than traditional neural network algorithms. Experimental results show that, compared with the pre-trained VGG16 model, adding the self-attention mechanism improves the accuracy by 3.02%. Using the stacking ensemble learning model as a classifier further increases the accuracy to 91.34%, exceeding any single classifier such as LR (89.86%) and SVM (90.34%) and RF (90.73%). The proposed hybrid method can effectively improve the efficiency and accuracy of MASLD ultrasound image detection.

Phase-separated ParB enforces diverse DNA compaction modes and stabilizes the parS-centered partition complex.

The tripartite ParABS system mediates chromosome segregation in the majority of bacterial species. Typically, DNA-bound ParB proteins around the parS sites condense the chromosomal DNA into a higher-order multimeric nucleoprotein complex for the ParA-driven partition. Despite extensive studies, the molecular mechanism underlying the dynamic assembly of the partition complex remains unclear. Herein, we demonstrate that Bacillus subtilis ParB (Spo0J), through the multimerization of its N-terminal domain, forms phase-separated condensates along a single DNA molecule, leading to the concurrent organization of DNA into a compact structure. Specifically, in addition to the co-condensation of ParB dimers with DNA, the engagement of well-established ParB condensates with DNA allows for the compression of adjacent DNA and the looping of distant DNA. Notably, the presence of CTP promotes the formation of condensates by a low amount of ParB at parS sites, triggering two-step DNA condensation. Remarkably, parS-centered ParB-DNA co-condensate constitutes a robust nucleoprotein architecture capable of withstanding disruptive forces of tens of piconewton. Overall, our findings unveil diverse modes of DNA compaction enabled by phase-separated ParB and offer new insights into the dynamic assembly and maintenance of the bacterial partition complex.

Vertically Oriented Perovskites with Minimized Intrinsic Boundaries for Efficient Photovoltaics.

Intrinsic boundaries formed by grain stacks of randomly oriented perovskite crystallites seriously restrict charge transport in the resultant photovoltaic devices, whereas direct passivation of these defects remains unexplored, and it is desirable to modulate perovskite growth with uniform orientation. Herein, we report a simple but effective method to regulate perovskite crystallization by employing a volatile and polymerizable monomer of hydroxyethyl methacrylate (HEMA), which can simultaneously interact with both FA+ and Pb2+ via hydrogen and coordination bonding, respectively, to seed perovskite crystallization with accelerated nucleation and retarded crystal growth. Upon thermal annealing, the gradual volatilization and partial self-condensation of the HEMA drive the perovskite growth perpendicularly to the substrate, leading to largely suppressed defect states, improved crystallinity, and a reduced Young's modulus of the perovskite film. As a result, champion efficiencies exceeding 24 and 22% with improved operational and mechanical stability of the optimized perovskite solar cells based on rigid and flexible substrates were finally achieved.

Research progress on oncoprotein hepatitis B X­interacting protein (Review).

Hepatitis B X­interacting protein (HBXIP) is a membrane protein located on the lysosomal surface and encoded by the Lamtor gene. It is expressed by a wide range of tumor types, including breast cancer, esophageal squamous cell carcinoma and hepatocellular carcinoma, and its expression is associated with certain clinicopathological characteristics. In the past decade, research on the oncogenic mechanisms of HBXIP has increased and the function of HBXIP in normal cells has been gradually elucidated. In the present review, the following was discussed: The normal physiological role of the HBXIP carcinogenic mechanism; the clinical significance of high levels of HBXIP expression in different tumors; HBXIP regulation of transcription, post­transcription and post­translation processes in tumors; the role of HBXIP in improving the antioxidant capacity of tumor cells; the inhibition of ferroptosis of tumor cells and regulating the metabolic reprogramming of tumor cells; and the role of HBXIP in promoting the malignant progression of tumors. In conclusion, the present review summarized the existing knowledge of HBXIP, established its carcinogenic mechanism and discussed future related research on HBXIP.

Risk of interstitial lung disease with the use of programmed cell death 1 (PD-1) inhibitor compared with programmed cell death ligand 1 (PD-L1) inhibitor in patients with breast cancer: A systematic review and meta-analysis.

Background: Programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have become integral elements within the current landscape of breast cancer treatment modalities; however, they are associated with interstitial lung disease (ILD), which is rare but potentially fatal. Notably, only a few studies have compared the difference in ILD incidence between PD-1 and PD-L1 inhibitors. Therefore, this study aimed to assess the discrepancies regarding ILD risk between the two immune checkpoint inhibitors. We also reported three cases of ILD after PD-1 inhibitor treatment. Methods: We comprehensively searched PubMed, EMBASE, and the Cochrane Library to identify clinical trials that investigated PD-1/PD-L1 inhibitor treatment for patients with breast cancer. Pooled overall estimates of incidence and risk ratio (RR) were calculated with a 95% confidence interval (CI), and a mirror group analysis was performed using eligible studies. Results: This meta-analysis included 29 studies with 4639 patients who received PD-1/PD-L1 inhibitor treatment. A higher ILD incidence was observed among 2508 patients treated with PD-1 inhibitors than among 2131 patients treated with PD-L1 inhibitors (0.05 vs. 0.02). The mirror group analysis further revealed a higher ILD event risk in patients treated with PD-1 inhibitors than in those treated with PD-L1 inhibitors (RR = 2.34, 95% CI, 1.13-4.82, P = 0.02). Conclusion: Our findings suggest a greater risk of ILD with PD-1 inhibitors than with PD-L1 inhibitors. These findings are instrumental for clinicians in treatment deliberations, and the adoption of more structured diagnostic approaches and management protocols is necessary to mitigate the risk of ILD.

Baicalin reduces inflammation to inhibit lung cancer via targeting SOCS1/NF-κB/STAT3 axis.

Inflammation affects several aspects of lung cancer progression including cell proliferation, metastasis, apoptosis, angiogenesis, and drug resistance. Baicalin, an active component of Scutellaria baicalensis Georgi, exhibits anticancer activity in various cancers. However, the effects of baicalin on lung cancer and the underlying molecular mechanisms remain largely unknown. This study is to explore the effect and mechanism of baicalin on lung cancer cell A549 and urethane-induced mouse lung cancer. A cell viability assay, colony formation assay, wound healing assay, acridine orange/ethidium bromide (AO/EB) staining assay, Western blot assay, urethane-induced mouse lung cancer model, hematoxylin and eosin (HE) staining, immunohistochemistry (IHC), and ELISA assay were performed to investigate the effects of baicalin on lung cancer in vitro and in vivo. Network pharmacology analysis, molecular docking, gene silencing assays, and LPS-induced inflammation model were utilized to explore the molecular mechanisms underlying the effect of baicalin on lung cancer. Baicalin showed significant anti-proliferative, anti-migratory, anti-inflammatory and pro-apoptotic effects in vitro; it also inhibited the progression of urethane-induced mouse lung cancer in vivo. Mechanistically, suppressor of cytokine signaling 1 (SOCS1) was the key determinant for baicalin-induced inhibition of lung cancer. Baicalin increased SOCS1 expression to inactivate the NF-κB/STAT3 pathway to inhibit lung cancer in vitro and in vivo. Taken together, baicalin reduces inflammation to inhibit lung cancer via targeting SOCS1/NF-κB/STAT3 axis, providing a prospective compound and novel target for lung cancer treatment.

Protective effect of alizarin on vascular endothelial dysfunction via inhibiting the type 2 diabetes-induced synthesis of THBS1 and activating the AMPK signaling pathway.

BACKGROUND: In this study, we investigated the protective effects of alizarin (AZ) on endothelial dysfunction (ED). AZ has inhibition of the type 2 diabetes mellitus (T2DM)-induced synthesis of thrombospondin 1 (THBS1). Adenosine 5'-monophosphate- activated protein kinase (AMPK), particularly AMPKα2 isoform, plays a critical role in maintaining cardiac homeostasis. PURPOSE: The aim of this study was to investigate the ameliorative effect of AZ on vascular injury caused by T2DM and to reveal the potential mechanism of AZ in high glucose (HG)-stimulated human umbilical vein endothelial cells (HUVECs) and diabetic model rats. STUDY DESIGN: HUVECs, rats and AMPK-/- transgenic mice were used to investigate the mitigating effects of AZ on vascular endothelial dysfunction caused by T2DM and its in vitro and in vivo molecular mechanisms. METHODS: In type 2 diabetes mellitus rats and HUVECs, the inhibitory effect of alizarin on THBS1 synthesis was verified by immunohistochemistry (IHC), immunofluorescence (IF) and Western blot (WB) so that increase endothelial nitric oxide synthase (eNOS) content in vitro and in vivo. In addition, we verified protein interactions with immunoprecipitation (IP). To probe the mechanism, we also performed AMPKα2 transfection. AMPK's pivotal role in AZ-mediated prevention against T2DM-induced vascular endothelial dysfunction was tested using AMPKα2-/- mice. RESULTS: We first demonstrated that THBS1 and AMPK are targets of AZ. In T2DM, THBS1 was robustly induced by high glucose and inhibited by AZ. Furthermore, AZ activates the AMPK signaling pathway, and recoupled eNOS in stressed endothelial cells which plays a protective role in vascular endothelial dysfunction. CONCLUSIONS: The main finding of this study is that AZ can play a role in different pathways of vascular injury due to T2DM. Mechanistically, alizarin inhibits the increase in THBS1 protein synthesis after high glucose induction and activates AMPKα2, which increases NO release from eNOS, which is essential in the prevention of vascular endothelial dysfunction caused by T2DM.

Dietary antioxidant intake is associated with heart failure: Results from the NHANES 2003-2019.

BACKGROUND: Growing evidence has shown that antioxidant diets protect against heart failure (HF). However, the association between the composite dietary antioxidant index (CDAI), an important measure of overall antioxidants in the diet, and HF has received little attention. OBJECTIVE: The purpose of this study was to examine the relationship between the CDAI and HF. METHODS: A secondary cross-sectional analysis of the 2003 to 2019 National Health and Nutrition Examination Survey (NHANES) was performed. Weighted multivariable logistic regression was used to test the association between the CDAI and HF in four different models, with subgroup analysis and an interaction test subsequently performed. RESULTS: A total of 37,390 participants were included. The HF groups had lower CDAI levels than those in the non-HF group (0.29 ± 0.04 vs. -0.74 ± 0.16, p < 0.0001). After adjusting for demographic characteristics, lifestyle factors, and disease history, a negative association was found between the CDAI and HF (OR: 0.97, 95 % CI: 0.94, 1.00). There was an inverse trend whereby increasing the CDAI was associated with decreasing the odds of HF (p for trend < 0.001). The subgroup analysis and interaction test showed no significant dependence on demographic characteristics, lifestyle factors, and disease history with regard to this association (all p for interaction > 0.05). CONCLUSION: The CDAI was inversely associated with HF in US adults, with higher CDAI levels possibly being associated with a lower incidence of HF, suggesting that dietary antioxidants may help prevent HF.

Co-exposure to 55 endocrine-disrupting chemicals linking diminished sperm quality: Mixture effect, and the role of seminal plasma docosapentaenoic acid.

Isolated effects of single endocrine-disrupting chemicals (EDCs) on male reproductive health have been studied extensively, but their mixture effect remains unelucidated. Previous research has suggested that consuming diet enriched in omega-3 polyunsaturated fatty acids (PUFA) might be beneficial for reproductive health, whether omega-3 PUFA could moderate the effect of EDCs mixture on semen quality remains to be explored. In this study of 155 male recruited from a reproductive health center in China, we used targeted-exposomics to simultaneously measure 55 EDCs in the urine for exposure burden. Regression analyses were restricted to highly detected EDCs (≥55%, n = 34), and those with consistently elevated risk were further screened and brought into mixture effect models (Bisphenol A, ethyl paraben, methyl paraben [MeP], benzophenone-1 [BP1], benzophenone-3, mono(3-carboxypropyl) phthalate [MCPP]). Bayesian Kernel Machine Regression (BKMR) and quantile-based g-computation (QGC) models demonstrated that co-exposure to top-ranked EDCs was related to reduced sperm total (ß = -0.18, 95%CI: -0.29 - -0.07, P = 0.002) and progressive motility (ß = -0.27, 95%CI: -0.43 - -0.10, P = 0.002), but not to lower semen volume. BP1, MeP and MCPP were identified as the main effect driver for deteriorated sperm motion parameters using mixture model analyses. Seminal plasma fatty acid profiling showed that high omega-3 PUFA status, notably elevated docosapentaenoic acid (DPA, C22:5n-3) status, moderated the association between MCPP and sperm motion parameters (total motility: ß = 0.26, 95%CI: 0.01 - -0.51, Pinteraction = 0.047; progressive motility: ß = 0.64, 95%CI: 0.23 - 1.05, Pinteraction = 0.003). Co-exposure to a range of EDCs is mainly associated with deteriorated sperm quality, but to a lesser extent on sperm quantity, high seminal plasma DPA status might be protective against the effect. Our work emphasizes the importance of exposomic approach to assess chemical exposures and highlighted a new possible intervention target for mitigating the potential adverse effect of EDCs on semen quality.

Application of TiLOOP bra in implant-based breast reconstruction is associated with decreased complication risk compared with other meshes: A systematic review and meta-analysis.

BACKGROUND: TiLOOP bra has been used for over 15 years, however, evidence regarding its safety in implant-based breast reconstruction (IBBR) for patients with breast cancer after mastectomy is still limited. We performed this meta-analysis to evaluate its risks and benefits in IBBR comparing with other meshes. METHODS: Electronic databases were searched to identify relevant studies comparing postoperative complications between TiLOOP bra and other reconstruction techniques in IBBR with or without meshes. We also compared patient satisfaction in physical well-being between two groups. Risk ratios (RRs) and mean differences with 95% confidence interval (CI) were calculated. RESULTS: Seven studies representing 1203 cases were analyzed. Compared with other meshes, the use of TiLOOP bra significantly reduced the risk of infection (RR = 0.53, 95% CI, 0.32-0.86), seroma (RR = 0.21, 95% CI, 0.07-0.61), red breast syndrome (RR = 0.10, 95% CI, 0.02-0.45), and capsular contracture (RR = 0.20, 95% CI, 0.05-0.75). Patient satisfaction in physical well-being was comparable between two groups. CONCLUSIONS: TiLOOP bra in IBBR has a favored safety profile over other meshes, which significantly reduced postoperative complication risk and did not affect patient satisfaction. Although prospective well-designed controlled studies are still warranted, TiLOOP bra is safe and reliable at present.

Joint Efforts of Replicative Helicase and SSB Ensure Inherent Replicative Tolerance of G-Quadruplex.

G-quadruplex (G4) is a four-stranded noncanonical DNA structure that has long been recognized as a potential hindrance to DNA replication. However, how replisomes effectively deal with G4s to avoid replication failure is still obscure. Here, using single-molecule and ensemble approaches, the consequence of the collision between bacteriophage T7 replisome and an intramolecular G4 located on either the leading or lagging strand is examined. It is found that the adjacent fork junctions induced by G4 formation incur the binding of T7 DNA polymerase (DNAP). In addition to G4, these inactive DNAPs present insuperable obstacles, impeding the progression of DNA synthesis. Nevertheless, T7 helicase can dismantle them and resolve lagging-strand G4s, paving the way for the advancement of the replication fork. Moreover, with the assistance of the single-stranded DNA binding protein (SSB) gp2.5, T7 helicase is also capable of maintaining a leading-strand G4 structure in an unfolded state, allowing for a fraction of T7 DNAPs to synthesize through without collapse. These findings broaden the functional repertoire of a replicative helicase and underscore the inherent G4 tolerance of a replisome.

Mollugin prevents CLP-induced sepsis in mice by inhibiting TAK1-NF-κB/MAPKs pathways and activating Keap1-Nrf2 pathway in macrophages.

Sepsis is a life-threatening organ dysfunction associated with macrophage overactivation. Targeted therapy against macrophages is considered a promising strategy for sepsis treatment. Mollugin (MLG), a compound extracted from traditional Chinese medicine Rubia cordifolia L., possesses anti-tumor and anti-inflammatory activities. This study aimed to investigate the anti-inflammatory effects and mechanisms of MLG in macrophages and its therapeutic role in CLP-induced sepsis in mice. The results demonstrated that MLG downregulated the inflammatory response induced by LPS or tumor necrosis factor α (TNF-α) in macrophages. Mechanistically, MLG suppressed the phosphorylation of TAK1, the upstream modulator of IKKα/ß and MAPKs, thereby inhibiting the pro-inflammatory signaling transduction of NF-κB and MAPKs. Additionally, MLG also activated the Nrf2 antioxidant pathway, reducing intracellular reactive oxygen species. CETSA and molecular docking analyses revealed that MLG could effectively bind to TAK1 and Keap1, which may be involved in the inhibition of TAK1- NF-κB/MAPKs and activation of Nrf2 mediated by MLG. Animal study demonstrated that MLG ameliorated inflammatory injury of lung and liver in CLP-induced sepsis mice probably by reducing the levels of pro-inflammatory cytokines. Therefore, our study suggests that bi-directional roles of MLG in improving sepsis via blocking the TAK1-NF-κB/MAPKs and activating Nrf2 pathways, indicating its potential as a promising candidate drug for sepsis treatment.

Case report: Supratherapeutic tacrolimus concentrations with nirmatrelvir/ritonavir in a lung transplant patient: a case report using Rifampin for reversal.

Paxlovid (nirmatrelvir/ritonavir) is an antiviral drug used to treat COVID-19, nirmatrelvir, a SARS-CoV-2 main protease inhibitor, works by inhibiting viral replication in the early stages, and ritonavir is a strong cytochrome P450 (CYP) 3A inhibitor that helps the nirmatrelvir reach and maintain the therapeutic concentrations. Paxlovid has a potential risk of drug interaction by elevating the plasma concentration of other drugs metabolized by CYP3A, like tacrolimus. This report examines the case of a 57-year-old female lung transplant patient self-administered Paxlovid for 5 days without discontinuing tacrolimus. She presented to the hospital with symptoms of headache, dizziness, palpitations, abdominal distension, nausea, vomiting, and diarrhea. The patient presented with tacrolimus toxicity and the blood concentration of tacrolimus was measured at 106 ng/mL. Urgent medical intervention was initiated, and Rifampin was administered to induce enzyme activity and rapidly decrease the concentration of tacrolimus. By adjusting the tacrolimus dosage, the final concentration was brought within the appropriate range. Clinical pharmacists should prioritize medication education for transplant patients to prevent severe drug interactions and minimize the impact on the patient's overall well-being.