The mechanosensitive ion channel Piezo1 contributes to podocyte cytoskeleton remodeling and development of proteinuria in lupus nephritis.

Piezo1 functions as a special transducer of mechanostress into electrochemical signals and is implicated in the pathogenesis of various diseases across different disciplines. However, whether Piezo1 contributes to the pathogenesis of lupus nephritis (LN) remains elusive. To study this, we applied an agonist and antagonist of Piezo1 to treat lupus-prone MRL/lpr mice. Additionally, a podocyte-specific Piezo1 knockout mouse model was also generated to substantiate the role of Piezo1 in podocyte injury induced by pristane, a murine model of LN. A marked upregulation of Piezo1 was found in podocytes in both human and murine LN. The Piezo1 antagonist, GsMTx4, significantly alleviated glomerulonephritis and tubulointerstitial damage, improved kidney function, decreased proteinuria, and mitigated podocyte foot process effacement in MRL/lpr mice. Moreover, podocyte-specific Piezo1 deletion showed protective effects on the progression of proteinuria and podocyte foot process effacement in the murine LN model. Mechanistically, Piezo1 expression was upregulated by inflammatory cytokines (IL-6, TNF-α and IFN-γ), soluble urokinase Plasminogen Activator Receptor and its own activation. Activation of Piezo1 elicited calcium influx, which subsequently enhanced Rac1 activity and increased active paxillin, thereby promoting cytoskeleton remodeling and decreasing podocyte motility. Thus, our work demonstrated that Piezo1 contributed to podocyte injury and proteinuria progression in LN. Hence, targeted therapy aimed at decreasing or inhibiting Piezo1 could represent a novel strategy to treat LN.

Low thyroid function is associated with metabolic dysfunction-associated steatotic liver disease.

Background and Aim: Metabolic dysfunction-associated steatotic liver disease (MASLD) is recently introduced to better highlight the pathogenic significance of cardiometabolic dysfunction, as compared with non-alcoholic fatty liver disease. This study aimed to investigate the association between low thyroid function and MASLD in the new context. Methods: We recruited 2901 participants for our retrospective cohort study from 2016 to 2021. Participants were divided into strict-normal thyroid function and low thyroid function groups (low-normal thyroid function, subclinical hypothyroidism) based on initial thyroid stimulating hormone (TSH) levels, respectively. Cox regression models were used to estimate the hazard ratios (HRs) and 95% CI. Results: During a median follow-up of 15.6 months, 165 (8.9%) strict-normal thyroid function subjects and 141 (13.4%) low thyroid function subjects developed MASLD; this result was statistically relevant (P < 0.05). Univariate regression analysis showed that low thyroid function and subclinical hypothyroidism were statistically significantly associated with MASLD (low thyroid function: HR1.53; 95% CI 1.22-1.92; subclinical hypothyroidism: HR1.95; 95% CI 1.47-2.60). Conclusions: MASLD is associated with low thyroid function and the relationship between MASLD and low thyroid function is independent.

Effects of co-application of tiotropium bromide and traditional Chinese medicine on patients with stable chronic obstructive pulmonary disease: a muilticenter, randomized, controlled trial study.

Background: Chronic Obstructive Pulmonary Disease (COPD) is a common, preventable, and treatable disease. Traditional Chinese Medicine (TCM) has shown promising potential in COPD treatment. and we conducted a multi-center RCT to evaluate the effectiveness of TCM-based therapy in stable COPD patients. Methods: In this multicenter, double-blind RCT, a total of 200 patients were supposed to be assigned to either trial or control group randomly. Both groups received Tiotropium (18 µg) from month 0 to month 12. Trial group received additional TCM granules, while control group received a placebo from month 0 to month 6. Symptom assessment, total effective rate, lung function measurements, hospitalization rates, and quality of life were evaluated at month 0, month 6, and month 12. Adverse events were assessed at month 12. Results: Of the initial 105 patients (aged 40-80) who completed the study, 51 were in trial group and 54 were in control group. At month 6, significant differences were observed between two groups in total effective rate (p = 0.020), sputum score (p = 0.047), changes in FVC% (p = 0.047) and FEV1 (p = 0.046). At month 12, significant differences were observed in sputum score (p = 0.020), FVC (p = 0.042), and change in FEV1 (p = 0.013). Compared to baseline, they both demonstrated improvements in symptoms, acute exacerbation, lung function, quality of life, and exercise tolerance. Conclusion: TCM treatment effectively improved total effective rate, sputum symptom, FVC%, FEV1, and exhibited prolonged efficacy in improving sputum symptoms and FEV1 in stable COPD patients.Clinical trial registration:https://www.chictr.org.cn/showproj.html?proj=6029 identifier ChiCTR-TRC-13003531.

Engineered extracellular vesicles efficiently deliver CRISPR-Cas9 ribonucleoprotein (RNP) to inhibit herpes simplex virus1 infection in vitro and in vivo.

Extracellular vesicles (EVs) have recently emerged as a promising delivery platform for CRISPR/Cas9 ribonucleoproteins (RNPs), owing to their ability to minimize off-target effects and immune responses. However, enhancements are required to boost the efficiency and safety of Cas9 RNP enrichment within EVs. In response, we employed the Fc/Spa interaction system, in which the human Fc domain was fused to the intracellular domain of PTGFRN-Δ687 and anchored to the EV membrane. Simultaneously, the B domain of the Spa protein was fused to the C domain of cargos such as Cre or spCas9. Due to the robust interaction between Fc and Spa, this method enriched nearly twice the amount of cargo within the EVs. EVs loaded with spCas9 RNP targeting the HSV1 genome exhibited significant inhibition of viral replication in vitro and in vivo. Moreover, following neuron-targeting peptide RVG modification, the in vivo dosage in neural tissues substantially increased, contributing to the clearance of the HSV1 virus in neural tissues and exhibiting a lower off-target efficiency. These findings establish a robust platform for efficient EV-based SpCas9 delivery, offering potential therapeutic advantages for HSV1 infections and other neurological disorders.

Risk factors for progression to severe infection and prolonged viral clearance time in hospitalized elderly patients infected with the Omicron variant of SARS-CoV-2: a retrospective study at Shanghai Fourth People's Hospital, School of Medicine, Tongji University.

Introduction: In elderly patients infected with the Omicron variant, disease progression to severe infection can result in poor outcomes. This study aimed to identify risk and protective factors associated with disease progression to severe infection and viral clearance time in elderly Omicron-infected patients. Methods: Shanghai Fourth People's Hospital, School of Medicine, Tongji University, was officially designated to provide treatment to patients with COVID-19. This study was conducted on confirmed Omicron cases admitted to the hospital between 10 April 2022 and 21 June 2022. In total, 1,568 patients aged 65 years or older were included. We conducted a retrospective, observational study using logistic regression to analyze risk and protective factors for the development of severe disease and Cox proportional hazards regression models to analyze factors influencing viral clearance time. Results: Aged over 80 years, having 2 or more comorbidities, combined cerebrovascular disease, chronic neurological disease, and mental disorders were associated with the development of severe disease, and full vaccination was a protective factor. Furthermore, aged over 80 years, combined chronic respiratory disease, chronic renal disease, cerebrovascular disease, mental disorders, and high viral load were associated with prolonged viral clearance time, and full vaccination was a protective factor. Discussion: This study analyzed risk factors for progression to severe infection and prolonged viral clearance time in hospitalized elderly Omicron-infected patients. Aged patients with comorbidities had a higher risk of developing severe infection and had longer viral clearance, while vaccination protected them against the Omicron infection.

Association of Advanced Glycation End Products with Cognitive Function: HealthyDance Study.

Background: The current research on advanced glycosylation end products (AGEs) and cognitive function is limited. Objective: We aimed to investigate the relationship between multiple plasma AGEs and cognitive function and mild cognitive impairment (MCI). Methods: Baseline data from The Lifestyle and Healthy Aging of Chinese Square Dancer Study was used in this cross-sectional study. Ultra-high-performance liquid chromatography tandem mass spectrometry was used to determine plasma levels of carboxymethyl lysine (CML), carboxyethyl lysine (CEL), and methyl imidazolinone (MG-H1). Four cognitive tests were used to obtain the four cognitive domain scores and the composite z scores. The Petersen criteria were used to diagnose MCI. The data were analyzed by multivariable linear and logistic regression models. Results: This study included 1,018 participants (median age 61.0 years, 87.3% female). After multivariate adjustment, the ßs of the highest quartile of CML and CEL compared to the lowest quartile were -0.28 (-0.38, -0.17) and -0.13 (-0.23, -0.03), respectively, for the composite z score. For the four cognitive domains, CML was negatively correlated with memory, attention, and executive function, and CEL was negatively associated with memory and language function. In addition, higher CML was associated with a higher odds of MCI. MG-H1 was not associated with cognitive function. Conclusions: High plasma AGE levels were correlated with poorer cognitive function, particularly CML and CEL, higher levels of CML were also associated with higher odds of MCI. To clarify the effects of different AGEs on cognitive function and the underlying mechanisms, further longitudinal and experimental studies are needed.

The modulation effects of the mind-body and physical exercises on the basolateral amygdala-temporal pole pathway on individuals with knee osteoarthritis.

Background/Objective: To investigate the modulatory effects of different physical exercise modalities on connectivity of amygdala subregions and its association with pain symptoms in patients with knee osteoarthritis (KOA). Methods: 140 patients with KOA were randomly allocated either to the Tai Chi, Baduanjin, Stationary cycling, or health education group and conducted a 12 week-long intervention in one of the four groups. The behavioral, magnetic resonance imaging (MRI), and blood data were collected at baseline and the end of the study. Results: Compared to the control group, all physical exercise modalities lead to significant increases in Knee Injury and Osteoarthritis Outcome Score (KOOS) pain score (pain relief) and serum Programmed Death-1 (PD-1) levels. Additionally, all physical exercise modalities resulted in decreased resting state functional connectivity (rsFC) of the basolateral amygdala (BA)-temporal pole and BA-medial prefrontal cortex (mPFC). The overlapping BA-temporal pole rsFC observed in both Tai Chi and Baduanjin groups was significantly associated with pain relief, while the BA-mPFC rsFC was significantly associated with PD-1 levels. In addition, we found increased fractional anisotropy (FA) values, a measurement of water diffusion anisotropy of tissue that responded to changes in brain microstructure, within the mind-body exercise groups' BA-temporal pole pathway. The average FA value of this pathway was positively correlated with KOOS pain score at baseline across all subjects. Conclusions: Our findings suggest that physical exercise has the potential to modulate both functional and anatomical connectivity of the amygdala subregions, indicating a possible shared pathway for various physical exercise modalities.

The modulation effects of the mind-body and physical exercises on the basolateral amygdala-temporal pole pathway on individuals with knee osteoarthritis / Los efectos de modulación de la mente-cuerpo y los ejercicios físicos en la vía del polo basolateral amígdala-temporal en personas con osteoartritis de rodilla

Background/Objective: To investigate the modulatory effects of different physical exercise modalities on connectivity of amygdala subregions and its association with pain symptoms in patients with knee osteoarthritis (KOA). Methods: 140 patients with KOA were randomly allocated either to the Tai Chi, Baduanjin, Stationary cycling, or health education group and conducted a 12 week-long intervention in one of the four groups. The behavioral, magnetic resonance imaging (MRI), and blood data were collected at baseline and the end of the study. Results: Compared to the control group, all physical exercise modalities lead to significant increases in Knee Injury and Osteoarthritis Outcome Score (KOOS) pain score (pain relief) and serum Programmed Death-1 (PD-1) levels. Additionally, all physical exercise modalities resulted in decreased resting state functional connectivity (rsFC) of the basolateral amygdala (BA)-temporal pole and BA-medial prefrontal cortex (mPFC). The overlapping BA-temporal pole rsFC observed in both Tai Chi and Baduanjin groups was significantly associated with pain relief, while the BA-mPFC rsFC was significantly associated with PD-1 levels. In addition, we found increased fractional anisotropy (FA) values, a measurement of water diffusion anisotropy of tissue that responded to changes in brain microstructure, within the mind-body exercise groups' BA-temporal pole pathway. The average FA value of this pathway was positively correlated with KOOS pain score at baseline across all subjects. Conclusions: Our findings suggest that physical exercise has the potential to modulate both functional and anatomical connectivity of the amygdala subregions, indicating a possible shared pathway for various physical exercise modalities.(AU)