Salidroside reduces neuropathology in Alzheimer's disease models by targeting NRF2/SIRT3 pathway.

BACKGROUND: Neurite dystrophy is a pathologic hallmark of Alzheimer's disease (AD). However, drug discovery targeting neurite protection in AD remains largely unexplored. METHODS: Aß-induced neurite and mitochondrial damage assays were used to evaluate Aß toxicity and the neuroprotective efficacy of a natural compound salidroside (SAL). The 5×FAD transgenic mouse model of AD was used to study the neuroprotective function of SAL. To verify the direct target of SAL, we used surface plasmon resonance and cellular thermal shift assays to analyze the drug-protein interaction. RESULTS: SAL ameliorates Aß-mediated neurite damage in cell culture. We further reveal that SAL represses mitochondrial damage in neurites by promoting mitophagy and maintaining mitochondrial homeostasis, dependent on an NAD-dependent deacetylase SIRT3. In AD mice, SAL protects neurite morphology, mitigates Aß pathology, and improves cognitive function, which are all SIRT3-dependent. Notably, SAL directly binds to transcription factor NRF2, inhibits its degradation by blocking its interaction with KEAP1 ubiquitin ligase, and then advances NRF2-mediated SIRT3 transcription. CONCLUSIONS: Overall, we demonstrate that SAL, a potential anti-aging drug candidate, attenuates AD pathology by targeting NRF2/SIRT3 pathway for mitochondrial and neurite protection. Drug discovery strategies focusing on SAL may thus provide promising therapeutics for AD.

Impact of Kangaroo Mother Care Intervention on Immunological and Pulmonary Functions of Preterm Infants during Breastfeeding.

Objective: Preterm infants (PTIs) are prone to respiratory failure or other diseases due to immature organ development and poor immunological function. Herein, the effects of Kangaroo Mother Care (KMC) on the immunological and pulmonary functions of PTIs during breastfeeding were investigated in this study. Methods: The study recruited 86 delivery women and their PTIs with preterm pregnancy outcomes, consisting of 46 cases receiving breastfeeding plus KMC intervention (KMC group) and 40 cases receiving breastfeeding plus routine care (control group). The time of first lactation, time of first breastfeeding, and duration of first breastfeeding were observed in both cohorts. The breastfeeding status was assessed using the LATCH system. Maternal psychological status was evaluated by the breastfeeding self-efficacy scale (BSES) and self-rating anxiety/depression scale (SAS/SDS). The growth and development of PTIs were recorded, and the levels of postalbumin (PA), transferrin (TRF), plasma albumin (ALB), immunoglobulin (Ig) A, IgG, IgM, and complement C3 and C4 were measured. The tidal volume (VT), tidal volume per kilogram (VT/kg), minute volume (MV), and minute volume per kilogram (MV/kg) were detected using a pulmonary function tester. Results: The KMC group presented shorter time of first lactation and first breastfeeding than the control group, with longer duration of first breastfeeding (P < 0.05). After intervention, the BSES scores of delivery women were increased, while the SAS and SDS scores were decreased, with more notable improvements in the KMC group (P < 0.05). The levels of PA, TRF, ALB, IgA, IgG, VT, and MV were elevated in PTIs in both groups, with more evident increase in the KMC group than in the control group (P < 0.05). A better growth of PTIs was found in the KMC group than the control group (P < 0.05). Conclusions: The study demonstrated that KMC intervention during breastfeeding could benefit PTIs specifically regarding their immunological and pulmonary functions.

Renal tubular cell necroptosis: A novel mechanism of kidney damage in trichloroethylene hypersensitivity syndrome mice.

Trichloroethylene (TCE) hypersensitivity syndrome (THS), called occupational medicamentosa-like dermatitis due to TCE (OMDT) in China, is a fatal occupational disorder caused by TCE exposure. Visceral damage, including kidney injury, is one of the major complications. Necroptosis is a regulated cell death form linked to local inflammatory response. This study aimed to investigate whether renal cell necroptosis was involved in TCE-induced kidney injury. A Balb/c mouse model of TCE sensitization was utilized to study mechanisms of modulation of TCE-induced renal necroptosis. Renal histology (using light and transmission electron microscopy) and renal tubular impairment indexes, including α1-microglobulin (α1-MG), and ß2-microglobulin (ß2-MG), were evaluated. In addition, tissue expression of necroptosis-related proteins, including tumor necrosis factor (TNF)-α, TNF receptor 1 (TNFR1), receptor-interacting protein kinase 3 (RIPK3), p-RIK3, mixed lineage kinase domain-like protein (MLKL), and p-MLKL, were also evaluated. The study here confirmed TCE sensitization caused damage to renal tubules and renal tubular epithelial cell (RTEC) necroptosis. In mice treated with R7050 (a specific TNFα antagonist), it was also seen that inhibition of TNFα expression could effectively inhibit RTEC necroptosis and improve renal function in the TCE-sensitized mice. Taken together, these results help to define a novel mechanism by which RTEC necroptosis plays a key role in TCE-induced kidney damage.

Association between Serum Free Fatty Acids to HDL-Cholesterol Ratio and Nonalcoholic Fatty Liver Disease: a Cross-Sectional Study.

BACKGROUND: This cross-sectional study aimed to investigate the association between serum free fatty acids and high-density lipoprotein-cholesterol ratio (FHR) and nonalcoholic fatty liver disease (NAFLD) in a Chinese population. METHODS: A total of 760 NAFLD subjects and 379 healthy controls who took their annual health checkups were enrolled during 2019. Fasting blood samples were obtained from the population. NAFLD was diagnosed based on hepatic ultrasound examination. RESULTS: Serum FHR (*100) in NAFLD subjects was significantly higher than that in controls. We found that the serum FHR in NAFLD participants was positively correlated with BMI, DBP, WBC, HGB, ALT, AST, GGT, TG, FPG, UA, and hsCRP. Univariate and multivariate logistic regression analysis showed that FHR was independently associated with the presence of NAFLD. The area under curve (AUC) of the receiver operating characteristic (ROC) curve of FHR for NAFLD was 0.781 with the 95% confidence interval from 0.753 to 0.810. The optimal cutoff point of FHR for predicting NAFLD was 41.14 with 78.8% sensitivity and 77.3%, respectively. CONCLUSIONS: FHR was significantly associated with NAFLD and may serve as an effective indicator in NAFLD patients.

Glomerular Damage in Trichloroethylene-Sensitized Mice: Targeting Cathepsin L-Induced Hyperactive mTOR Signaling.

Trichloroethylene (TCE) is a serious health hazard for workers with daily exposure, causing occupational medicamentosa-like dermatitis due to TCE (OMDT) and glomerular damage. Recent studies suggest that mTORC1 signaling is activated in various glomerular disorders; however, the role of mTORC1 signaling in TCE-induced glomerular damage remains to be explored. In the present study, 6 OMDT patients were enrolled and a TCE-sensitized mouse model was established to investigate molecular mechanisms underlying the glomerular damage associated with OMDT. Glomerular damage was assessed by levels of urine nephrin, H&E staining, and renal function test. Ultrastructural change of podocyte was investigated by transmission electron microscopy. The podocyte-related molecules including nephrin, α-actinin-4, and integrin ß1 were visualized by immunofluorescence. The activation of mTORC1 signaling was confirmed by Western blot. Glomerular apoptosis was examined by the TUNEL test and Western blotting. Expression and location of cathepsin L (CTSL) were assessed by RT-PCR and immunofluorescence. Our results showed that TCE sensitization caused damage to glomerular structural integrity and also increased the activation of mTORC1 signaling, which was accompanied by podocyte loss, hypertrophy, and glomerular apoptosis. Importantly, we also found that over-expressed CTSL was mainly located in podocyte and CTSL inhibition could partially block the activation of mTORC1 signaling. Thus, our findings suggested a novel mechanism whereby hyperactive mTOR signaling contributes to TCE sensitization-induced and immune-mediated glomerular damage via CTSL activation.

Intracellular complement activation in podocytes aggravates immune kidney injury in trichloroethylene-sensitized mice.

Trichloroethylene (TCE) as a common organic solvent in industrial production can cause occupational medicamentosa-like dermatitis (OMDT) in some exposed workers. In addition to systemic skin damage, OMDT is also accompanied by severe kidney injury. Our previous studies show that complement (C) plays an important role in immune kidney injury caused by TCE. Specifically, C3 is mainly deposited on glomeruli. Recent studies have found that intracellular complement can be activated by cathepsin L (CTSL) and exert a series of biological effects. The purpose of this study was to explore where C3 on glomeruli comes from and what role it plays. A BALB/c mouse model of skin sensitization induced by TCE in the presence or absence of CTSL inhibitor (CTSLi,10 mg/kg). In TCE sensitization-positive mice, C3 was mainly expressed on podocytes and the expression of CTSL significantly increased in podocytes. Kidney function test and related indicators showed abnormal glomerular filtration and transmission electron microscopy revealed ultrastructure damage to podocytes. These lesions were alleviated in TCE/CTSLi positive mice. These results provide the first evidence that in TCE-induced immune kidney injury, intracellular complement in podocytes can be over-activated by CTSL and aggravates podocytes injury, thereby damaging glomerular filtration function. Intracellular complement activation and cathepsin L in podocytes may be a potential target for treating immune kidney injury induced by TCE.

Serum Thyroid Hormones Levels are Significantly Associated with Nonalcoholic Fatty Liver Disease in Euthyroid Chinese Population.

BACKGROUND: Thyroid hormones play an essential role in metabolic homeostasis. Previous studies have demon-strated a close relationship between thyroid abnormalities and metabolic disorders. This retrospective cross-sectional study was to investigate whether significant differences of circulating thyroid profiles exist and to explore the potential of serum thyroid hormones in reflecting advanced fibrosis in subjects with Nonalcoholic Fatty Liver Disease (NAFLD). METHODS: Abdominal ultrasonography was performed to diagnose NAFLD. For all the participants including 522 NAFLD patients and 415 gender- and age-matched controls recruited, demographic, clinical data and thyroid functions were recorded. Fasting serum thyroid hormones including free triiodothyronine (FT3), free thyroxine (FT4), total thyroxine (TT4), total triiodothyronine (TT3), and thyroid-stimulating hormone (TSH) were evaluated. RESULTS: Serum FT3 levels in subjects with NAFLD were significantly reduced, while TSH was increased compared to that in controls. The NAFLD subjects with metabolic syndrome (MS) had significantly lower FT3 and FT4 levels and higher TSH levels than the non-MS group. Serum TSH levels were positively associated with the risk for NAFLD, while FT3 levels were inversely correlated with NAFLD. Among thyroid hormones, low serum FT4 was the only independent predictor of reflecting advanced fibrosis in NAFLD participants. CONCLUSIONS: An altered thyroid profile not only can be significantly associated with an increased incidence of NAFLD, but also had clinical predictive value for assessing significant fibrosis.

Local renal complement activation mediates immune kidney injury by inducing endothelin-1 signalling and inflammation in trichloroethylene-sensitised mice.

Trichloroethylene (TCE) is a widely used industrial solvent that causes trichloroethylene hypersensitivity syndrome (THS) with multi-system damage, including kidney injury. Clinical studies have shown that the complement system is important for TCE-induced kidney injury. Our previous study found excessive deposition of complement C3, mainly on the glomerulus, indicating that local renal complement is activated after TCE sensitisation. However, whether local renal complement activation mediates TCE-induced immune kidney injury and the underlying mechanisms remain unknown. Therefore, we established a TCE percutaneous sensitisation BALB/c mouse model to explore the mechanisms by pretreating with or without the complement activation antagonist, cathepsin L inhibitor (CatLi). As expected, more C3 and C3a were detected mainly on glomerulus of TCE positive sensitisation (TCE+) mice. Renal dysfunction and pathological damage were also clearly observed in TCE+ mice. Moreover, the mRNA and protein expression of ET-1 increased significantly with local renal complement activation after TCE sensitisation, leading to cytokines release and inflammation. In addition, activation of p38MAPK and NF-κBp65 pathways were detected in kidneys of TCE+ mice, and CatLi pretreatment decreased these changes through complement activation antagonisation. Our research uncovered a novel role of local renal complement activation during immune kidney injury after TCE sensitisation through induction of ET-1 signalling and inflammation.

MiR-218-XOR-ROS Pathway Regulates the Progression of Nonalcoholic Steatohepatitis.

BACKGROUND: To investigate the role of the miR-218-xanthine oxidoreductase (XOR) pathway in the pathogenesis of nonalcoholic steatohepatitis (NASH) and to explore the potential downstream mechanisms involving oxidative stress and energy metabolism. METHODS: The NASH animal model was established by feeding BALB/c mice with an MCD diet, while BRL-3A cells were cultured with a mixture of oleate and palmitate for 72 hours to mimic the steatosis and inflammation of NASH in vitro. The steatosis and inflammation levels were assessed by H-E/oil-red staining and serum/supernatant TG, ALT, and AST levels. The apoptosis degree was tested by the TUNEL/flow cytometry method both in animals and cultured cells. The XOR and miR-218 levels were detected by western blotting and qRT-PCR. RESULTS: Decreased miR-218 and increased XOR levels were identified in the NASH animal and cell models, while the regulation of miR-218 on XOR was also confirmed. NASH alleviation was achieved after miR-218 over-expression in vivo and in vitro, according to the declination of steatosis and inflammation-related markers. Although H2O2 and ATP levels were increased and decreased in NASH models, respectively, antagonizing miR-218 could significantly alleviate those changes. CONCLUSIONS: The miR-218-XOR pathway may provide a novel mechanism and treatment option for NASH.

Terminal complement complex C5b-9 reduced megalin and cubilin-mediated tubule proteins uptake in a mouse model of trichloroethylene hypersensitivity syndrome.

Trichloroethylene (TCE), a commonly used industrial solvent and degreasing agent, is known to cause trichloroethylene hypersensitivity syndrome (THS) with multi-system damage, including skin, liver and kidney. Clinical evidence have shown that the kidney injury occurs in THS and our previous studies suggested that the terminal complement complex C5b-9 deposited in impaired renal tubules induced by TCE with unclear mechanisms. In the present study, we questioned whether activation of the complement system with renal deposition of C5b-9 contributes to TCE-induced kidney injury in THS. We established a BALB/c mouse model of TCE sensitization with or without pretreatment of exogenous CD59, a C5b-9 inhibitory protein. H&E staining, PAS staining, and biochemical detection of urinary proteins were performed to assess renal function. Deposition of C5b-9 and expression of CD59 were evaluated by immunohistochemistry. Sub-lytic effects of C5b-9 in tubular epithelial cells were assessed by lactate dehydrogenase (LDH) cytotoxicity assay. Expression of endocytosis receptors megalin and cubilin on proximal tubules were assessed by immunofluorescence and qRT-PCR. We found that TCE sensitization induced structural and functional changes of renal tubules in mice, associated with the deposition of sub-lytic C5b-9 on proximal tubular epithelial cells. TCE sensitization decreased proximal tubule uptake of filtered proteins and renal expression of megalin and cubilin, phenotypes that were attenuated by pretreatment with exogenous CD59. Overall, our findings reveal a novel mechanism underlying sub-lytic C5b-9 acting on megalin and cubilin, contributes to the renal tubules damage by TCE exposure.

Reference Intervals of Apolipoprotein E in Healthy Chinese Han Adults.

BACKGROUND: Reference intervals (RIs) of Apo E levels are an important parameter for the clinical evaluation of patient health, and the RIs of serum Apo E could be variable in different population. We plan to establish RIs of apolipoprotein E (Apo E) according to the CLSI EP28-A3 guideline in healthy Chinese Han adults. METHODS: Serum Apo E values of 1,206 healthy adults (from 19 to 87 years old) were measured by immunoturbidimetry. The relationship between Apo E and age was analyzed by using Spearman's correlation. The differences between the gender and age groups were compared using Mann-Whitney U test/Kruskal-Wallis H test. We calculated recommended nonparametric Q2.5 and Q97.5 percentile intervals and the 90% confidence intervals (CI) of lower and upper limits to define the age- and gender- related RIs. RESULTS: The level of Apo E was higher in females than males. Apo E was significantly associated with aging in adult females (r = 0.108, p < 0.05), but not in males (p = 0.518). The RIs of Apo E for females were 0.0268 - 0.0619, 0.0247 - 0.0603, and 0.0269 - 0.0658 g/L for 18 - 29, 30 - 59, and ≥ 60 years old, respectively, that for males was 0.0242 - 0.0579 g/L. CONCLUSIONS: Our results established the age- and gender-specific RIs of serum Apo E in healthy Chinese Han adults in our laboratory.

Association between Serum Ferritin Level and Nonalcoholic Fatty Liver Disease in a Non-Obese Chinese Population: a Cross-Sectional Study.

BACKGROUND: The aim of the study is to evaluate the cross-sectional association between serum ferritin level and nonalcoholic fatty liver disease (NAFLD) in a non-obese Chinese population. METHODS: A cross-sectional study was performed among 1,020 non-obese subjects (body mass index < 25 kg/m2) who took their annual health examination at the First Affiliated Hospital, College of Medicine, Zhejiang University. Serum ferritin level and other clinical and laboratory parameters were measured in the population. Liver ultrasound examinations were performed to diagnose NAFLD. RESULTS: Of the 1,020 enrolled participants, 148 (14.51%) fulfilled the diagnostic criteria for NAFLD. Subjects with NAFLD had a higher level of serum ferritin than individuals without NAFLD in non-obese subjects. Serum ferritin level was significantly and positively correlated with parameters of MS (BMI, SBP, TG and FPG) in NAFLD group. Stepwise logistic regression analysis showed that serum ferritin level was significantly associated with the risk factor for NAFLD. After adjusting for confounders, serum ferritin level was an independent factor predicting advanced fibrosis (FIB-4 ≥ 1.3) in NAFLD participants. CONCLUSIONS: Increased serum ferritin level is significantly associated with NAFLD, and elevated serum ferritin level is an independent factor predicting advanced fibrosis for NAFLD in a non-obese Chinese population.

Association Between Serum Free Fatty Acids Levels and Gestational Diabetes Mellitus: a Cross-Sectional Study.

BACKGROUND: This study aimed to assess the relationship between serum free fatty acid (FFA) levels and gestational diabetes mellitus (GDM) in Chinese pregnant women. METHODS: A cross-sectional study was performed among 779 eligible pregnant women who underwent detailed prenatal visits in Hangzhou, China. RESULTS: Patients with GDM had significantly higher serum FFA levels than those without GDM. Spearman's correlation analysis showed that FFA levels were positively correlated with fasting plasma glucose, 1hPG, 2hPG, HOMA-IR, triglyceride, and sialic acid (p < 0.05) and negatively correlated with serum amylase level (all with p < 0.05). Stepwise logistic regression analysis further showed that elevated FFA levels significantly contributed to the risk for GDM. CONCLUSIONS: Our findings suggested that serum FFA levels were significantly associated with GDM.

Effect of the drainage of cerebrospinal fluid in patients with aneurismal subarachnoid hemorrhage: A meta-analysis.

BACKGROUND AND OBJECTIVES: Vasospasm-related injury such as delayed ischemic neurological defect (DIND) or cerebral infarction is an important prognostic factor for aneurismal subarachnoid hemorrhage (SAH). Whether cerebrospinal fluid (CSF) drainage can achieve a better outcome in aneurismal SAH patients after coiling or clipping remains the subject of debate. Here, we report a meta-analysis of the related available literature to assess the effect of continuous CSF drainage on clinical outcomes in patients with aneurismal SAH. METHODS: Case-control studies regarding the association between aneurismal SAH and CSF drainage were systematically identified through online databases (PubMed, Web of Science, Elsevier Science Direct, and Springer Link). Inclusion and exclusion criteria were defined for the eligible studies. The fixed-effects model was performed when homogeneity was indicated. Alternatively, the random-effects model was utilized. RESULTS: This meta-analysis included 11 studies. Continuous CSF drainage obviously improved patients' long-term outcome (odds ratio [OR] of 2.86, 95% confidence interval [CI], 1.37-5.98, P < 0.01). CSF drainage also reduced angiographic vasospasm (OR of 0.35, 95% CI, 0.23-0.51, P < 0.01), symptomatic vasospasm (OR of 0.32, 95% CI, 0.32-0.43, P < 0.01), and DIND (OR of 0.48, 95% CI, 0.25-0.91, P = 0.03), but there was no significant difference between the CSF drainage group and the no CSF drainage group on shunt-dependent hydrocephalus (SDHC) prevention (OR of 1.04, 95% CI, 0.52-2.07, P = 0.91). Further analysis on lumbar drainage (LD) and external ventricular drainage (EVD) indicated that LD had a better outcome (OR of 3.11, 95% CI, 1.18-8.23, P = 0.02), whereas no significant difference in vasospasm-related injury was detected between the groups (OR of 1.13, 95% CI, 0.54-2.37, P = 0.75). CONCLUSION: Continuous CSF drainage is an effective treatment for aneurismal SAH patients; lumbar drainage showed lower complications, but more well-designed studies are required to verify and consolidate this conclusion.

Progesterone alleviates acute brain injury via reducing apoptosis and oxidative stress in a rat experimental subarachnoid hemorrhage model.

This study aimed to investigate the therapeutic effect of progesterone on acute brain injury after subarachnoid hemorrhage (SAH). Subarachnoid hemorrhage was induced in male Sprague-Dawley rats (n=72) by endovascular perforation. Progesterone (8 mg/kg or 16 mg/kg) was administered to rats at 1, 6, and 12h after SAH. Mortality, neurologic deficits, cell apoptosis, expression of apoptotic markers, the level of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) were assayed at 24h after experimental SAH. Mortality, cell apoptosis and the expression of caspase-3 were decreased, and improved neurological function was observed in the progesterone-treated SAH rats. Further, exploration demonstrated that progesterone significantly reduced the ratio of Bax/Bcl-2 and attenuated the release of cytochrome c from mitochondria. Progesterone also induced anti-oxidative effects by elevating the activity of SOD and decreasing MDA content after SAH. Furthermore, dose-response relationships for progesterone treatment were observed, and high doses of progesterone enhanced the neuroprotective effects. Progesterone treatment could alleviate acute brain injury after SAH by inhibiting cell apoptosis and decreasing damage due to oxidative stress. The mechanism involved in the anti-apoptotic effect was related to the mitochondrial pathway. These results indicate that progesterone possesses the potential to be a novel therapeutic agent for the treatment of acute brain injury after SAH.

Effects on quinolone resistance due to the biofilm formation activity in Ureaplasma urealyticum.

BACKGROUND/AIM: To detect the effects on quinolone resistance due to biofilm formation activity in Ureaplasma urealyticum. MATERIALS AND METHODS: An improved checkerboard dilution susceptibility test was used to analyze the quinolone resistance of clinical Ureaplasma isolates and a postbiofilm formation susceptibility assay was used to compare the effects on the quinolone susceptibility between pre- and postbiofilm formations. Several important functional gene expressions were detected to evaluate their roles in the process of the quinolone resistance mechanism. RESULTS: The quinolone-resistant isolates produced more biofilms than the sensitive isolates. In both the quinolone-resistant and -sensitive groups, the minimal inhibitory concentrations after biofilm formation were higher than those before biofilm formation. The expression of the metabolism-related gene ureC in postbiofilm formation was higher than those in prebiofilm formation. CONCLUSION: It seems that biofilm formation is quite important in the generation of quinolone resistance in Ureaplasma. It is very useful to detect biofilm formation activity as well as to analyze other laboratory parameters for Ureaplasma.

Norepinephrine potentiates proinflammatory responses of human vaginal epithelial cells.

The vaginal epithelium provides a barrier to pathogens and recruits immune defenses through the secretion of cytokines and chemokines. Several studies have shown that mucosal sites are innervated by norepinephrine-containing nerve fibers. Here we report that norepinephrine potentiates the proinflammatory response of human vaginal epithelial cells to products produced by Staphylococcus aureus, a pathogen that causes menstrual toxic shock syndrome. The cells exhibit immunoreactivity for catecholamine synthesis enzymes and the norepinephrine transporter. Moreover, the cells secrete norepinephrine and dopamine at low concentrations. These results indicate that norepinephrine may serve as an autocrine modulator of proinflammatory responses in the vaginal epithelium.