Whole blood cadmium levels and depressive symptoms in Chinese young adults: A prospective cohort study combing metabolomics.

OBJECTIVES: To investigate the association between Cd exposure and depressive symptoms in Chinese young adults. And to investigate the potential metabolic changes associated with high blood Cd concentrations. METHODS: We conducted a cohort study in 2019 and 2021. Blood Cd and depressive symptoms were collected during baseline and follow-up. The nine-item Patient Health Questionnaire (PHQ-9) scores were used to assess depressive symptoms. We used the generalized linear mixed model to estimate the association between blood Cd levels and depressive symptoms. A metabolomic and lipidomic analysis based on liquid chromatography-mass spectrometry was conducted on a total of 679 blood samples. The metabolomic data were analyzed using variance analysis and linear mixed effects models. RESULTS: Blood Cd concentrations were significantly associated with increased severity of depression symptoms [odds ratio (OR) 2.07, 95% confidence interval (CI) 1.04-4.11]. Metabolomics analysis found 93 metabolites with significant statistical differences between the lowest blood Cd level group and the highest Cd level group. Among the 93 differential metabolites, 17 were enriched in 7 differential metabolic pathways. CONCLUSIONS: Blood Cd was associated with increased severity of depression symptoms in Chinese young adults. Cd exposure may affect depressive symptoms by inducing oxidative stress, inflammation, and disrupting amino acid metabolism.

Effect of gastrodin against cognitive impairment and neurodegeneration in APP/PS1 mice via regulating gut microbiota-gut-brain axis.

Gastrodin (Gas) has exhibited protective activity in neurological disorders. Here, we investigated the neuroprotective effect and potential mechanisms of Gas against cognitive impairment via regulating gut microbiota. APPswe/PSEN1dE9 transgenic (APP/PS1) mice were treated intragastrically with Gas for 4 weeks, and then cognitive deficits, deposits of amyloid-ß (Aß) and phosphorylation of tau were analyzed. The expression levels of insulin-like growth factor-1 (IGF-1) pathway-related proteins, such as cAMP response element-binding protein (CREB), were detected. Meanwhile, gut microbiota composition was evaluated. Our results showed that Gas treatment significantly improved cognitive deficits and Aß deposition in APP/PS1 mice. Moreover, Gas treatment increased the level of Bcl-2 and decreased level of Bax and ultimately inhibited neuronal apoptosis. Gas treatment markedly increased the expression levels of IGF-1 and CREB in APP/PS1 mice. Moreover, Gas treatment improved abnormal composition and structure of gut microbiota in APP/PS1 mice. These findings revealed that Gas actively participated in regulating the IGF-1 pathway to inhibit neuronal apoptosis via the gut-brain axis and that it can be considered a new therapeutic strategy against Alzheimer's disease.

Microbiota-derived metabolite Indoles induced aryl hydrocarbon receptor activation and inhibited neuroinflammation in APP/PS1 mice.

Gut microbiota alterations might affect the development of Alzheimer's disease (AD) through microbiota-derived metabolites. For example, microbiota-derived Indoles via tryptophan metabolism prevented Aß accumulation and Tau hyperphosphorylation, restored synaptic plasticity, and then promoted the cognitive and behavioral ability of APP/PS1 mice. The imbalanced compositions of Indoles-producing bacteria with tryptophan deficiency were found in male APP/PS1 mice, but the molecular mechanisms remained unclear. Our current study revealed that Indoles (including indole, indole-3-acetic acid and indole-3-propionic acid) upregulated the production of aryl hydrocarbon receptor (AhR), inhibited the activation of the NF-κB signal pathway as well as the formation of the NLRP3 inflammasome, reduced the release of inflammatory cytokines, including TNF-α, IL-6, IL-1ß and IL-18, alleviating the inflammatory response of APP/PS1 mice. These findings demonstrated the roles of Indoles-producing bacteria in activating the AhR pathway to regulate neuroinflammation of AD through gut microbiota-derived Indoles, which implied a novel way for AD treatment.

Effect of Probiotic Fungi against Cognitive Impairment in Mice via Regulation of the Fungal Microbiota-Gut-Brain Axis.

The fungal microbiota may be involved in the regulation of cognition and behavior, while the role of probiotic fungi against cognitive impairment is unclear. Here, we explored the idea that probiotic Saccharomyces boulardii could participate in the regulation of microglia-induced neuroinflammation in Alzheimer's disease (AD) model mice. Cognitive deficits, deposits of amyloid-ß (Aß) and phosphorylation of tau, synaptic plasticity, microglia activation, and neuroinflammatory reactions were observed. The expression levels of Toll-like receptors (TLRs) pathway-related proteins were detected. Meanwhile, intestinal barrier integrity and fungal microbiota composition were evaluated. Our results showed fungal microbiota dysbiosis in APP/PS1 mice, which might result in the neuroinflammation of AD. The increased levels of interleukin (IL)-6, IL-1ß, and cluster of differentiation 11b (CD11b) were observed in APP/PS1 mice, which were associated with activation of microglia, indicative of a broader recognition of neuroinflammation mediated by fungal microbiota compared to hitherto appreciated. Probiotic S. boulardii treatment improved dysbiosis, alleviated the neuroinflammation as well as synaptic injury, and ultimately improved cognitive impairment. Moreover, S. boulardii therapy could inhibit microglia activation and the TLRs pathway, which were reversed by antifungal treatment. These findings revealed that S. boulardii actively participated in regulating the TLRs pathway to inhibit the neuroinflammation via the gut-brain axis.

Effect of Coffee against MPTP-Induced Motor Deficits and Neurodegeneration in Mice Via Regulating Gut Microbiota.

The mechanisms of coffee against Parkinson disease (PD) remained incompletely elucidated. Numerous studies suggested that gut microbiota played a crucial role in the pathogenesis of PD. Here, we explored the further mechanisms of coffee against PD via regulating gut microbiota. C57BL/6 mice were intraperitoneally injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce a PD mouse model, then treated with coffee for 4 consecutive weeks. Behavioral tests consisting of the pole test and beam-walking test were conducted to evaluate the motor function of mice. The levels of tyrosine hydroxylase (TH) and α-synuclein (α-syn) were assessed for dopaminergic neuronal loss. The levels of occludin, glial fibrillary acidic protein (GFAP), Bcl-2, Bax, cleaved caspase-3, and cytochrome c (Cyt c) were detected. Moreover, microbial components were measured by 16s rRNA sequencing. Our results showed that coffee significantly improved the motor deficits and TH neuron loss, and reduced the level of α-syn in the MPTP-induced mice. Moreover, coffee increased the level of BBB tight junction protein occludin and reduced the level of astrocyte activation marker GFAP in the MPTP-induced mice. Furthermore, coffee significantly decreased the levels of proapoptotic proteins, including Bax, cleaved caspase-3, and cytochrome c, while it increased the level of antiapoptotic protein Bcl-2, consequently preventing MPTP-induced apoptotic cascade. Moreover, coffee improved MPTP-induced gut microbiota dysbiosis. These findings suggested that the neuroprotective effects of coffee on PD were involved in the regulation of gut microbiota, which might provide a novel option to elucidate the effects of coffee on PD.

Expression of PTEN-long nephritis and its effect on renal inflammation.

Based on the important functions of phosphatase and tensin homolog (PTEN)-Long for renal diseases, the present study aimed to investigate the expression of PTEN-Long in patients and mice with nephritis and its effect on nephritis. Expression levels of PTEN-Long in serum of patients with nephritis, renal cell carcinoma (RCC) as well as normal controls, and in serum and renal tissues of mice were measured by western blotting. PTEN-Long knock-in and knock-out mice were constructed via the CRISPR-Cas9 technique. Intraperitoneal injection of lipopolysaccharide+renal homogenate was performed to construct a mouse nephritis model. Mice were divided into control group, model group, knock-in group and knock-out group. A Bio-Plex system was used to detect secretion of serum inflammatory factors. Expression of inflammatory factors in renal tissues of different groups was detected by reverse transcription semi-quantitative polymerase chain reaction. Hematoxylin and eosin staining was used to observe the pathological changes of renal tissue. PTEN-Long was downregulated in patients with nephritis and RCC compared with controls, whereas the expression levels of inflammatory factors were increased. PTEN-long knock-in significantly reduced the serum content and expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1ß and IL-18. PTEN-long knock-out also decreased the expression levels of TNF-α and IL-6 but exhibited no effects on expression of IL-1ß and IL-18. Compared with knock-out and model groups, renal tissue inflammation was significantly reduced in knock-in group. The protein level of PTEN-Long was significantly lower in serum than in renal tissue. These findings suggest that PTEN-long can inhibit the progression of nephritis by interacting with inflammatory factors to protect kidney.

[Distribution of traditional Chinese medicine syndrome types of male infertility in Chengdu area].

OBJECTIVE: To explore the distribution characteristics of the traditional Chinese medicine (TCM) syndrome types of male infertility in Chengdu area, China, in order to provide some objective evidence for the clinical treatment and studies of male infertility. METHODS: We collected the clinical data on 500 cases of male infertility treated in the outpatient and inpatient departments of the Affiliated Hospital of Chengdu University of Chinese Medicine and Chengdu Hospital for Reproduction, Women and Children from January to December 2017. Based on the results of examinations using the four diagnostic methods of TCM, namely, observation, auscultation and olfaction, interrogation, and palpation, we differentiated the TCM syndromes of the patients and analyzed the distribution characteristics of the syndrome types. RESULTS: Analysis of the baseline characteristics and the results of Chi-square test showed statistically significant differences in the distribution of the frequency of sexual intercourse, body mass index, history of urinary tract infection, testis volume, testicular texture, vas deferens and varicocele among the 500 patients (P < 0.05). As for the distribution of the TCM syndrome types, 115 cases (23.0%) were diagnosed with the unlicensed discernible type of syndrome, 109 (21.8%) with kidney-yang deficiency, 36 (7.2%) with kidney-essence deficiency, 30 (6.0%) with both kidney-yang deficiency and liver-qi stagnation, 30 (6.0%) with both kidney-yang deficiency and spleen-asthenia with excessive dampness, 28 (5.6%) with kidney-yin deficiency, 20 (4.0%) with spleen-asthenia and excessive dampness, 19 (3.8%) with liver-qi stagnation, 19 (3.8%) with phlegm dampness obstruction, 19 (3.8%) with kidney-yang and kidney-essence deficiency, 16 (3.2%) with downward damp-heat, 11 (2.2%) with both kidney-yin and kidney-yang deficiency, 10 (2.0%) with qi-stagnation and blood stasis, and 38 (7.6%) with other types of syndromes. CONCLUSIONS: The main TCM syndrome types of male infertility in Chengdu area include kidney-yang deficiency, kidney-yang deficiency with liver-qi stagnation, and kidney-yang deficiency with spleen-asthenia and excessive dampness. The distribution and influencing factors of the syndrome types need to be further explored and clarified by more large-sample and high-quality studies.

Platelet desialylation is a novel mechanism and a therapeutic target in thrombocytopenia during sepsis: an open-label, multicenter, randomized controlled trial.

BACKGROUND: Studies in murine models suggested that platelet desialylation was an important mechanism of thrombocytopenia during sepsis. METHODS: First, we performed a prospective, multicenter, observational study that enrolled septic patients with or without thrombocytopenia to determine the association between platelet desialylation and thrombocytopenia in patients with sepsis, severe sepsis, and septic shock. Gender- and age-matched healthy adults were selected as normal controls in analysis of the platelet desialylation levels (study I). Next, we conducted an open-label randomized controlled trial (RCT) in which the patients who had severe sepsis with thrombocytopenia (platelet counts ≤50 × 109/L) were randomly assigned to receive antimicrobial therapy alone (control group) or antimicrobial therapy plus oseltamivir (oseltamivir group) in a 1:1 ratio (study II). The primary outcomes were platelet desialylation level at study entry, overall platelet response rate within 14 days post-randomization, and all-cause mortality within 28 days post-randomization. Secondary outcomes included platelet recovery time, the occurrence of bleeding events, and the amount of platelets transfused within 14 days post-randomization. RESULTS: The platelet desialylation levels increased significantly in the 127 septic patients with thrombocytopenia compared to the 134 patients without thrombocytopenia. A platelet response was achieved in 45 of the 54 patients in the oseltamivir group (83.3%) compared with 34 of the 52 patients in the control group (65.4%; P = 0.045). The median platelet recovery time was 5 days (interquartile range 4-6) in the oseltamivir group compared with 7 days (interquartile range 5-10) in the control group (P = 0.003). The amount of platelets transfused decreased significantly in the oseltamivir group compared to the control group (P = 0.044). There was no difference in the overall 28-day mortality regardless of whether oseltamivir was used. The Sequential Organ Failure Assessment score and platelet recovery time were independent indicators of oseltamivir therapy. The main reason for all of the mortalities was multiple-organ failure. CONCLUSIONS: Thrombocytopenia was associated with increased platelet desialylation in septic patients. The addition of oseltamivir could significantly increase the platelet response rate, shorten platelet recovery time, and reduce platelet transfusion. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-IPR-16008542 .

Assessment of acute lung injury/acute respiratory distress syndrome using B-type brain natriuretic peptide.

OBJECTIVES: To investigate the clinical value of B-type natriuretic peptide (BNP) in the assessment of severity and prognosis in acute lung injury/acute respiratory distress syndrome (ALI/ARDS). METHODS: Plasma BNP level, arterial blood gases, serum C-reactive protein level, alveolar-arterial oxygen tension difference and oxygenation index were measured in patients with and without ALI/ARDS within 24 h of admission to an intensive care unit. Patients with ALI/ARDS were divided into mild, moderate or severe groups according to the degree of hypoxaemia. Survival >28 days was recorded. RESULTS: A total of 59 patients with ALI/ARDS and 14 patients without ALI/ARDS were included in the study. Of the patients with ALI/ARDS, 18 had mild hypoxaemia, 20 had moderate hypoxaemia and 21 had severe hypoxaemia. The mean ± SD BNP level was significantly higher in all three ALI/ARDS groups (92.41 ± 28.19 pg/ml, 170.64 ± 57.34 pg/ml and 239.06 ± 59.62 pg/ml, respectively, in the mild, moderate and severe groups) than in the non-ALI/ARDS group (47.27 ± 19.63 pg/ml); the increase in BNP level with increasing severity was also statistically significant. When divided according to outcome, the BNP level in the death group (267.07 ± 45.06 pg/ml) was significantly higher than in the survival group (128.99 ± 45.42 pg/ml). CONCLUSIONS: The BNP level may be of value in evaluating severity and prognosis in patients with ALI/ARDS.

Relevance and therapeutic possibility of PTEN-long in renal cell carcinoma.

PTEN-Long is a translational variant of PTEN (Phosphatase and Tensin Homolog). Like PTEN, PTEN-Long is able to antagonize the PI3K-Akt pathway and inhibits tumor growth. In this study, we investigated the role PTEN-Long plays in the development and progression of clear cell renal cell carcinoma (ccRCC) and explored the therapeutic possibility using proteinaceous PTEN-Long to treat ccRCC. We found that the protein levels of PTEN-Long were drastically reduced in ccRCC, which was correlated with increased levels of phosphorylated Akt (pAkt). Gain of function experiments showed overexpression of PTEN-Long in the ccRCC cell line 786-0 suppressed PI3K-Akt signaling, inhibited cell proliferation, migration and invasion, and eventually induced cell death. When purified PTEN-Long was added into cultured 786-0 cells, it entered cells, blocked Akt activation, and induced apoptosis involving Caspase 3 cleavage. Furthermore, PTEN-Long inhibited proliferation of 786-0 cells in xenograft mouse model. Our results implicated that understanding the roles of PTEN-Long in renal cell carcinogenesis has therapeutic significance.

Laparoscopic partial nephrectomy for T1a renal tumors is safe and feasible.

BACKGROUND: Some patients with exophytic renal masses less than 4 cm and suboptimal renal function, or a solitary kidney and bilateral renal tumors are considered for laparoscopic partial nephrectomy (LPN), which is feasible for early-stage renal tumors, although it is still considered technically difficult and time consuming. Shortening the time of the operation and renal warm ischemia are required urgently. In this study, we report our initial experiences of LPN, especially with some improved surgical techniques. METHODS: Between July 2005 and October 2009, 74 patients with T(1a) renal tumor were treated by LPN, 39 using transperitoneal approach and 35 using retroperitoneal approach. In all cases, the tumor was removed with a margin of 0.5 cm. We compared glomerular filtration rate (GFR) preoperatively and postoperatively, and renal warm ischemia time between traditional ligature and Hem-o-lok methods. RESULTS: All operations were completed successfully, and there was no conversion to open surgery. Mean operation time was 76 minutes (range, 68 - 120), mean time of renal warm ischemia was 23 minutes (range, 15 - 32), and mean blood loss was 65 ml (range, 40 - 300). No hemorrhage or urine leak was observed in two cases with the collecting system sewn. Thirteen cases used Hem-o-lok to clamp the suture instead of traditional ligature, and mean time of renal warm ischemia was (16.5 ± 2.3) minutes (range, 12 - 18). Mean postoperative hospital stay was 6.3 days (range, 5 - 12). Sixty-seven cases had renal clear cell carcinoma, six papillary renal cell carcinoma, and one renal collecting duct carcinoma. All the tumor margin specimens were negative. The mean follow-up was 30.6 months (range, 3 - 51), and no recurrence or metastasis was observed. CONCLUSIONS: LPN for pT(1) stage renal tumor was safe and feasible. Hem-o-lok instead of traditional ligature to clamp the suture when sewing the renal wound could shorten the warm ischemia time.