Click Reaction-Mediated Fluorescent Immunosensor Based on Cu-MOF Nanoparticles for Ultrasensitive and High-Throughput Detection of Aflatoxin B1 in Food Samples.

Due to the high toxicity of aflatoxin B1 and its risks to human health, we developed a click reaction-mediated automated fluorescent immunosensor (CAFI) for sensitive detection of aflatoxin B1 based on the Cu(I)-catalyzed click reaction. With its large specific surface area, a copper-based metal-organic framework (Cu-MOF) was synthesized to adsorb and enrich the copper ion (Cu(II)) and then load the complete antigen (BSA-AFB1). After the immunoreaction, Cu(II) inside the Cu-MOF-Antigen conjugate would be reduced to Cu(I) in the presence of sodium ascorbate, which triggered the click reaction between the fluorescent donor-modified DNA and the receptor-modified complementary DNA to lead to a fluorescence signal readout. The whole reaction steps were finished by the self-developed automated immunoreaction device. This CAFI method showed a limit of detection (LOD) of 0.48 pg/mL as well as a 670-fold enhancement in sensitivity compared to conventional ELISA, revealing its great potential in practical applications and automated detection.

Acupuncture alleviates CUMS-induced depression-like behaviors of rats by regulating oxidative stress, neuroinflammation and ferroptosis.

BACKGROUND: The treatment of depression with acupuncture has been documented. The mechanism behind acupuncture's curative and preventative effects is still unknown. METHODS: The current study examined the effects of acupuncture on depression-like behaviors in a rat model of chronic unpredictable mild stress (CUMS), while also exploring its potential mechanisms. A total of six groups of rats were randomly assigned: control, CUMS, acupuncture, fluoxetine, acupoint catgut embedding and sham acupoint catgut embedding. Fluoxetine (2.1 mg/kg) and acupoint catgut embedding were used for comparative research to acupuncture. The modelling evaluation is measured by body weight and behavior tests. Western blotting and reverse transcription-polymerase chain reaction were used to detect the proteins and mRNA expression of Silent information regulator 1 (Sirt1)/ nuclear factor-erythroid 2-related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1)/ Glutathione peroxidase 4 (GPX4) pathway in the hippocampus. The expression of oxidative stress (OS)-related proteins and inflammatory cytokines in the serum was detected with ELISA. Immunofluorescence showed microglia and astrocytes activity in the hippocampus. RESULTS: Acupuncture and fluoxetine could alleviate CUMS-induced depression-like behaviors. Acupuncture was also found to effectively reverse the levels of MDA, SOD, GSH, GSH-PX and T-AOC, IL-1ß, IL-6 and TNF-α in the serum of CUMS-induced rats. Rats with CUMS showed decreased levels of Sirt1, Nrf2, HO-1 and GPX4 in the hippocampus, while acupuncture treatment could partly reverse the diminished effects. In addition, acupuncture treatment significantly reduced the activation of hippocampal microglia and astrocytes in CUMS-induced rats. CONCLUSION: The study's findings indicate that acupuncture has the potential to mitigate depression-like behaviors in rats induced with CUMS by mitigating OS and reducing neuroinflammation.

Electroacupuncture ameliorates chronic unpredictable mild stress-induced depression-like behavior and cognitive impairment through suppressing oxidative stress and neuroinflammation in rats.

BACKGROUND: Depression is associated with lowered mood, anxiety, anhedonia, cognitive impairments, and even suicidal tendencies in severe cases. Yet few studies have directed acupuncture's mechanism toward enhancing axonal repair correlated with synaptic plasticity and anti-inflammatory effects related to oxidative stress in the hippocampus. METHODS: Male Sprague-Dawley (SD) rats were randomly divided into control group (CON), chronic unpredictable mild stress (CUMS) group, CUMS + electroacupuncture group (EA), and CUMS + fluoxetine group (FLX) (n = 10/group). Rats were given a 28-day treatment at the Shangxing (GV23) and Fengfu (GV16) acupoints with electroacupuncture or fluoxetine (2.1 mg/kg). RESULTS: Rats exposed to CUMS induced depression-like behaviors and spatial learning-memory impairment, changed the ionized calcium binding adaptor molecule 1 (IBA-1), Vglut1, myelin basic protein (MBP), and postsynaptic density protein 95 (PSD95) level of hippocampal, increased the Nod-like receptor protein 3 (NLRP3), atypical squamous cell (ASC), Caspase level and hippocampal reactive oxygen species (ROS), and prompted the activation of Epha4-mediated signaling and an inflammatory response. Conversely, electroacupuncture administration reduced these changes and prevented depression-like behaviors and cognitive impairment. Electroacupuncture also promoted hippocampal expression of Sirtuin1(SIRT1), Nuclear factor erythroid 2-like (Nrf2), Heme oxygenase-1 (HO-1); reduced the expression of interleukin-1ß (IL-1ß), interleukin-18 (IL-18), and tumor necrosis factor-alpha (TNF-α); and prevented neural damage, particularly the synaptic myelin sheath, and neuroinflammation by regulating Eph receptor A4 (EphA4) in the hippocampal. CONCLUSION: These results indicate that electroacupuncture prevents depression-like behaviors with cognitive impairment and synaptic and neuronal damage, probably by reducing EphA4, which mediates ROS hyperfunction and the inflammatory response.

Effects of long-term cultivation on spatial-temporal variation of soil nitrogen and phosphorus: a case study in Shaanxi Province, China.

Investigating the spatial-temporal variation of soil nitrogen (N) and phosphorus (P) is essential to determine the balance between increased food production and environmental protection. In this study, a total of 705 soil samples were collected at depths of 0-20 cm in 2017 and analyzed for laboratory tests of soil N and P. The results showed that from the 1980s to 2017, the total nitrogen (TN), available nitrogen (AN), and available phosphorus (AP) contents of farmland soils in Shaanxi Province increased by 33%, 17%, and 199%, respectively, while the total phosphorus (TP) content decreased by 40%. The best-fit model for spatial interpolation of soil TP and AP in Shaanxi Province was the exponential model (R2 = 0.92 and 0.95); the Gaussian model was the best-fit model for spatial interpolation of soil TN and AN (R2 = 0.98 and 0.96). The spatial distribution characteristics of soil TN, AN, TP, and AP were consistent, all being higher in southern Shaanxi than in northern Shaanxi. The value of N:P* ratio (molar ratio) of cultivated soils in Shaanxi Province is 2.9, which is lower than the Chinese average (N:P* = 5.0). Based on the spatial-temporal variations of soil N and P contents between regions, it is recommended that fertilization should be strictly controlled in central and southern Shaanxi and optimized in northern Shaanxi to improve ground strength.

Ootheca mantidis mitigates renal fibrosis in mice by the suppression of apoptosis via increasing the gut microbe Akkermansia muciniphila and modulating glutamine metabolism.

Renal interstitial fibrosis (RIF), a progressive process affecting the kidneys in chronic kidney disease (CKD), currently lacks an effective therapeutic intervention. Traditional Chinese medicine (TCM) has shown promise in reducing RIF and slowing CKD progression. In this study, we demonstrated the dose-dependent attenuation of RIF by Ootheca mantidis (SPX), a commonly prescribed TCM for CKD, in a mouse model of unilateral ureteral obstruction (UUO). RNA-sequencing analysis suggested that SPX treatment prominently downregulated apoptosis and inflammation-associated pathways, thereby inhibiting the fibrogenic signaling in the kidney. We further found that transplantation of fecal microbiota from SPX-treated mice conferred protection against renal injury and fibrosis through suppressing apoptosis in UUO mice, indicating that SPX ameliorated RIF via remodeling the gut microbiota and reducing apoptosis in the kidneys. Further functional exploration of the gut microbiota combined with fecal metabolomics revealed increased levels of some probiotics, including Akkermansia muciniphila (A. muciniphila), and modulations in glutamine-related amino acid metabolism in UUO mice treated with SPX. Subsequent colonization of A. muciniphila and supplementation with glutamine effectively mitigated cell apoptosis and RIF in UUO mice. Collectively, these findings unveil a functionally A. muciniphila- and glutamine-involved gut-renal axis that contributes to the action of SPX, and provide important clue for the therapeutic potential of SPX, A. muciniphila, and glutamine in combatting RIF.

The effect of acupuncture on lateral habenular nucleus and intestinal microflora in depression model rats.

BACKGROUND: Depression is a severe emotional condition that significantly affects the quality of life. Acupuncture exerts preventive effects on depression in rats with post-chronic unpredictable mild stress (CUMS). Methods The study involved chronic unpredictable mild stress (CUMS) depression model mice to administer acupuncture as a preventative measure to investigate the mechanism of acupuncture's antidepressant and observe the effect of acupuncture on impact via the Lateral Habenula (LHb) and Gut-Liver-Brain Axis. The researcher investigated molecules correlating with a nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway and assessed inflammation in the LHb and liver. In addition, 16 S rDNA bioinformatics study revealed the quantity and variety of gut microbiota. Rats were randomly divided into five groups: control (CON), CUMS, CUMS + acupuncture (AP), CUMS + fluoxetine (FX) and CUMS + N(G) -nitro -L- arginine methyl ester (LNAME) group. Except for the CON group, other rats were exposed to CUMS condition for 28 days. Simultaneously, manual acupuncture (at Fengfu and Shangxing acupoints, once every other day) and fluoxetine gavage (2.1 mg/kg, 0.21 mg/mL, daily) were conducted to the groups of AP and FX, respectively, after stressors. Rats in LNAME group were treated with LNAME normal saline (10 mg/kg, 1 mg/mL, i.p.) solution. Behavioural tests and biological detection methods were conducted sequentially to evaluate depressionlike phenotype in rats. RESULTS: The results showed CUMS induced depression-like behaviours, hyper-activation of NO/cGMP signaling pathway, inflammation in serum, LHb and liver, and dysbiosis of the gut microbiota. These changes could be prevented and ameliorated by acupuncture to varying extents. CONCLUSION: Acupuncture prevented and attenuated depression-like phenotype induced by CUMS, possibly via regulating the NO/cGMP signaling pathway and thus improving inflammation in serum, LHb and liver, and gut microbiota dysbiosis. In addition, these can be evidence of the existence of the gut-liver-brain axis.

Acupuncture Alleviates CUMS-Induced Depression-Like Behaviors by Restoring Prefrontal Cortex Neuroplasticity.

Purpose: To explore the therapeutic efficiency of acupuncture and the related molecular mechanism of neural plasticity in depression. Methods: Chronic unpredictable mild stress- (CUMS-) induced rats were established for the depression animal model. There were a total of four rat groups, including the control group, the CUMS group, the CUMS+acupuncture group, and the CUMS+fluoxetine group. The acupuncture group and the fluoxetine group were given a 3-week treatment after the modeling intervention. The researcher performed the open-field, elevated plus maze, and sucrose preference tests to evaluate depressive behaviors. The number of nerve cells, dendrites' length, and the prefrontal cortex's spine density were detected using Golgi staining. The prefrontal cortex expression, such as BDNF, PSD95, SYN, and PKMZ protein, was detected using the western blot and RT-PCR. Results: Acupuncture could alleviate depressive-like behaviors and promote the recovery of the neural plasticity functions in the prefrontal cortex, showing the increasing cell numbers, prolonging the length of the dendrites, and enhancing the spine density. The neural plasticity-related proteins in the prefrontal cortex, including BDNF, PSD95, SYN, and PKMZ, were all downregulated in the CUMS-induced group; however, these effects could be partly reversed after being treated by acupuncture and fluoxetine (P < 0.05). Conclusion: Acupuncture can ameliorate depressive-like behaviors by promoting the recovery of neural plasticity functions and neural plasticity-related protein upregulation in the prefrontal cortex of CUMS-induced depressed rats. Our study provides new insights into the antidepressant approach, and further studies are warranted to elucidate the mechanisms of acupuncture involved in depression treatment.

The effects of acupuncture on depression by regulating BDNF-related balance via lateral habenular nucleus BDNF/TrkB/CREB signaling pathway in rats.

Depression is a major mental disease worldwide, causing dysfunction of Lateral Habenular (LHb). As a non-invasive alternative, acupuncture (AP) has been widely used to treat depression in clinic, yet few basic studies have been focused on the effects and mechanism of acupuncture on synaptic plasticity in LHb. Therefore, this study aimed to explore the potential mechanism of the antidepressant effect of acupuncture. Male Sprague-Dawley (SD) rats were randomly divided into control, chronic unpredictable mild stress (CUMS), AP, fluoxetine (FLX), acupoint catgut embedding (ACE), sham-ACE groups (n = 9/group). Rats were given a 28-day treatment at the Shangxing (GV23) and Fengfu (GV16) acupoints with acupuncture, ACE, sham-ACE or fluoxetine (2.1 mg/kg). The results showed that AP, FLX and ACE suppressed the behavioral deficits, increased the level of the 5-hydroxytryptamine and FNDC5/IRISIN in serum, also reduced the expression of pro-BDNF impacted by CUMS. Both AP and FLX ameliorated the %area of IBA-1, GFAP, BrdU and DCX in the LHb and increased the expression of BDNF/TrkB/CREB, with non-significant difference between the two groups These findings suggest that AP therapy relieves depression-related manifestations in depressed rats, suggesting a potential mechanism via the BDNF/TrkB/CREB pathway in LHb.

The Qi-Bang-Yi-Shen formula ameliorates renal dysfunction and fibrosis in rats with diabetic kidney disease via regulating PI3K/AKT, ERK and PPARγ signaling pathways.

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) and a growing public health problem worldwide. Losartan potassium (Los), an angiotensin II receptor blocker, has been used to treat DKD clinically. Recently, multi-herbal formula has been shown to exhibit therapeutic activities in DKD in China. Thus, we aimed to explore the protective effects of combination of Los and Qi-Bang-Yi-Shen formula (QBF) on DKD rats. Streptozotocin (STZ) injection was used to establish a rat model of DKD. Next, the bloodurea nitrogen (BUN), creatinine (CRE) and uric acid (UA) levels were detected in serum samples from DKD rats. Hematoxylin and eosin (H&E), periodic Acid Schiff (PAS) and Masson staining were performed to observe glomerular injury and glomerular fibrosis in DKD rats. In this study, we found that QBF or Los treatment could decrease serum BUN, CRE, UA levels and reduce urine albumin-to-creatinine ratio (ACR) in DKD rats. Additionally, QBF or Los treatment obviously inhibited glomerular mesangial expansion and glomerular fibrosis, attenuated glomerular injury in kidney tissues of DKD rats. Moreover, QBF or Los treatment significantly reduced PI3K, AKT and ERK1/2 protein expressions, but increased PPARγ level in kidney tissues of DKD rats. As expected, combined treatment of QBF and Los could exert enhanced reno-protective effects compared with the single treatment. Collectively, combination of QBF and Los could ameliorate renal injury and fibrosis in DKD rats via regulating PI3K/AKT, ERK and PPARγ signaling pathways. These findings highlight the therapeutic potential of QBF to prevent DKD progression.

Acupuncture exerts preventive effects in rats of chronic unpredictable mild stress: The involvement of inflammation in amygdala and brain-spleen axis.

BACKGROUND: Acupuncture has shown the preventive effects on depression in rats with chronic unpredictable mild stress (CUMS). However, the mechanisms of acupuncture for preventing depression still need to be explored. In the study, acupuncture was applied to a rat depression model of CUMS, high-mobility group box 1(HMGB1)/toll-like receptor 4 (TLR4) and brain-spleen axis were assessed. METHODS: Male Sprague Dawley (SD) rats were exposed to CUMS with two stressors per day for 28 days. In the meantime, manual acupuncture (at GV16 and GV23 acupoints, once every other day) and fluoxetine gavage (2.1 mg/kg, 0.21 mg/mL) were administered daily post CUMS stressors. Behavioral tests and biological detection methods were conducted in sequence to evaluate depression-like phenotypes in rats. RESULTS: The results showed CUMS induced depression-like behaviors, hyper-activation of HMGB1/TLR4 signaling pathway, elevated inflammation in amygdala and peripheral blood, and hyperactivation of hypothalamic-pituitary-adrenal (HPA) axis. These changes could be prevented and reversed by acupuncture to varying extents. CONCLUSION: Acupuncture prevented and ameliorated depression-like symptoms induced by CUMS, possibly via regulating inflammation through brain-spleen axis mediated by HMGB1/TLR4 signaling pathway and HPA axis regulation.

Shenqi granule upregulates CD2AP and α-actinin4 and activates autophagy through regulation of mTOR/ULK1 pathway in MPC5 cells.

ETHNOPHARMACOLOGICAL RELEVANCE: The incidence of membranous nephropathy (MN) continues to rise globally. Shenqi granule (SQ), composed of thirteen Chinese medicinal herbs, has clinical efficacy in the treatment of MN and has been used in China for decades. However, the mechanism behind this effect remains unclear. AIM OF THE STUDY: In this study, we documented the effects of SQ on cultured mouse podocytes (MPC5) cytoskeletal proteins (CD2AP, α-actinin4) and autophagic activity, and identified the mechanism underlying the ameliorating effects of SQ on MN. MATERIALS AND METHODS: The main components of SQ was analysed using High-performance liquid chromatography (HPLC). We induced MPC5 cells with puromycin aminonucleoside (PAN) as a model of MN-like disease. Cyclosporine A (CsA) was used as a positive control drug. MPC5 cells viability was analysed using CCK-8 assays to select the PAN dose and SQ dose. CD2AP and α-actinin4 mRNA expression was examined by RT-PCR, CD2AP and α-actinin4 protein expression as well as autophagic activity (LC3, Beclin1) was examined by Western blot in MPC5 cells, and the mechanism of action of SQ granule was assessed by Western blot to detect the protein expression at the phosphorylation level of PI3K/AKT/mTOR pathway. RESULTS: In PAN-induced MPC5 cells, mRNA and protein expression of α-actinin-4 and CD2AP were significantly reduced, and SQ granule was able to alleviate this manifestation. In contrast to the inhibition of LC3 and Beclin1 expression in the PAN model, SQ granule was able to activate cellular autophagic activity. In addition to this, our study revealed that PAN could activate the mTOR/ULK1 pathway, resulting in a significant increase in p-mTOR and p-ULK1 protein expression, while the SQ group was able to significantly inhibit the phosphorylation level of this pathway. CONCLUSIONS: SQ granule attenuated PAN-induced MPC5 cell damage similar to MN. The mechanism may be to upregulate the expression of α-actinin-4 and CD2AP and activate autophagy activity, which may be achieved by inhibiting the phosphorylation level of mTOR/ULK1.

Coming ecological risks of organochlorine pesticides and novel brominated flame retardants in the Yellow River Basin.

To conduct ecological risk assessment, food, water and soil samples were collected from five densely populated irrigation areas in the Yellow River Basin (YRB), and analyzed for organochlorine pesticides (OCPs) and novel brominated flame retardants (NBFRs). The results showed that the OCP residues (∑14OCP were 0.748 ng L-1, 13.1 ng g-1 dw and 3.22 ng g-1 dw in water, soil and maize) were generally within moderate levels in the YRB. Dichlorodiphenyltrichloroethane (DDT) residues dominated the OCPs, and potential ecological risks to aquatic and terrestrial organisms likely stemmed from dichlorodiphenyldichloroethylene (DDE) pollution in the upper reaches of the YRB in the Ningxia and Hetao Plain. The NBFR concentrations in the YRB were 90.9 pg L-1 in water, 21.1 pg g-1 dw in soil and 3.81 pg g-1 dw in maize. Positive correlations were observed between soil and maize contamination in the five irrigated districts, indicating a potential threat to grain security and human health risks caused by OCPs and NBFRs. Pollutants detected in soil and maize primarily originated from historical use (36.3 %), while the sources in water were more complex (64.4 %) and new inputs could not be excluded. Integrated health risks of human exposure to agricultural products and water from the YRB were acceptable. However, the ecological risk of the Ningxia Plain would further deteriorate to the medium risk after 2032. The increasing ecological risk of DDT in water indicates that regular monitoring should strengthen to ensure grain and water safety in the YRB.

Anti-depressant effects of acupuncture: The insights from NLRP3 mediated pyroptosis and inflammation.

The NLRP3-mediated pyroptosis, which could affect inflammation response, plays a key role in the development of depression. Acupuncture has been shown to be an effective treatment for depression. In this study, we aimed to determine whether acupuncture could confer antidepressant activity via decreasing NLRP3-mediated pyroptosis by reducing inflammation. Here, depression model of rats was induced by chronic unpredictable mild stress (CUMS) for 4 weeks. Acupuncture group was subjected to acupuncture at the Shangxing (GV23) and Fengfu (GV16) acupoints for 20 min every other day (a total of 14 times). Fluoxetine group was administered with fluoxetine (2.1 mg/kg with the concentration of 0.21 mg/mL) by oral gavage (1 mL/100 g) once a day for 28 days. Rats' depression-like phenotypes were reflected with behavioral tests and biological detection methods. Results showed that acupuncture significantly improved the depression-like behavior of CUMS rat, suppressed the expressions of NLRP3, ASC, caspase-1, GSDMD, IL-1ß, IL-18, HMGB1, IFN-γ, IL-6 and TNF-α in the serum and hippocampus, restored the %area of microglia, astrocytes and neuronal cells in the hippocampus. These indicate that acupuncture can prevent CUMS-induced depression-like behaviors by reducing NLRP3-mediated pyroptosis and inflammation.

Independent and Joint Associations of Tea Consumption and Smoking with Parkinson's Disease Risk in Chinese Adults.

BACKGROUND: Existing limited evidence suggests that smoking and tea consumption may be associated with a lower risk of Parkinson's disease (PD). However, less is known about the independent and joint roles of these two habits, which are often clustered among Chinese, on PD risk. OBJECTIVE: To prospectively examine the independent and joint association of tea consumption and smoking with the risk of PD. METHODS: The China Kadoorie Biobank (CKB) study recruited 512,725 participants aged 30 to 79 years from ten areas across China since 2004. Information on smoking and tea consumption was collected at baseline, and PD cases were ascertained by linkage to the national health insurance system and death registry. Cox proportional hazards models were used to estimate the multivariable-adjusted hazard ratios (HRs) and corresponding 95%confidence intervals (CIs). RESULTS: During a median of 10.8 years of follow-up, 922 PD cases were recorded. Compared with participants who never consumed tea, the HR (95%CI) for daily consumers was 0.68 (0.55, 0.84). Compared with participants who never or occasionally smoked, the HR (95%CI) for current smokers was 0.66 (0.53, 0.82). Those who had a clustering habit of smoking and tea consumption had a 38%(HR = 0.62; 95%CI: 0.49, 0.79) lower PD risk than those who consumed none. However, there were no statistically significant multiplicative or additive interaction for tea consumption and smoking on PD risk. CONCLUSION: We found that smoking and daily tea consumption were independently inversely associated with the risk of PD.

[Professor LU Fan's clinical experience in shallow needling technique of acupuncture].

Professor LU Fan adheres to the principle in clinical practice, "the needling principle concentrated on regulating qi ". She takes the advantages of shallow needling technique of acupuncture in treatment of various diseases, e.g. exogenous disease, initial onset of disorder, chronic bi disorder, intractable diseases, disorder of yang nature, disorder of heat nature, thin body, pediatric diseases, disorders on the unilateral side of the body and acute diseases. Besides in compliance with classics, she has broadened the application scope of shallow needling technique of acupuncture and improved the clinical therapeutic effect.

Removal of chlortetracycline from water using spent tea leaves-based biochar as adsorption-enhanced persulfate activator.

Antibiotic compounds have caused serious environmental concerns. In this study, we developed an effective technology for treatment of chlortetracycline (CTC), a widely used antibiotic compound. A natural heteroatom-doped spent tea leaves-based biochar (STLB) with excellent adsorption and catalytic property was prepared by simple thermal treatment. An adsorption-promoted persulfate-based advanced oxidation process (PS-AOP) using STLB was studied for CTC removal. The results showed that the as-prepared STLB presented favorable adsorption affinity towards CTC with the maximum adsorption capacity of 627 mg g-1. Meanwhile, CTC enriched on the surface of STLB was good for in-situ decomposition of CTC and nearly 97.4 % of CTC was removed within 30 min of pre-adsorption and 60 min of subsequent degradation. The STLB had excellent recyclability and wide pH tolerance range of 3.0-9.0 in combined pre-adsorption and PS-AOP. Reactive oxygen species analysis confirmed that CTC degradation was mainly due to non-radical (singlet oxygen, 1O2) and radicals (SO4- and OH). This study suggests that STLB is a promising adsorption-enhanced PS activator for the treatment of refractory wastewater and also provides a strategy of waste control by spent tea leaves.

Hospital management of major stroke types in Chinese adults: a population-based study of 20 000 hospitalised stroke cases.

OBJECTIVES: To compare hospital treatments for major stroke types in Chinese adults by stroke pathological types, sex, age, calendar year, hospital tier, region and other factors. DESIGN: Cross-sectional analysis of medical records retrieved from 20 229 stroke cases in the China Kadoorie Biobank. SETTING: Ten diverse areas (five urban, five rural) in China. PARTICIPANTS: First-incident stroke cases who were recruited during an 11-year follow-up of 0.5M participants in the China Kadoorie Biobank. METHODS: Electronic copies of medical records of stroke cases were retrieved for clinical adjudication by local neurologists. Stroke cases were classified as ischaemic stroke (IS) (including lacunar infarction (LACI) and non-LACI (non-LACI)), intracerebral haemorrhage (ICH), subarachnoid haemorrhage (SAH) and unspecified stroke types. RESULTS: Among 20 299 first-ever stroke cases, 17 306 (85%) had IS, 7123 had non-LACI, 6690 had LACI, 3493 had silent LACI, 2623 (13%) had ICH and 370 (2%) had SAH. Among IS cases, antiplatelet treatment was used by 64% (65% non-LACI, 66% LACI, 56% silent LACI), lipid-lowering by 50% (52% non-LACI, 53% LACI, 43% silent LACI) and blood pressure-lowering by ~42% of all IS types, with positive trends in the use of these treatments by calendar year and hospital tier. Among ICH cases, 53% used blood pressure-lowering and 10% used lipid-lowering treatments, respectively. In contrast, traditional Chinese medicines (TCMs) were used by 59% of IS (50% non-LACI, 62% LACI, 74% silent LACI), 38% of ICH and 30% of SAH cases, with positive trends by calendar year and by hospital tier. CONCLUSIONS: Among IS cases, use of antiplatelet and lipid-lowering medications increased in recent years, but use of TCM still exceeded use of blood pressure-lowering treatment. In contrast, blood pressure-lowering treatment was widely used for ICH, but only half of all ICH cases used blood pressure-lowering treatment.

Association between Reduced Serum Zinc and Diastolic Dysfunction in Maintenance Hemodialysis Patients.

Diastolic dysfunction is an emerging challenge among hemodialysis (HD) patients, and the associations between serum zinc with echocardiographic parameters and diastolic function remain uncertain. A total of 185 maintenance HD patients were stratified by the tertiles of serum zinc level to compare their clinical characteristics and echocardiography. Correlations of serum zinc levels with echocardiographic parameters were examined using Pearson's analysis. Univariate and multivariate logistic regression analyses were performed to investigate the determinants of E/e' ratio >15 and left atrial volume index (LAVI) > 34 mL/m2, both indicators of diastolic dysfunction. Patients belonging to the first tertile of serum zinc level had a significantly higher E/e' ratio and LAVI. Serum zinc levels were negatively correlated with E (r = -0.204, p = 0.005), E/e' ratio (r = -0.217, p = 0.003), and LAVI (r = -0.197, p = 0.007). In a multivariate analysis, older age, diabetes, coronary artery disease, and lower serum zinc levels (OR = 0.974, 95% CI = 0.950-0.999, p = 0.039) were significantly associated with E/e' ratio >15. Furthermore, diabetes and lower serum zinc levels (OR = 0.978, 95% CI = 0.958-0.999, p = 0.041) were significantly associated with LAVI >34 mL/m2. Reduced serum zinc level was significantly associated with diastolic dysfunction among HD patients. Further prospective studies are warranted to investigate whether zinc supplementation can attenuate cardiac dysfunction in maintenance HD patients.

Establishing and Validating Cellular Functional Target Engagement Assay for Selective IRAK4 Inhibitor Discovery.

One of the main reasons for the lack of drug efficacy in late-stage clinical trials is the lack of specific and selective target engagement. To increase the likelihood of success of new therapeutics, one approach is to conduct proximal target engagement testing during the early phases of preclinical drug discovery. To identify and optimize selective IRAK4 inhibitors, a kinase that has been implicated in multiple inflammatory and autoimmune diseases, we established an electrochemiluminescence (ECL)-based cellular endogenous IRAK1 activation assay as the most proximal functional evaluation of IRAK4 engagement to support structure-activity relationship (SAR) studies. Since IRAK1 activation is dependent on both the IRAK4 scaffolding function in Myddosome formation and IRAK4 kinase activity for signal transduction, this assay potentially captures inhibitors with different mechanisms of action. Data from this IRAK1 assay with compounds representing different structural classes showed statistically significant correlations when compared with results from both IRAK4 biochemical kinase activity and functional peripheral blood mononuclear cell (PBMC)-derived tumor necrosis factor α (TNFα) secretion assays, validating the biological relevancy of the IRAK1 target engagement as a biomarker of the IRAK4 activity. Plate uniformity and potency reproducibility evaluations demonstrated that this assay is amenable to high throughput. Using Bland-Altman assay agreement analysis, we demonstrated that incorporating such proximal pharmacological assessment of cellular target engagement to an in vitro screening funnel for SAR studies can prevent compound optimization toward off-target activity.