Correlations of Serum Retinol-Binding Protein and Stromal Cell-Derived Factor-1 with Renal Function in Patients with Diabetic Kidney Disease.

BACKGROUND: The aim is to investigate the correlations of serum retinol-binding protein (RBP) and stromal cell-derived factor-1 (SDF-1) with renal function in patients with diabetic kidney disease (DKD). METHODS: A total of 438 patients with type 2 diabetes mellitus (T2DM) treated from October 2017 to October 2020 were enrolled in this prospective study and divided into simple T2DM and DKD groups. According to urinary albumin-to-creatinine ratio (UACR), DKD patients were divided into moderate, severe, and nephrotic groups. They were assigned to one of the following categories of estimated glomerular filtration rate (eGFR): G1, G2, G3a, G3b, G4, and G5 stages. The correlations of RBP and SDF-1 with renal function were analyzed. RESULTS: The DKD group had a longer T2DM course and higher RBP, uric acid (UA), blood urea nitrogen (BUN), ß2-microglobulin (ß2-MG), serum creatinine (Scr) levels and UACR, and lower SDF-1 level and eGFR than those of simple T2DM group (p < 0.05). The areas under the receiver operating characteristic curves of RBP and SDF-1 for identifying DKD were 0.903 and 0.868, and the optimal cutoff values were 70.71 mg/L and 5.69 ng/mL, respectively. With increasing urinary albumin and clinical stage, RBP, UA, BUN, ß2-MG and Scr levels and UACR significantly rose, while SDF-1 level and eGFR declined (p < 0.05). In patients with DKD, RBP was correlated positively with UACR, UA, BUN, ß2-MG, and Scr (r = 0.764/0.787/0.693/0.577/0.801, p < 0.0001), and negatively with eGFR (r = -0.782, p < 0.0001). SDF-1 was correlated negatively with UACR, UA, BUN, ß2-MG and Scr (r = -0.744/-0.794/-0.666/-0.605/-0.820, p < 0.0001), and positively with eGFR (r = 0.767, p < 0.0001). The multiple linear regression equation was RBP = 29.852 + 0.007 x UACR + 0.101 x UA + 0.497 x BUN + 0.034 x Scr-0.083 x eGFR (p < 0.001). CONCLUSIONS: RBP and SDF-1 can identify DKD in patients with T2DM, and the degree of renal function damage is correlated positively with RBP and negatively with SDF-1. Elevated levels of UA, BUN, Scr and UACR as well as reduced eGFR are risk factors for evaluating RBP.

Analysis of the Rolling Interface Contact Characteristics in Mixed Lubrication Based on Gaussian Distribution Theory.

To reveal the influence of surface morphology characteristics in mixed lubrication on the contact characteristics of the rolling interface, a random three-dimensional rough surface model based on Gaussian distribution theory was established. The model utilizes the finite element method (FEM) to simulate the regular contact and tangential sliding behavior of micro-asperities at the rolling interface in mixed lubrication conditions. The connection bearing capacity of models with varied roughness in mixed lubrication was studied. Furthermore, the effect of various sliding and normal indentation amounts on the normal and friction stress was investigated. The simulation result reveals that the roughness of the surface influences the distribution of the lubricating oil film. The lubricating oil layer between the interfaces with a lower roughness has a higher bearing capacity due to its more uniform distribution of peaks and valleys. An increase in the normal indentation amount raises the friction stress and normal stress. In contrast, an increase in sliding lowers the normal pressure, substantially impacting the fluctuation of the friction coefficient dramatically. Finally, the random three-dimensional rough surface model is verified by comparing it with the experimental data in the related literature.

Combination of Chinese herbal medicine and conventional western medicine for coronavirus disease 2019: a systematic review and meta-analysis.

Objective: This study aimed to assess the efficacy and safety of Chinese herbal medicine (CHM) plus conventional western medicine (CWM) in comparison with CWM against COVID-19. Methods: We searched eight electronic databases and three trial registers spanning from January 1, 2020 to May 18, 2023. We included randomized controlled trials (RCTs) comparing the effectiveness and safety of CHM plus CWM and CWM against COVID-19 in our study. The Cochrane Risk of Bias tool 2.0 (RoB2) was applied to evaluate the methodological quality of the included RCTs. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system was employed to assess the certainty of evidence. Statistical analysis was implemented in R version 4.1.2. Results: Our study included 50 RCTs involving 11,624 patients. In comparison with sole CWM, CHM plus CWM against COVID-19 significantly enhanced clinical effective rate (RR = 1.18, 95% CI [1.13, 1.22]), improved chest image (RR = 1.19, 95% CI [1.11, 1.28]), inhibited clinical deterioration (RR = 0.45, 95% CI [0.33, 0.60]), lowered mortality (RR = 0.53, 95% CI [0.40, 0.70]), and reduced the total score of TCM syndrome (SMD = -1.24, 95% CI [-1.82, -0.66]). SARS-CoV-2 nucleic acid conversion time (MD = -2.66, 95% CI [-3.88, -1.44]), duration of hospitalization (MD = -2.36, 95% CI [-3.89, -0.82]), and clinical symptom (fever, cough, fatigue, and shortness of breath) recovery times were shorter in CHM plus CWM groups than in CWM groups. Further, CHM plus CWM treatment was more conducive for some laboratory indicators returning to normal levels. No statistical difference was found in the incidence of total adverse reactions between the two groups (RR = 0.97, 95% CI [0.88, 1.07]). We assessed the risk of bias for 246 outcomes, and categorized 55 into "low risk", 151 into "some concerns", and 40 into "high risk". Overall, the certainty of the evidence ranged from moderate to very low. Conclusions: Potentially, CHM listed in this study, as an adjunctive therapy, combining with CWM is an effective and safe therapy mode for COVID-19. However, more high-quality RCTs are needed to draw more accurate conclusions. Clinical trial registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=293963.

Enhanced Microcystis Aeruginosa removal and novel flocculation mechanisms using a novel continuous co-coagulation flotation (CCF).

Co-coagulation flotation (CCF) is a novel flotation technology that renders more efficient algal removal compared to traditional mechanical coagulation flotation (MCF) due to a short residence time (< 30 s) and fast rising behavior of algal flocs (> 250 m·h-1). This study compared the algal removal performance using continuous CCF and MCF using water samples taken from Lake Dianchi with severe Microcystis aeruginosa blooms. Removal efficiency, dosage of coagulant/flocculant, rising velocity and structural characteristics of the resulting flocs in the two processes were systematically compared. The results show that CCF could save >50 % polyaluminum chloride (PAC) and polyacrylamide (PAM) compared with MCF when the removal efficiency was both over 95 %. The average rising velocity of flocs in CCF could reach 254.3 m·h-1, much higher than that in MCF (154.5 m·h-1). In the respective optimal coagulation conditions, the flocs formed in CCF (G = 164.8 s-1) were larger (1843 ± 128 µm) and more spherical with a higher fractal dimension (Df = 1.85 ± 0.01) than those generated in MCF (G = 34.1 s-1). The Stokes's Law was found to correctly predict the rising velocity of spherical flocs with large fractal dimensions (Df > 1.7). In contrast, the Haarhoff and Edzwald's extended equation was more suitable for calculating the rising velocity of irregular flocs with small fractal dimension. This study provides new insights into the mechanisms of the enhanced algal removal by CCF and lays foundation for developing cost-efficient algal mitigation processes.

Anti-Inflammatory Anthranilate Analogue Enhances Autophagy through mTOR and Promotes ER-Turnover through TEX264 during Alzheimer-Associated Neuroinflammation.

Autophagy degrades impaired organelles and toxic proteins to maintain cellular homeostasis. Dysregulated autophagy is a pathogenic participant in Alzheimer's disease (AD) progression. In early-stage AD, autophagy is beneficially initiated by mild endoplasmic reticulum (ER) stress to alleviate cellular damage and inflammation. However, chronic overproduction of toxic Aß oligomers eventually causes Ca2+ dysregulation in the ER, subsequently elevating ER-stress and impairing autophagy. Our previous work showed that a novel anthranilate analogue (SI-W052) inhibited lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α and interleukin (IL)-6 on microglia. To investigate its mechanism of action, herein, we postulate that SI-W052 exhibits anti-inflammatory activity through ER-stress-mediated autophagy. We initially demonstrate that autophagy inhibits inflammation, but it becomes impaired during acute inflammation. SI-W052 significantly induces the conversion ratio of LC3 II/I and inhibits LPS-upregulated p-mTOR, thereby restoring impaired autophagy to modulate inflammation. Our signaling study further indicates that SI-W052 inhibits the upregulation of ER-stress marker genes, including Atf4 and sXbp1/tXbp1, explaining compound activity against IL-6. This evidence encouraged us to evaluate ER-stress-triggered ER-phagy using TEX264. ER-phagy mediates ER-turnover by the degradation of ER fragments to maintain homeostasis. TEX264 is an important ER-phagy receptor involved in ATF4-mediated ER-phagy under ER-stress. In our study, elevated TEX264 degradation is identified during inflammation; SI-W052 enhances TEX264 expression, producing a positive effect in ER-turnover. Our knockdown experiment further verifies the important role of TEX264 in SI-W052 activity against IL-6 and ER-stress. In conclusion, this study demonstrates that an anthranilate analogue is a novel neuroinflammation agent functioning through ER-stress-mediated autophagy and ER-phagy mechanisms.

Investigation of the occupational exposure to blood-borne pathogens of staff at a third-class specialist hospital in 2015-2018: a retrospective study.

To understand the current situation of occupational exposure to blood-borne pathogens in a women's and children's hospital and analyze the causes to provide a scientific basis for improving occupational exposure prevention and control measures. We analyzed occupational exposure to blood-borne pathogens in a third-class women's and children's hospital from 2015 to 2018, considering the workers' occupational categories and length of service; the sites, types, and causes of exposure; and the pathogens of the source patients. From 2015 to 2018, there were 146 cases of occupational exposure to blood-borne pathogens, mainly from sharp-instrument injuries (81.5%; 119/146). Trainees represented the highest proportion of occupational exposure (30.1%; 44/146), followed by nurses (29.5%; 43/146). Occupational exposure among staff with less than one year of service accounted for 43.2% (63/146) of cases. Fisher's exact test showed that different occupational groups had different types of occupational exposure, and among the occupationally exposed populations, the proportion of sharp injuries is higher than that of blood and body fluid exposure, and the difference is statistically significant (χ2 = 12.937, P = 0.008). Different occupational groups faced exposure to different types of pathogens: medical staff were more likely than workmen to be exposed to hepatitis B, while workmen were more likely than medical staff to be exposed to unknown pathogens; these differences were statistically significant (χ2 = 55.344, P < 0.001). Health records were established for all cases of occupational exposure to blood-borne pathogens, and no staff members contracted a blood-borne disease due to occupational exposure. In order to reduce occupational exposure, regular training in occupational protection for junior medical staff and workers should be strengthened, the monitoring and protection system of occupational exposure to blood-borne pathogens improved, standard prevention measures strengthened, operations standardized, safe injection equipment provided, and comprehensive measures taken.

Smoothened is a therapeutic target for reducing glutamate toxicity in ischemic stroke.

Extracellular glutamate contributes to brain damage in ischemia. Under physiological conditions, glutamate transporters are responsible for regulating its intracellular/extracellular concentrations in the brain. However, how the extracellular glutamate is regulated in ischemia remains unclear. Here, we showed that the sonic hedgehog (SHH)­Smoothened (SMO)­GLT-1 pathway controlled extracellular glutamate and blocking SMO reduced ischemic brain damage in rodents. SHH was quickly released in a rodent model of ischemia, and activation of its pathway was associated with neuronal damage. Inhibiting SMO, the mediator of SHH signaling, maintained GLT-1 membrane expression, lowered extracellular glutamate, reduced infarct volume, and improved neurological functions in mice. Mechanistically, SHH suppressed GLT-1 membrane expression via PKCα phosphorylation of serine-562 on GLT-1. Last, administration of NVP-LDE225, an FDA-approved SMO antagonist used for cancer treatment in clinic, had protective effects in mice and cynomolgus monkeys subjected to ischemia. Together, these results suggest that SMO could be targeted for treating glutamate toxicity in ischemia.

Furosemide as a Probe Molecule for the Treatment of Neuroinflammation in Alzheimer's Disease.

The accumulation and deposition of ß-amyloid (Aß) is one postulated cause of Alzheimer's disease (AD). In addition to its direct toxicity on neurons, Aß may induce neuroinflammation through the concomitant activation of microglia. Emerging evidence suggests that microglia-mediated neuroinflammation plays an important role in the pathogenesis of AD. As brain macrophages, microglia engulf misfolded-Aß by phagocytosis. However, the accumulated toxic Aß may paradoxically "hyper-activate" microglia into a neurotoxic proinflammatory and less phagocytotic phenotype, contributing to neuronal death. This study reports that the known drug furosemide is a potential probe molecule for reducing AD-neuroinflammation. Our data demonstrate that furosemide inhibits the secretion of proinflammatory TNF-α, IL-6, and nitric oxide; downregulates the mRNA level of Cd86 and the protein expression of COX-2, iNOS; promotes phagocytic activity; and enhances the expression of anti-inflammatory IL-1RA and arginase. Our mechanism of action studies further demonstrate that furosemide reduces LPS-induced upregulation of endoplasmic reticulum (ER) stress marker genes, including Grp78, Atf4, Chop, tXbp1, and sXbp1. These data support the observation that furosemide is a known drug with the capacity to downregulate the proinflammatory microglial M1 phenotype and upregulate the anti-inflammatory M2 phenotype, a potentially powerful and beneficial pharmacologic effect for inflammatory diseases such as AD.

Functional Characterization of VvSK Gene Family in Grapevine (Vitis vinifera L.) Revealing their Role in Berry Ripening.

The glycogen synthase kinase 3/shaggy kinase (GSK3) is a serine/threonine kinase that plays important roles in brassinosteroid signaling, abiotic stress responses, cell division, and elongation, etc. In this study, we characterized seven grape GSK3 genes, showing high similarities with homologs from other species including Arabidopsis, white pear, apple, orange, and peach. Gene chip microarray data derived from an online database revealed very diverse developmental and tissue-specific expression patterns of VvSKs. VvSK3 and VvSK7 showed much higher expression levels in almost every tissue compared with other members. VvSK7 was highly enriched in young tissues like berries before the veraison stage, young leaves and green stems, etc., but immediately downregulated after these tissues entered maturation or senescence phases. Prediction of cis-elements in VvSK promoters indicated that VvSKs might be sensitive to light stimulation, which is further confirmed by the qPCR data. Constitutive overexpression of VvSK7 in Arabidopsis leads to dwarf plants that resembles BR-deficient mutants. The photosynthetic rate was significantly reduced in these plants, even though they accumulated more chlorophyll in leaves. Transient overexpression of VvSKs in tomatoes delayed the fruit ripening process, consistent with the observation in grapevine which blocks VvSKs by EBR- or BIKININ-promoted berry expansion and soluble solids accumulation. Data presented in the current study may serve as a theoretical basis for the future application of BRs or related compounds in quality grape production.

TRPC Channels and Stroke.

TRPC channels play important roles in neuronal death/survival in ischemic stroke, vasospasm in hemorrhagic stroke, thrombin-induced astrocyte pathological changes, and also in the initiation of stroke by affecting blood pressure and atherogenesis. TRPCs' unique channel characters and downstream pathways make them possible new targets for stroke therapy. TRPC proteins have different functions in different cell types. Considering TRPCs' extensive distribution in various tissues and cell types, drugs targeting them could induce more complicated effects. More specific agonists/antagonists and antibodies are required for future study of TRPCs as potential targets for stroke therapy.

[Experimental study on loading naringin composite scaffolds for repairing rabbit osteochondral defects].

Objective: To investigate the performance of loading naringin composite scaffolds and its effects on repair of osteochondral defects. Methods: The loading naringin and unloading naringin sustained release microspheres were prepared by W/O/W method; with the materials of the attpulgite and the collagen type I, the loading naringin, unloading naringin, and loading transforming growth factor ß 1 (TGF-ß 1) osteochondral composite scaffolds were constructed respectively by "3 layers sandwich method". The effect of sustained-release of loading naringin microspheres, the morphology of the composite scaffolds, and the biocompatibility were evaluated respectively by releasing in vitro, scanning electron microscope, and cell counting kit 8. Forty Japanese white rabbits were randomly divided into groups A, B, C, and D, 10 rabbits each group. After a osteochondral defect of 4.5 mm in diameter and 4 mm in depth was made in the intercondylar fossa of two femurs. Defect was not repaired in group A (blank control), and defect was repaired with unloading naringin composite scaffolds (negative control group), loading naringin composite scaffolds (experimental group), and loading TGF-ß 1 composite scaffolds (positive control group) in groups B, C, and D respectively. At 3 and 6 months after repair, the intercondylar fossa was harvested for the general, HE staining, and toluidine blue staining to observe the repair effect. Western blot was used to detect the expression of collagen type II in the new cartilage. Results: Loading naringin microspheres had good effect of sustained-release; the osteochondral composite scaffolds had good porosity; the cell proliferation rate on loading naringin composite scaffold was increased significantly when compared with unloading naringin scaffold ( P<0.05). General observation revealed that defect range of groups C and D was reduced significantly when compared with groups A and B at 3 months after repair; at 6 months after repair, defects of group C were covered by new cartilage, and new cartilage well integrated with the adjacent cartilage in group D. The results of histological staining revealed that defects were filled with a small amount of fibrous tissue in groups A and B, and a small amount of new cartilage in groups C and D at 3 months after repair; new cartilage of groups C and D was similar to normal cartilage, but defects were filled with a large amount of fibrous tissue in groups A and B at 6 months after repair. The expression of collagen type II in groups C and D was significantly higher than that in groups A and B ( P<0.05), but no significant difference was found between groups C and D ( P>0.05). Conclusion: Loading naringin composite scaffolds have good biocompatibility and effect in repair of rabbit articular osteochondral defects.

Canonical transient receptor potential 3 channels regulate mitochondrial calcium uptake.

Mitochondrial Ca(2+) homeostasis is fundamental to regulation of mitochondrial membrane potential, ATP production, and cellular Ca(2+) homeostasis. It has been known for decades that isolated mitochondria can take up Ca(2+) from the extramitochondrial solution, but the molecular identity of the Ca(2+) channels involved in this action is largely unknown. Here, we show that a fraction of canonical transient receptor potential 3 (TRPC3) channels is localized to mitochondria, a significant fraction of mitochondrial Ca(2+) uptake that relies on extramitochondrial Ca(2+) concentration is TRPC3-dependent, and the up- and down-regulation of TRPC3 expression in the cell influences the mitochondrial membrane potential. Our findings suggest that TRPC3 channels contribute to mitochondrial Ca(2+) uptake. We anticipate our observations may provide insights into the mechanisms of mitochondrial Ca(2+) uptake and advance understanding of the physiological role of TRPC3.

TRPC6 inhibited NMDA receptor activities and protected neurons from ischemic excitotoxicity.

Excitotoxicity induced by NMDA receptor-mediated intracellular Ca(2+) ([Ca(2+) ](i)) overload is a major cause of delayed neuronal death in cerebral ischemia. Transient receptor potential canonical (TRPC) 6 protects neurons from ischemic brain damage. However, the mechanisms by which TRPC6 protects neurons are largely unknown. Here, we reported that TRPC6 suppressed the [Ca(2+)](i) elevation induced by NMDA and protected neurons from excitotoxicity. Over-expressing or down-regulating TRPC6 suppressed or aggravated Ca(2+) overload under excitotoxicity, respectively. TRPC6 protected cultured neurons from damage caused by NMDA toxicity or oxygen glucose deprivation (OGD). Moreover, the infarct volume in TRPC6 transgenic (Tg) mice was smaller than that in wild-type (WT) littermates. The TRPC6 Tg mice had better behavior performance and lower mortality than their WT littermates. Thus, TRPC6 inhibited NMDA receptor-triggered neurotoxicity and protected neurons from ischemic brain damage. Increase in TRPC6 activity could be a potential strategy for stroke prevention and therapy.

Inhibition of TRPC6 degradation suppresses ischemic brain damage in rats.

Brain injury after focal cerebral ischemia, the most common cause of stroke, develops from a series of pathological processes, including excitotoxicity, inflammation, and apoptosis. While NMDA receptors have been implicated in excitotoxicity, attempts to prevent ischemic brain damage by blocking NMDA receptors have been disappointing. Disruption of neuroprotective pathways may be another avenue responsible for ischemic damage, and thus preservation of neuronal survival may be important for prevention of ischemic brain injury. Here, we report that suppression of proteolytic degradation of transient receptor potential canonical 6 (TRPC6) prevented ischemic neuronal cell death in a rat model of stroke. The TRPC6 protein level in neurons was greatly reduced in ischemia via NMDA receptor-dependent calpain proteolysis of the N-terminal domain of TRPC6 at Lys¹6. This downregulation was specific for TRPC6 and preceded neuronal death. In a rat model of ischemia, activating TRPC6 prevented neuronal death, while blocking TRPC6 increased sensitivity to ischemia. A fusion peptide derived from the calpain cleavage site in TRPC6 inhibited degradation of TRPC6, reduced infarct size, and improved behavioral performance measures via the cAMP response element-binding protein (CREB) signaling pathway. Thus, TRPC6 proteolysis contributed to ischemic neuronal cell death, and suppression of its degradation preserved neuronal survival and prevented ischemic brain damage.

Study of tauopathies by comparing Drosophila and human tau in Drosophila.

The microtubule-binding protein tau has been investigated for its contribution to various neurodegenerative disorders. However, the findings from transgenic studies, using the same tau transgene, vary widely among different laboratories. Here, we have investigated the potential mechanisms underlying tauopathies by comparing Drosophila (d-tau) and human (h-tau) tau in a Drosophila model. Overexpression of a single copy of either tau isoform in the retina results in a similar rough eye phenotype. However, co-expression of Par-1 with d-tau leads to lethality, whereas co-expression of Par-1 with h-tau has little effect on the rough eye phenotype. We have found analogous results by comparing larval proteomes. Through genetic screening and proteomic analysis, we have identified some important potential modifiers and tau-associated proteins. These results suggest that the two tau genes differ significantly. This comparison between species-specific isoforms may help to clarify whether the homologous tau genes are conserved.