Cytosolic DNA initiates a vicious circle of aging-related endothelial inflammation and mitochondrial dysfunction via STING: the inhibitory effect of Cilostazol.

Endothelial senescence, aging-related inflammation, and mitochondrial dysfunction are prominent features of vascular aging and contribute to the development of aging-associated vascular disease. Accumulating evidence indicates that DNA damage occurs in aging vascular cells, especially in endothelial cells (ECs). However, the mechanism of EC senescence has not been completely elucidated, and so far, there is no specific drug in the clinic to treat EC senescence and vascular aging. Here we show that various aging stimuli induce nuclear DNA and mitochondrial damage in ECs, thus facilitating the release of cytoplasmic free DNA (cfDNA), which activates the DNA-sensing adapter protein STING. STING activation led to a senescence-associated secretory phenotype (SASP), thereby releasing pro-aging cytokines and cfDNA to further exacerbate mitochondrial damage and EC senescence, thus forming a vicious circle, all of which can be suppressed by STING knockdown or inhibition. Using next-generation RNA sequencing, we demonstrate that STING activation stimulates, whereas STING inhibition disrupts pathways associated with cell senescence and SASP. In vivo studies unravel that endothelial-specific Sting deficiency alleviates aging-related endothelial inflammation and mitochondrial dysfunction and prevents the development of atherosclerosis in mice. By screening FDA-approved vasoprotective drugs, we identified Cilostazol as a new STING inhibitor that attenuates aging-related endothelial inflammation both in vitro and in vivo. We demonstrated that Cilostazol significantly inhibited STING translocation from the ER to the Golgi apparatus during STING activation by targeting S162 and S243 residues of STING. These results disclose the deleterious effects of a cfDNA-STING-SASP-cfDNA vicious circle on EC senescence and atherogenesis and suggest that the STING pathway is a promising therapeutic target for vascular aging-related diseases. A proposed model illustrates the central role of STING in mediating a vicious circle of cfDNA-STING-SASP-cfDNA to aggravate age-related endothelial inflammation and mitochondrial damage.

Connections between body composition and dysregulation of islet α- and ß-cells in type 2 diabetes.

BACKGROUND: Accompanying islet α- and ß-cell dysregulation in type 2 diabetes (T2D) at the microscopic scale, alterations in body composition at the macroscopic scale may affect the pathogenesis of T2D. However, the connections between body composition and islet α-cell and ß-cell functions in T2D have not been thoroughly explored. METHODS: For this cross-sectional study, we recruited a total of 729 Chinese Han patients with T2D in a consecutive manner. Dual-energy X-ray absorptiometry (DXA) was used to measure body composition, which included total bone-free mass, total fat and lean mass, trunk fat and lean mass and limb fat and lean mass. Every patient underwent an oral glucose tolerance test to simultaneously detect glucose, C-peptide and glucagon. The indices of islet α-cell function included fasting glucagon levels and the area under the curve of glucagon after a challenge (AUCglucagon), while the indices of ß-cell function included the insulin sensitivity index derived from C-peptide (ISIC-peptide) and the area under the curve of C-peptide after a challenge (AUCC-peptide). RESULTS: Among all patients, fat mass, especially trunk fat mass, was significantly correlated with ISIC-peptide and AUCC-peptide levels (r = - 0.330 and 0.317, respectively, p < 0.001), while lean mass, especially limb lean mass, was significantly correlated with fasting glucagon and AUCglucagon levels (r = - 0.196 and - 0.214, respectively, p < 0.001). Moreover, after adjusting for other relevant variables via multivariate linear regression analysis, increased trunk fat mass was independently associated with decreased ISIC-peptide (ß = - 0.247, t = - 3.628, p < 0.001, partial R2 = 10.9%) and increased AUCC-peptide (ß = 0.229, t = 3.581, p < 0.001, partial R2 = 8.2%), while decreased limb lean mass was independently associated with increased fasting glucagon (ß = - 0.226, t = - 2.127, p = 0.034, partial R2 = 3.8%) and increased AUCglucagon (ß = - 0.218, t = - 2.050, p = 0.041, partial R2 = 2.3%). Additionally, when separate analyses were performed with the same concept for both sexes, we found that increased trunk fat mass was still independently associated with decreased ISIC-peptide and increased AUCC-peptide, while decreased limb lean mass was still independently associated with increased fasting glucagon and AUCglucagon. CONCLUSIONS: Increased trunk fat mass may partly account for decreased insulin sensitivity and increased insulin secretion, while decreased limb lean mass may be connected to increased fasting glucagon and postprandial glucagon secretion.

ß-sitosterol alleviates dextran sulfate sodium-induced experimental colitis via inhibition of NLRP3/Caspase-1/GSDMD-mediated pyroptosis.

Background: Inflammation-related NLRP3/Caspase-1/GSDMD-mediated pyroptosis is involved in the progression of ulcerative colitis (UC). ß-sitosterol (SIT) was reported to have anti-inflammatory effects on experimental colitis, while the regulation of SIT on pyroptosis is unclear. Therefore, the present study aimed to define the protective and healing effects of SIT on dextran sulfate sodium (DSS)-induced experimental UC rats and human epithelial colorectal adenocarcinoma cells (Caco-2) and explore the underlying mechanisms that are responsible for its effects on NLRP3/Caspase-1/GSDMD-mediated pyroptosis in UC. Methods: UC model rats were established by oral 4% DSS. Following colitis injury, the animals received SIT (doses of 50, 100, and 200 mg/kg) treatment for 2 weeks. For in vitro study, we exposed Caco-2-50 mg/mL DSS with or without SIT (concentrations of 8 and 16 µg/mL). Disease activity index (DAI) and histopathological injury were assessed in vivo. Activation proteins of nuclear factor kappa B (NF-κB) signaling axis, and tight junction-related proteins of zonula occludens-1 (ZO-1) and occludin were detected in colon tissues. TNF-α, IL-1ß, and IL-18 in serum and cell supernatant were measured by enzyme-linked immunosorbent assay (ELISA). Changes in NLRP3/Caspase-1/GSDMD-mediated pyroptosis signaling pathway activation were analyzed both in tissues and cells. Results: Our findings suggested that SIT treatment attenuated the severity of 4% DSS-induced UC by protecting rats from weight and colon length loss, and macroscopic damage. SIT also reduced proinflammatory factors production (TNF-α, IL-1ß, and IL-18) in serum and cell supernatant. Mechanistically, SIT downregulated the expression levels of pyroptosis-related proteins including Caspase-1, cleaved-Caspase-1, NLRP3, GSDMD, and GSDMD-N in colon tissues and Caco-2 cells. Further analysis indicated that SIT maintained the colonic barrier integrity by enhancing the protein expression of ZO-1 and occludin. Conclusion: We confirmed that SIT exerts protective and therapeutic effects on DSS-induced colitis injury by suppressing NLRP3/Caspase-1/GSDMD-mediated pyroptosis and inflammation response. These findings demonstrated that SIT could be a potential medication for UC treatment.

The associations of non-essential metal mixture with fasting plasma glucose among Chinese older adults without diabetes.

The evidence about the effect of non-essential metal mixture on fasting plasma glucose (FPG) levels among older adults without diabetes is limited. This study aims to estimate the individual and joint relationship between five non-essential metals and FPG levels in Chinese older adults without diabetes. This study included 2362 older adults without diabetes. Urinary concentrations of five non-essential metals, i.e., cesium (Cs), aluminum (Al), thallium (Tl), cadmium (Cd), and arsenic (As), were detected by inductively coupled plasma mass spectrometry (ICP-MS). The associations of single metals and the metal mixture with FPG levels were assessed using linear regression and Bayesian kernel machine regression (BKMR) models, respectively. Adjusted single-metal linear regression models showed positive associations of urinary Al (ß = 0.016, 95%CI: 0.001-0.030) and Cs (ß = 0.018, 95%CI: 0.006-0.031) with FPG levels. When comparing the 2th, 3th, and 4th quartiles of urine Cs to its 1th quartile, the significant associations between Cs and FPG levels were found and presented as an "inverted U" trend (ßQ2 vs. Q1: 0.034; ßQ3 vs. Q1:0.054; ßQ4 vs. Q1: 0.040; all P<0.05). BKMR analyses showed urinary level of Cs exhibited an "inverted U" shape association with FPG levels. Moreover, the FPG levels increased linearly with the raised levels of the non-essential metal mixture, and the posterior inclusion probability (PIP) of Cs was the highest (0.92). Potential positive interaction of As and Cs on FPG levels was found in BKMR model. Stratified analysis displayed significant interactions of hyperlipidemia and urine Cs or Tl on FPG levels. An inverse U-shaped association between Cs and FPG was found, individually and as mixture. The FPG levels increased with the raised levels of the non-essential metal mixture, and Cs was the most contributor to FPG levels. Further research is required to confirm the correlation between non-essential metals and FPG levels and to clarify the underlying mechanisms.

The association between the essential metal mixture and fasting plasma glucose in Chinese community-dwelling elderly people.

BACKGROUND: Epidemiological studies about the effect of essential metal mixture on fasting plasma glucose (FPG) levels among elderly people are sparse. The object of this study was to examine the associations of single essential metals and essential metal mixture with FPG levels in Chinese community-dwelling elderly people. METHODS: The study recruited 2348 community-dwelling elderly people in total. Inductively coupled plasma-mass spectrometry was adopted to detect the levels of vanadium (V), selenium (Se), magnesium (Mg), cobalt (Co), calcium (Ca), and molybdenum (Mo) in urine. The relationships between single essential metals and essential metal mixture and FPG levels were evaluated by linear regression and Bayesian kernel machine regression (BKMR) models, respectively. RESULTS: In multiple-metal linear regression models, urine V and Mg were negatively related to the FPG levels (ß = - 0.016, 95 % CI: - 0.030 to - 0.003 for V; ß = - 0.021, 95 % CI: - 0.033 to - 0.009 for Mg), and urine Se was positively related to the FPG levels (ß = 0.024, 95 % CI: 0.014-0.034). In BKMR model, the significant relationships of Se and Mg with the FPG levels were also found. The essential metal mixture was negatively associated with FPG levels in a dose-response pattern, and Mg had the maximum posterior inclusion probability (PIP) value (PIP = 1.0000), followed by Se (PIP = 0.9968). Besides, Co showed a significant association with decreased FPG levels in older adults without hyperlipemia and in women. CONCLUSIONS: Both Mg and Se were associated with FPG levels, individually and as a mixture. The essential metal mixture displayed a linear dose-response relationship with reduced FPG levels, with Mg having the largest contribution to FPG levels, followed by Se. Further prospective investigations are necessary to validate these exploratory findings.

Stable Co(II)-based coordination polymer as fluorescence sensor for the discriminative sensing of biomarker methylmalonic acid.

Three novel Co-based coordination polymers including {[Co(L)(µ3-O)1/3]2}n (1), {[Co(L)(bimb)]}n (2) and {[Co(L)(bimmb)1/2]}n (3) (H2L = 2,6-di(4-carboxylphenyl)-4-(4-(triazol-1-ylphenyl))pyridine), bimb = 1,4-bis(lmidazol) butane, bimmb = 1,4-bis(imidazole-1-ylmethyl)benzene) were successfully prepared under solvothermal conditions and characterized. Single-crystal X-ray diffraction analyses revealed that 1 possesses a 3D architecture composed of a trinuclear cluster [Co3N3(CO2)6(µ3-O)], 2 exhibits a 2D new topological framework with the point symbol (84·122)(8)2, whereas 3 shows a unique six-fold interpenetrated 3D framework with a (63·82·10)2(63)2(8) topology. Impressively, all of them can function as a highly selective and sensitive fluorescent sensor for the biomarker methylmalonic acid (MMA) via fluorescence quenching. The low detection limit, reusability and high anti-interference performance together make 1-3 become promising sensors for the practical detection of MMA. Furthermore, the successful application of MMA detection in urine sample was demonstrated, which may be a potential candidate for the further development of clinical diagnostic tools.

Improved bone and renal safety in younger tenofovir disoproxil fumarate experienced chronic hepatitis B patients after switching to tenofovir alafenamide or entecavir.

INTRODUCTION AND OBJECTIVES: Renal and bone impairment has been reported in chronic hepatitis B (CHB) patients receiving long-term tenofovir disoproxil fumarate (TDF) therapy. This study aimed to assess the incidence of renal and bone impairment in CHB patients with long-term TDF therapy and to identify the changes in bone mineral density (BMD) and renal function in these patients after switching to entecavir (ETV) or tenofovir alafenamide (TAF). MATERIALS AND METHODS: This retrospective study collected clinical data from CHB patients who received TDF monotherapy over 96 weeks. The changes in BMD and renal function were analyzed after 96 weeks of switching antiviral regimens (ETV or TAF) or maintenance TDF. RESULTS: At baseline, 154 patients receiving TDF monotherapy over 96 weeks were enrolled, with a younger median age of 36.75 years, 35.1% (54/154) of patients experienced elevated urinary ß2 microglobulin and 20.1% (31/154) of patients had reduced hip BMD (T<-1). At week 96, among the 123 patients with baseline normal BMD, patients who maintained TDF (n=85) had experienced a decrease in hip BMD, while patients who switched antiviral regimens (n=38) experienced an increase (-13.97% vs 2.34%, p<0.05). Among patients with a baseline reduced BMD (n=31), the alterations in BMD were similar in patients who maintained TDF (n=5) and those who switched antiviral regimens (n=26) (-15.81% vs 7.35%, p<0.05). Irrespective of baseline BMD status, renal function decreased significantly in patients who maintained TDF and improved in patients who switched antiviral regimens. CONCLUSIONS: Younger CHB patients on long-term TDF therapy are at high risk for bone and renal impairment, with the risk being reduced when switched to ETV or TAF.

Gender-Specific Association of Handgrip Strength with Type 2 Diabetes Mellitus in Chinese Han Older Adults.

Purpose: We aimed to analyze the relationship between handgrip strength/relative handgrip strength among older Han adults with type 2 diabetes mellitus (T2DM) by gender to determine the optimal cut-off value of grip strength for older adults. Methods: A multi-stage sampling method was used to conduct a questionnaire survey and physical examination of 6128 older adults in Anhui Province. Chi-squares tests, t-tests, analysis of variance, and logistic regression analysis were used to analyze the association between handgrip strength/relative handgrip strength and T2DM between the sexes. The decision tree model (CRT) was used to explore the predictive value of handgrip strength /relative handgrip strength on T2DM. Results: There was an association between handgrip strength and T2DM (P = 0.006, OR = 0.985, 95% CI = 0.975, 0.996), which was found in females (P = 0.013, OR = 0.978, 95% CI = 0.961, 0.995) but not in males (P = 0.125, OR = 0.989, 95% CI = 0.976, 1.003). Relative handgrip strength was also correlated with T2DM (P = 0.014, OR = 0.730, 95% CI = 0.568, 0.939), which was found in females (P = 0.003, OR = 0.534, 95% CI = 0.352, 0.809) but not in males (P = 0.432, OR = 0.879, 95% CI = 0.638, 1.212). The incidence of T2DM in elderly females with hypertension who were uneducated and with a handgrip strength of <17.350 kg was 24.3% (115 cases), whereas that in elderly females with hypertension and a relative handgrip strength of <0.240 was 29.0% (127 cases). Conclusion: According to our results, handgrip strength and relative handgrip strength were associated with T2DM. People with hypertension had a higher risk of T2DM in women with a handgrip strength of ≤ 17.350kg and a relative grip strength of ≤ 0.240. Further research is needed to validate the effectiveness of this cut-off for implementing interventions and avoiding risks.

ICF-Based simple scale for children with cerebral palsy: Application of Mokken scale analysis and Rasch modeling.

Children with cerebral palsy (CP) are faced with long-term dysfunction. The International Classification of Functioning, Disability and Health for Children and Youth (ICF-CY) has been proposed but the complicated procedure limits the feasibility of clinical application and the exploration of health degrees. This study was aimed to establish a Mokken scale based on the ICF-CY for CP, and then to estimate psychometric properties through the derived Rasch model. 150 children with CP were assessed by the categories of "b" and "d" components in the core set. The binarized data was screened by the Mokken scale analysis and utilized for generating a reliable Rasch model. The validity of the final model was checked by the correlation between person ability, Gross Motor Function Classification System (GMFCS) and total scores. Using the Mokken scale to guide Rasch modeling, we can parameterize the properties of ICF-CY and realize the simple assessment of person abilities for children with CP.

Selenium attenuates the association of co-exposure to arsenic, cadmium, and lead with cognitive function among Chinese community-dwelling older adults.

The effects of interactions between the toxic and essential metal mixtures on cognitive function are poorly understood. This study aims to identify the joint association of arsenic (As), cadmium (Cd), and lead (Pb) with cognitive function in older adults and the moderating role of selenium (Se), zinc (Zn), and copper (Cu) in this association. This study included 1000 community-dwelling older adults. Cognitive function was assessed by the Mini-Mental State Examination (MMSE). Blood concentrations of As, Cd, Pb, Se, Zn, and Cu were measured using inductively coupled plasma mass spectrometry. Linear regression and Bayesian kernel machine regression (BKMR) models were applied to assess the individual and joint associations of As, Cd, and Pb with cognitive function and to examine whether Se, Zn, and Cu (individually and as a mixture) modified these associations. In the adjusted single-metal models, both Cd (ß = - 0.37, 95% CI: - 0.73 to - 0.01) and Pb (ß = - 0.44, 95% CI: - 0.86 to - 0.02) were associated with MMSE scores, while Se (ß = 0.71, 95% CI: 0.30 to 1.13) exhibited a positive relationship with MMSE scores. Univariate exposure-response functions from BKMR models showed similar results. Moreover, the toxic metal mixture (As, Cd, and Pb) exhibited a significant negative association with MMSE scores in a dose-response pattern, with Pb being the greatest contributor within the mixture. The negative association of Pb alone or the toxic metal mixture with MMSE scores became weaker at higher concentrations of Se within its normal range, especially when Se levels were greater than the median (89.18 µg/L). Our findings support that Se can attenuate the negative associations of exposure to single Pb or the As, Cd, and Pb mixtures with cognitive function. Future prospective studies are needed to replicate our findings.

Polymorphisms of pvcrt-o and pvmdr1 genes of 48 Plasmodium vivax isolates from the China-Myanmar border / 中国热带医学

@#Abstract: Objective To detect the polymorphisms of drug resistance-related genes pvcrt-o and pvmdr1 of Plasmodium vivax in lazan city in the China-Myanmar border, in order to guide the treatment plan of Plasmodium vivax. Methods A total of 48 Plasmodium vivax samples were collected from Lazan in the China-Myanmar border in 2007, and fragments of pvcrt-o and pvmdr1 genes were amplified by PCR and sequenced. The sequences were aligned with the Salvador I (Sal-I) strain reference genome sequences to determine the presence of SNPs. Results The target fragments of pvcrt-o gene were amplified from 39 Plasmodium vivax samples, while pvmdr1 genes were amplified from 40 samples. Amongst them, 25 samples had AAG insertion before the 10th amino acid (K10 insertion) of pvcrt-o gene, accounting for 64.1%. Non-synonymous mutations were detected at three loci of pvmdr1 gene (T958M, Y976F, and F1076L), the mutation rates were 100%, 22.5%, and 55.0%, respectively. There were three haplotypes of pvmdr1 gene, of which the triple mutant 958M/976F/1076L accounted for 22.5% (9/40), the double mutant 958M/Y976/1076L accounted for 32.5% (13/40), and the single mutant 958M/Y976/F1076 accounted for 45.0% (18/40). The proportion of strains with pvcrt-o and pvmdr1 gene mutation is 63.16%, which is significantly different from those only with pvmdr1 mutation. Conclusions The proportion of pvcrt-o and pvmdr1 gene mutation of 48 Plasmodium vivax isolates is high in the China-Myanmar border, and there is a certain degree of correlation between the two gene mutations. To assess changes in Plasmodium vivax drug resistance in this region, it is required to improve the surveillance of these two molecular markers.

Increased levels of serum adenosine deaminase and increased risk of diabetic peripheral neuropathy in type 2 diabetes.

Background: Increased serum adenosine deaminase (ADA) levels have been shown to be involved in metabolic abnormalities and immune disequilibrium, which may in turn contribute to inflammatory diseases. This study aimed to determine whether increased serum ADA levels are related to diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes (T2D). Methods: This study was part of a series exploring the potential risks for DPN. All patients received DPN assessment based on neuropathic symptoms, neuropathic signs, and nerve conduction studies to calculate the composite Z score of nerve latency, amplitude and conduction velocity (NCV). DPN was confirmed by both at least a presentation of neuropathic symptoms/signs and an abnormal nerve conduction index. Serum ADA levels were also synchronously detected. Results: A total of 384 eligible patients with T2D were recruited for this study, and 24.5% (n=94) were determined to have DPN. Increases in serum ADA levels were closely associated with increases in composite Z score of latency (ß=0.263, t=5.273, p<0.001) and decreases in composite Z score of amplitude (ß=-0.126, t=-2.352, p=0.019) and NCV (ß=-0.201, t=-3.841, p<0.001) after adjusting for other clinical covariates. Moreover, each 5 U/L increase in serum ADA levels was associated with a 1.781-fold increased adjusted odds ratio of having DPN (95% confidence interval: 1.271-2.495). Furthermore, the optimal cut-off value of serum ADA levels to discriminate DPN was ≥14.2 U/L (sensitivity=59.57%, specificity=75.52% and Youden index=0.351) after analysis by receiver operating characteristic curve. Conclusions: Increased serum ADA levels may be a potential risk factor for DPN in patients with T2D.

Increased plasma D-dimer levels may be a promising indicator for diabetic peripheral neuropathy in type 2 diabetes.

Background: Increased plasma D-dimer levels have been reported to be associated with a range of adverse health outcomes. This study aimed to determine whether plasma D-dimer is connected to diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes (T2D). Methods: This study was part of a series exploring the potential risks for DPN. All patients were questioned for neurologic symptoms, examined for neurologic signs, and received nerve conduction studies to collect nerve action potential onset latency, amplitude, and nerve conduction velocity (NCV). Composite Z scores of latency, amplitude, and NCV were calculated. DPN was confirmed as both at least a neurologic symptom/sign and an abnormality of nerve conduction studies. Coagulation function indices, such as plasma D-dimer levels, were also synchronously detected. Results: We finally recruited 393 eligible patients for this study, of whom 24.7% (n = 97) were determined to have DPN. The plasma D-dimer level was found to be closely associated with the composite Z score of latency, amplitude, and NCV after adjusting for other coagulation function indices and clinical covariates (latency: ß = 0.134, t = 2.299, p = 0.022; amplitude: ß = -0.138, t = -2.286, p = 0.023; NCV: ß = -0.139, t = -2.433, p = 0.016). Moreover, the prevalence of DPN in the first, second, third, and fourth quartiles (Q1, Q2, Q3, and Q4) of the D-dimer level was 15.2%, 15.9%, 26.4%, and 42.7%, respectively (p for trend < 0.001). The corresponding adjusted odds ratios and 95% CIs for DPN in D-dimer quartiles were 1, 0.79 (0.21-2.99), 1.75 (0.49-6.26), and 5.17 (1.38-19.42), respectively. Furthermore, the optimal cutoff value of the plasma D-dimer level to discriminate DPN was ≥0.22 mg/L (sensitivity = 67.01%, specificity = 58.78%, and Youden index = 0.26) after analysis by the receiver operating characteristic curve. Conclusions: Increased plasma D-dimer levels may be a promising indicator for DPN in patients with T2D.

High-normal serum carcinoembryonic antigen levels and increased risk of diabetic peripheral neuropathy in type 2 diabetes.

BACKGROUND: Increased serum carcinoembryonic antigen (CEA) levels are reported to be associated with various metabolic and inflammatory diseases. This study assessed whether high-normal serum CEA is related to diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes (T2D). METHODS: All subjects received DPN assessment based on neuropathic symptoms, neuropathic signs, and nerve conduction studies to calculate composite Z scores of nerve latency, amplitude and conduction velocity (NCV). DPN was confirmed by both at least a presentation of neuropathic symptoms/signs and an abnormal nerve conduction index. Serum CEA levels and other clinical indices were also synchronously detected. Multivariable linear regression analyses were used to determine the independent effects of serum CEA levels on nerve conduction indices, multivariable logistic regression analyses were used to determine the independent impact of CEA levels on the risk of DPN, and receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic capability of CEA levels to discriminate DPN. RESULTS: We ultimately recruited 402 eligible subjects with normal ranges of serum CEA for this study, and 25.4% (n = 102) were determined to have DPN. After adjusting for other clinical covariates, serum CEA levels were independently associated with the composite Z score for latency (ß = 0.132, t = 2.330, p = 0.021), amplitude (ß = - 0.164, t = - 2.838, p = 0.005) and NCV (ß = - 0.210, t = - 3.662, p < 0.001). Moreover, the prevalence of DPN in the first, second, third and fourth quartiles of CEA level was 12.9%, 19.0%, 29.4% and 40.4%, respectively (p for trend < 0.001); the corresponding adjusted odds ratios and 95% CIs for DPN in CEA quartiles were 1, 1.47 (0.45-4.82), 1.72 (0.54-5.53) and 4.58 (1.39-15.06), respectively. Furthermore, the optimal cut-off value of high-normal serum CEA to discriminate DPN was ≥ 2.66 ng/mL, with a Youden index of 0.28, sensitivity of 66.67% and specificity of 61.00%. CONCLUSIONS: Increased serum CEA levels within the normal range are closely linked to dysfunction of peripheral nerve conduction and the risk of DPN, and high-normal serum CEA levels are a potential risk factor for DPN in T2D.

Serum Pregenomic RNA Combined With Hepatitis B Core-Related Antigen Helps Predict the Risk of Virological Relapse After Discontinuation of Nucleos(t)ide Analogs in Patients With Chronic Hepatitis B.

Background and Aim: Cessation of nucleos(t)ide analogs (NAs) therapy in patients with chronic hepatitis B (CHB) is uncommon. Although criteria for discontinuation appear in some guidelines, the indicators for assessing discontinuation of NAs are limited, whether NAs can be safely ceased remains a difficult clinical issue. Our study aimed to investigate the role of serum pregenomic RNA (pgRNA) and hepatitis B core-related antigen (HBcrAg) at the end of treatment (EOT) in guiding the safe discontinuation of NAs in CHB patients. Methods: This is a retrospective study, clinical data of all CHB patients who discontinued NAs treatment at West China Hospital between June 2020 and January 2021 were collected, including EOT pgRNA, HBcrAg, hepatitis B surface antigen (HBsAg), etc. All patients should meet the Asian-Pacific guideline for discontinuation. Observing virological relapse (VR) rates during 1 year of NAs discontinuation and analyzing the relationship between EOT pgRNA, HBcrAg, and VR. Results: A total of 64 patients were enrolled in this study and 33 (51.5%) patients experienced VR in 1 year. EOT pgRNA positivity (OR = 14.59, p = 0.026) and EOT higher HBcrAg levels (OR = 14.14, p = 0.001) were independent risk factors for VR. The area under the receiver-operating characteristic (AUROC) value of EOT HBcrAg for VR was 0.817 (p < 0.001), optimal cut-off value was 3.3 log10 U/mL. Patients with EOT pgRNA positivity and EOT HBcrAg >3.3 log10 U/mL were more likely to experience VR after discontinuation of NAs (88.9 vs. 45.5%, p = 0.027). Conclusion: According to current guidelines, a higher VR rate occurs after cessation of NAs. EOT pgRNA positivity and higher HBcrAg level carries a higher risk of VR. Combining these novel markers can better help us assess whether patients can safely cease NAs treatment.

Synthesis and biological evaluation of marine natural product, Cryptoechinuline D derivatives as novel antiangiogenic agents.

Tumor angiogenesis is an important biological process involved in the proliferation and migration of endothelial cells, regulated by Ang/Tie-2 signaling pathways, which is essential for tumor growth and metastasis. Therefore, blocking Ang/Tie-2 signaling pathways is a promising anti-angiogenic strategy for tumor treatment. 2,5-Diketopiperazines (DKPs) are a kind of bioactive compounds derived from marine fungi and they present a wide spectrum of pharmacological properties, particularly in the field of cancer treatment. Herein, a DKP marine natural product, Cryptoechinuline D (Cry D) was applied to structural modification and twelve derivatives were synthesized. Among which, compound 5 showed significant inhibitory activity against HUVECs with an IC50 value of 12.6 µmol/L, which weakened the proliferation, migration and invasion of HUVECs by inhibiting the Ang2/Tie-2 signaling pathway. The results of these evaluations indicated that compound 5 might be a promising anti-angiogeneic agent and worth further optimization and development for cancer therapy.

Increased serum cystatin C levels and responses of pancreatic α- and ß-cells in type 2 diabetes.

Background: Increased serum cystatin C (CysC) can predict the onset of type 2 diabetes (T2D). Meanwhile, impaired pancreatic α- and ß-cell functions get involved in the pathophysiological processes of T2D. So this study was to explore the relationships between serum CysC levels and pancreatic α- and ß-cell functions in T2D. Methods: In this cross-sectional observational study, a total of 2634 patients with T2D were consecutively recruited. Each recruited patient received a serum CysC test and oral glucose tolerance test for synchronous detection of serum C-peptide and plasma glucagon. As components of pancreatic ß-cell function, insulin secretion and sensitivity indices were evaluated by C-peptide area under the curve (AUC-CP) and C-peptide-substituted Matsuda's index (Matsuda-CP), respectively. Fasting glucagon (F-GLA) and post-challenge glucagon calculated by glucagon area under the curve (AUC-GLA) were used to assess pancreatic α-cell function. These skewed indices and were further natural log-transformed (ln). Results: With quartiles of serum CysC levels ascending, AUC-CP, F-GLA and AUC-GLA were increased, while Matsuda-CP was decreased (P for trend <0.001). Moreover, serum CysC levels were positively related to lnAUC-CP, lnF-GLA and lnAUC-GLA (r= 0.241, 0.131 and 0.208, respectively, P < 0.001), and inversely related to lnMatsuda-CP (r= -0.195, P < 0.001). Furthermore, after controlling for other relevant variables via multivariable linear regression analysis, serum CysC levels were identified to account for lnAUC-CP (ß= 0.178, t= 10.518, P < 0.001), lnMatsuda-CP (ß= -0.137, t= -7.118, P < 0.001), lnF-GLA (ß= 0.049, t= 2.263, P = 0.024) and lnAUC-GLA (ß= 0.121, t= 5.730, P < 0.001). Conclusions: Increased serum CysC levels may be partly responsible for increased insulin secretion from ß-cells, decreased systemic insulin sensitivity, and elevated fasting and postprandial glucagon secretion from α-cells in T2D.

Angiogenesis-Inhibitory Piperidine Alkaloids from the Leaves of Microcos paniculata.

Eight new 2,6-disubstituted piperidin-3-ol alkaloids (1-8), featuring a C10 unsaturated alkyl side chain, together with three previously reported analogues (9-11) were isolated from the leaves of medicinal plant Microcos paniculata. Their structures and absolute configurations were elucidated unambiguously by means of 1D and 2D NMR spectroscopic data analysis, modified Mosher's method, Snatzke's method, and quantum chemical electronic circular dichroism (ECD) calculations, as well as single-crystal X-ray crystallography. The isolates were evaluated for their antiangiogenic effects on human umbilical vein endothelial cells (HUVECs). Compound 2 displayed an inhibitory effect on tube formation of HUVECs in a concentration-dependent manner.