Stevioside Ameliorates Palmitic Acid-Induced Abnormal Glucose Uptake via the PDK4/AMPK/TBC1D1 Pathway in C2C12 Myotubes.

BACKGROUND: Stevioside (SV) with minimal calories is widely used as a natural sweetener in beverages due to its high sweetness and safety. However, the effects of SV on glucose uptake and the pyruvate dehydrogenase kinase isoenzyme (PDK4) as an important protein in the regulation of glucose metabolism, remain largely unexplored. In this study, we used C2C12 skeletal muscle cells that was induced by palmitic acid (PA) to assess the effects and mechanisms of SV on glucose uptake and PDK4. METHODS: The glucose uptake of C2C12 cells was determined by 2-NBDG; expression of the Pdk4 gene was measured by quantitative real-time PCR; and expression of the proteins PDK4, p-AMPK, TBC1D1 and GLUT4 was assessed by Western blotting. RESULTS: In PA-induced C2C12 myotubes, SV could significantly promote cellular glucose uptake by decreasing PDK4 levels and increasing p-AMPK and TBC1D1 levels. SV could promote the translocation of GLUT4 from the cytoplasm to the cell membrane in cells. Moreover, in Pdk4-overexpressing C2C12 myotubes, SV decreased the level of PDK4 and increased the levels of p-AMPK and TBC1D1. CONCLUSION: SV was found to ameliorate PA-induced abnormal glucose uptake via the PDK4/AMPK/TBC1D1 pathway in C2C12 myotubes. Although these results warranted further investigation for validation, they may provide some evidence of SV as a safe natural sweetener for its use in sugar-free beverages to prevent and control T2DM.

Effect of steviol glycosides as natural sweeteners on glucose metabolism in adult participants.

Steviol glycosides (SGs) are recognized as safe natural sweeteners; however, evidence from randomized controlled trials (RCTs) showed an inconclusive effect of SGs on glucose metabolism in adult participants. We aimed to conduct a systematic review and meta-analysis of RCTs to assess the effect of SGs on glucose metabolism. We systematically searched PubMed, Web of Science and EMBASE to include eligible RCTs. Our primary outcomes were differences between SGs and the control group with respect to changes in blood glucose from the baseline to the end of intervention (including fasting blood glucose [FBG], and HbA1c measurements). A random-effects meta-analysis was conducted for data synthesis to calculate the pooled mean difference (MD). There were twelve RCTs included for analyses with a total of 871 participants (48% females). A significant effect of SGs on FBG (MD = -4.10 mg dl-1, 95% CI -6.55 to -1.65) was found, while no significant difference in HbA1c (MD = 0.01%, 95% CI -0.12% to 0.13%) was observed between SGs and controls. The whole quality of evidence was rated as low. Subgroup analyses demonstrated favorable effects of SGs on FBG in participants aged ≤50 years, those without diabetes mellitus (DM) or hypertension at the baseline, and overweight and obese adults. Sensitivity analyses yielded results largely similar to the main findings. To conclude, SGs are found to produce significant improvement in glucose metabolism in adult participants when compared with the control. More evidence is required to further clarify and support the benefit of SGs as a sugar substitute for glucose metabolism.

Relationship Between Lipoprotein(a), Renal Function Indicators, and Chronic Kidney Disease: Evidence From a Large Prospective Cohort Study.

BACKGROUND: Chronic kidney disease (CKD) poses a significant global public health challenge. While lipoprotein(a) (Lp[a]) has been established as a significant factor in cardiovascular disease, its connection to CKD risk remains a topic of debate. Existing evidence indicates diverse risks of kidney disease among individuals with various renal function indicators, even when within the normal range. OBJECTIVE: This study aims to investigate the joint associations between different renal function indicators and Lp(a) regarding the risks of incident CKD in the general population. METHODS: The analysis involved a cohort of 329,415 participants without prior CKD who were enrolled in the UK Biobank between 2006 and 2010. The participants, with an average age of 56 (SD 8.1) years, included 154,298/329,415 (46.84%) males. At baseline, Lp(a) levels were measured using an immunoturbidimetric assay and classified into 2 groups: low (<75 nmol/L) and high (≥75 nmol/L). To assess participants' baseline renal function, we used the baseline urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). The relationship between Lp(a), renal function indicators, and the risk of CKD was evaluated using multivariable Cox regression models. These models were adjusted for various factors, including sociodemographic variables, lifestyle factors, comorbidities, and laboratory measures. RESULTS: A total of 6003 incident CKD events were documented over a median follow-up period of 12.5 years. The association between elevated Lp(a) levels and CKD risk did not achieve statistical significance among all participants, with a hazard ratio (HR) of 1.05 and a 95% CI ranging from 0.98 to 1.13 (P=.16). However, a notable interaction was identified between Lp(a) and UACR in relation to CKD risk (P for interaction=.04), whereas no significant interaction was observed between Lp(a) and eGFR (P for interaction=.96). When compared with the reference group with low Lp(a) and low-normal UACR (<10 mg/g), the group with high Lp(a) and low-normal UACR exhibited a nonsignificant association with CKD risk (HR 0.98, 95% CI 0.90-1.08; P=.74). By contrast, both the low Lp(a) and high-normal UACR (≥10 mg/g) group (HR 1.16, 95% CI 1.08-1.24; P<.001) and the high Lp(a) and high-normal UACR group (HR 1.32, 95% CI 1.19-1.46; P<.001) demonstrated significant associations with increased CKD risks. In individuals with high-normal UACR, elevated Lp(a) was linked to a significant increase in CKD risk, with an HR of 1.14 and a 95% CI ranging from 1.03 to 1.26 (P=.01). Subgroup analyses and sensitivity analyses consistently produced results that were largely in line with the main findings. CONCLUSIONS: The analysis revealed a significant interaction between Lp(a) and UACR in relation to CKD risk. This implies that Lp(a) may act as a risk factor for CKD even when considering UACR. Our findings have the potential to provide valuable insights into the assessment and prevention of CKD, emphasizing the combined impact of Lp(a) and UACR from a public health perspective within the general population. This could contribute to enhancing public awareness regarding the management of Lp(a) for the prevention of CKD.

Structure-Activity Relationship Study of 1H-Pyrrole-3-carbonitrile Derivatives as STING Receptor Agonists.

The use of small agonists to target stimulators of interferon genes (STING) has been demonstrated to be a promising strategy for the treatment of various cancers and infectious diseases. Herein, we discovered a series of 1H-pyrrole-3-carbonitrile derivatives as potential STING agonists. On this basis, the structure-activity relationship of this scaffold was studied by introducing various substituents on the aniline ring system. Representative compounds 7F, 7P, and 7R all displayed comparable activities to the reported STING agonist SR-717 in binding various hSTING alleles and induced reporter signal in human THP1 cell lines. Model compound 7F induced phosphorylation of TBK1, IRF3, p65, and STAT3 in a STING-dependent fashion and stimulated the expression of target genes IFNB1, CXCL10, and IL6 in a time-dependent manner in human THP1 cells. Our findings afforded a series of novel STING agonists with promising potential.

Co-pyrolysis of dyeing sludge and pine sawdust in a fluidized bed: Characterization and analysis of pyrolytic products and investigation of synergetic effects.

Co-pyrolysis of dyeing sludge (DS) and pine sawdust (PS) was carried out in a fluidized bed pyrolyser. The results revealed that addition of PS increased the yields of condensate and gas, and dramatically improved pore structure of co-pyrolysis char, enhancing immobilization of the metals, nutrient and pollution elements. Catalysts (Na-ZSM-5 and HZSM-5) significantly reduced tar and coke, strengthened the integrity of pore structure. Yield of nitrogen-containing compounds declined sharply from 88.66% to 8.14% when 25% of PS was added. Addition of 50% PS promoted ring opening to generate chain compounds and abundant oxygenates (such as ketones, aldehydes and carboxylic acids) in pyrolysis oil (PO) at 650 °C. Correspondingly, yield of gaseous products was inhibited except CO2 and H2 when PS content was dominant. The catalysts greatly increased yield of gaseous products by enhancing primary and secondary cracking depending on different feedstocks and catalysts (e.g., DS over Na-ZSM-5 and PS over HZSM-5). The maximum energy efficiency (69.75%) was obtained at 650 °C when 75% PS was added.

Design, Synthesis, and Biological Evaluation of Bipyridazine Derivatives as Stimulator of Interferon Genes (STING) Receptor Agonists.

The development of stimulator of interferon genes (STING) agonists has been of potential applications for the treatment of cancer and infectious diseases. Based on the crystal structure of SR-717 bound to hSTING, we designed and synthesized a novel series of bipyridazine derivatives as highly potent STING agonists. Among them, compound 12L led to significant thermal stability shifts of the common alleles of hSTING, as well as that of mSTING. 12L also displayed potent activities in various hSTING alleles and mSTING competition binding assay. Specifically, 12L displayed higher cell-based activities than SR-717 in both human THP1 (EC50 = 0.38 ± 0.03 µM) and mouse RAW 264.7 cells (EC50 = 12.94 ± 1.78 µM), and was validated to activate the downstream signaling pathway of STING via a STING-dependent manner. Furthermore, compound 12L showed favorable pharmacokinetic (PK) properties and antitumor efficacy. These findings suggested that compound 12L has development potential as an antitumor agent.

Consumption of Non-Nutritive Sweetener during Pregnancy and Weight Gain in Offspring: Evidence from Human Studies.

The relationship between the consumption of maternal non-nutritive sweeteners (NNS) during pregnancy and the risk of obesity in offspring remains inconsistent. We aimed to systematically evaluate and clarify the relationship between NNS intake during pregnancy and weight gain in offspring based on evidence from population and clinical research. Databases including PubMed (via Medline), EMBASE, and the Cochrane Library were systematically searched for eligible human studies. The primary outcome was the differences in body mass index (BMI) z-scores between offspring at 1 year of age who were with and without NNS intake during pregnancy or between offspring with different NNS intake levels during pregnancy. A random-effects meta-analysis was conducted for data synthesis to calculate the weighted mean difference (WMD). A total of six prospective cohort studies were eligible for inclusion, among which three were used for pooled analysis of the BMI z-score. A significant increase was found in an offspring's weight at 1 year of age in the NNS group when compared with the control group: WMD in BMI z-score = 0.19 (95% CI: 0.07, 0.31), p-value = 0.002. Results from the dose-response analysis showed a linear relationship between NNS intake during pregnancy and WMD at 1 year of age: beta = 0.02 (95% CI: 0.001, 0.04) for per serving/week increase in NNS consumption. The whole body of evidence for the review was rated as low quality. In summary, maternal NNS intake during pregnancy was found to be associated with increased weight gain in offspring based on evidence from human studies. Further well-designed and adequately powered studies are needed to confirm this relationship.

Iron-biochar production from oily sludge pyrolysis and its application for organic dyes removal.

In this study, a single-step pyrolysis approach was developed to directly convert oily sludge (OS) with high iron content into a magnetic iron-char catalyst for organic dyes removal. Magnetic iron-char catalysts were employed to degrade crystal violet (CV), methylene blue (MB), and sunset yellow (SY). The OC800 iron-char catalyst prepared from OS was not only rich in iron (mainly stable Fe3O4), but also showed favorable pore structures. Effects of operation parameters like temperature, H2O2 dosage, and pH on dye removal based on Fenton degradation were examined. In OC800 Fenton system (0.5 mL H2O2, 500 mg/L dye concentration, and pH = 2 in 50 mL solution), the maximum dye removal capacities of SY, CV, and MB were 83.61, 639.19, and 414.25 mg/g, respectively. In dyes degradation experiments, the prepared catalyst could be reused (more than 3 successive cycles) due to higher stability and less leaching of iron. One-step pyrolysis of OS with high iron content thereby represents a promising approach to transform sludge waste to functional biochar that removes hazardous dyes.

Pyrolysis of vegetable oil soapstock in fluidized bed: Characteristics of thermal decomposition and analysis of pyrolysis products.

This study investigated the effect of temperature on pyrolysis of soapstock in a fluidized bed reactor, and the characterization of soapstock chars (SCs) and pyrolysis oils (POs) were analyzed. TGA, TG-FTIR, TG-MS, and Py-GCMS were employed to investigate characteristics of SS pyrolysis. Experimental results indicated that the yield of SC decreased with increasing temperature. Pyrolysis oil (PO) yield reached the maximum of 21.05 wt% at 600 °C and the yield of non-condensable gas varied with temperatures. The content of carbon, hydrogen and nitrogen distributed in the SC decreased with the increasing temperature, and sulfur tended to be retained in SC during pyrolysis with the distribution ratio of 0.55-0.62. Ketones, alcohols and hydrocarbons were the dominate substances in PO, and higher temperature promoted the production of short-chain alkanes and the conversion of alkenes to benzene derivatives. SS pyrolysis can be divided into three stages. Stage I was mainly the evaporation of free water and light organics in the raw material. Decomposition and conversion of organics mainly occurred at stage II. Stage III was the decomposition of CaCO3 and secondary cracking of residual organics. Ca2+ delayed the pyrolysis reaction of fatty acids and promoted decarboxylation which was the main deoxygenation pathway, and alkene production. This study provided a theoretical basis for the application of soapstock thermochemical treatment. It is of great significance for the quality improvement of PO and pollution control for pyrolysis processes.

MAPRE2 regulates the first meiotic progression in mouse oocytes.

Microtubule plus-end tracking proteins (+TIPs) associate with growing microtubule plus ends and control microtubule dynamics and interactions with different cellular structures during cell division, cell migration and morphogenesis. Microtubule-associated RP/EB family member 2 (MAPRE2/EB2) is a highly conserved core component of +TIPs networks, but whether this molecule is required for mammalian meiotic progression is unknown. In this study, we investigated the expression and function of MAPRE2 during oocyte maturation. Our results showed that MAPRE2 was consistently expressed from germinal vesicle (GV) to metaphase II (MII) stages and that MAPRE2 was distributed in the cytoplasm of oocytes at GV stage and along the spindle at metaphase I (MI) and MII stages. Small interfering RNA-mediated knockdown of Mapre2 severely impaired microtubule stability, kinetochore-microtubule attachment, and chromosome alignment and subsequently caused spindle assembly checkpoint (SAC) activation and cyclin B1 nondegradation, leading to failure of chromosome segregation and first polar body extrusion. This study demonstrates for the first time that MAPRE2 plays an important role during mouse oocyte meiosis.

Reduction of mtDNA heteroplasmy in mitochondrial replacement therapy by inducing forced mitophagy.

Mitochondrial replacement therapy (MRT) has been used to prevent maternal transmission of disease-causing mutations in mitochondrial DNA (mtDNA). However, because MRT requires nuclear transfer, it carries the risk of mtDNA carryover and hence of the reversion of mtDNA to pathogenic levels owing to selective replication and genetic drift. Here we show in HeLa cells, mouse embryos and human embryos that mtDNA heteroplasmy can be reduced by pre-labelling the mitochondrial outer membrane of a donor zygote via microinjection with an mRNA coding for a transmembrane peptide fused to an autophagy receptor, to induce the degradation of the labelled mitochondria via forced mitophagy. Forced mitophagy reduced mtDNA carryover in newly reconstructed embryos after MRT, and had negligible effects on the growth curve, reproduction, exercise capacity and other behavioural characteristics of the offspring mice. The induction of forced mitophagy to degrade undesired donor mtDNA may increase the clinical feasibility of MRT and could be extended to other nuclear transfer techniques.

Co-pyrolysis of biomass and polyvinyl chloride under microwave irradiation: Distribution of chlorine.

Co-pyrolysis of sophora wood (SW) and polyvinyl chloride (PVC) was conducted in a microwave reactor at different temperatures and different mixing ratios, and the transformation and distribution of chlorine in pyrolysis products were investigated. Microwave pyrolysis is a simple and efficient technique with better heating uniformity and process controllability than conventional heating. Compared with PVC pyrolysis, the addition of SW significantly reduced CO2 yield and greatly increased the yield of CO. The yield and quality of pyrolysis oil were effectively improved by SW, and the content of chlorine-containing compounds in the oil was suppressed to <1% at low temperatures (<550 °C). Co-pyrolysis of SW and PVC reduced the chlorine emissions from 59.07% to 28.09% and promoted the retention of chlorine in char (from 0.33% to 4.72%). Cellulose, hemicellulose, and lignin were co-pyrolyzed with PVC to investigate their effects on chlorine distribution. The experiments demonstrated that lignin had the most significant effects on reducing gas phase chlorine emission and achieving chlorine immobilization, and chlorine mainly existed in the form of sodium chloride in the char of lignin-PVC co-pyrolysis. Hence co-pyrolysis of lignocellulosic biomass and PVC provides a practical pathway for utilization of PVC waste in an environmentally friendly manner, realizing efficient chlorine retention and significantly reducing chlorine-related emissions.

Influence of corn straw on distribution and migration of nitrogen and heavy metals during microwave-assisted pyrolysis of municipal sewage sludge.

This study explored pyrolysis characteristics, nitrogen transformation and migration of heavy metals during microwave-assisted pyrolysis of municipal sewage sludge in a continuously operated auger pyrolyser at different temperatures and corn straw ratios. The results showed higher temperatures and more corn straw resulted in more gas yield (e.g., CO2, CO, CH4 and H2) and less char yield. 5 wt% corn straw addition at 750 °C achieved high-quality bio-oil with less O-containing compounds, which was more favorable for upgrading to transportation fuels. Sludge chars prepared at higher corn straw ratios had lower ratios of H/C and N/C, and higher carbon content. Nitrogen transformation pathways and mechanisms were investigated. The residual ratio of heavy metals (except Cd) in sludge char was 67.74-100%. However, the residual ratio of Cd decreased significantly to 6.46% at 750 °C. Concentrations of all heavy metals in sludge char conformed to national standard (CJ/T 362-2011, China), and the potential ecological risk was slight. Sludge chars prepared in the presence of corn straw had lower ecological risk and higher retention capacity of heavy metals (e.g., Pb, Cr, Mn, Cu, Zn, and Ni) compared with pyrolysis of sewage sludge.

A strategy for screening trypsin inhibitors from traditional Chinese medicine based on a monolithic capillary immobilized enzyme reactor coupled with offline liquid chromatography and mass spectrometry.

A novel strategy was successfully developed for screening trypsin inhibitors in traditional Chinese medicines based on monolithic capillary immobilized enzyme reactors combined with liquid chromatography-tandem mass spectrometry. Organic polymer based monolithic enzyme reactors were firstly prepared by covalently bonding trypsin to a poly(glycidyl methacrylate-co-poly (ethylene glycol) diacrylate) monolith by the ring-opening reaction of epoxy groups. The activity and kinetic parameters of the obtained monolithic trypsin reactors were systematically evaluated using micro-liquid chromatography. Fourier transform infrared spectroscopy and scanning electron microscopy were also used to characterize the monolithic trypsin reactors. The resulting functional and denatured monolithic trypsin reactors were applied as affinity solid-phase extraction columns, and offline coupled with a liquid chromatography-tandem mass spectrometry system to construct a binding affinity screening platform. Subsequently, the proposed platform was applied for screening trypsin binders in a Scutellaria baicalensis Georgi extract. Three compounds, namely scutellarin, baicalin, and wogonoside were identified, and their inhibitory activities were further confirmed via an in vitro enzymatic inhibition assay. Additionally, molecular docking was also performed to study the interactions between trypsin and these three compounds.

(Benzyl phenyl sulfoxide-κO)-chlorido-triphenyl-tin(IV).

The Sn(IV) atom in the title compound, [Sn(C(6)H(5))(3)Cl(C(13)H(12)OS)], is situated within a distorted C(3)ClO trigonal-bipyramidal coordination geometry with a mean Sn-C distance of 2.136 (6) Šand with an Sn-O distance of 2.393 (4) Å. The Sn(IV) atom lies 0.171 (3) Šout of the equatorial C(3) plane in the direction of the axially bound Cl atom.

(Benzyl phenyl sulfoxide-κO)dichloridodiphenyl-tin(IV).

The Sn(IV) atom in the title compound, [Sn(C(6)H(5))(2)Cl(2)(C(13)H(12)OS)], displays a distorted C(2)Cl(2)O trigonal-bipyramidal coordination environment, with a mean Sn-C distance of 2.121 (9) Šand with Sn-O = 2.331 (2) Å. The Sn(IV) atom is displaced by 0.169 (2) Šfrom the equatorial C(2)Cl plane towards the direction of the second axially bonded Cl atom.