Empagliflozin, a sodium-glucose cotransporter inhibitor enhancing mitochondrial action and cardioprotection in metabolic syndrome.

Metabolic syndrome (MetS) has a large clinical population nowadays, usually due to excessive energy intake and lack of exercise. During MetS, excess nutrients stress the mitochondria, resulting in relative hypoxia in tissues and organs, even when blood supply is not interrupted or reduced, making mitochondrial dysfunction a central pathogenesis of cardiovascular disease in the MetS. Sodium-glucose cotransporter 2 inhibitors were designed as a hyperglycemic drug that acts on the renal tubules to block sugar reabsorption in primary urine. Recently they have been shown to have anti-inflammatory and other protective effects on cardiomyocytes in MetS, and have also been recommended in the latest heart failure guidelines as a routine therapy. Among these inhibitors, empagliflozin shows better clinical promise due to less influence from glomerular filtration rate. This review focuses on the mitochondrial mechanisms of empagliflozin, which underlie the anti-inflammatory and recover cellular functions in MetS cardiomyocytes, including stabilizing calcium concentration, mediating metabolic reprogramming, maintaining homeostasis of mitochondrial quantity and quality, stable mitochondrial DNA copy number, and repairing damaged mitochondrial DNA.

Palladium/XuPhos-catalyzed enantioselective cascade Heck/intermolecular C(sp2)-H alkylation reaction.

Palladium-catalyzed enantioselective domino Heck/intramolecular C-H functionalization reaction, as a valuable strategy for creating molecular diversity, has remained a prominent challenge. Here, we describe a Pd/XuPhos catalyst for asymmetric domino Heck/intermolecular C-H alkylation of unactivated alkenes with diverse polyfluoro- and heteroarenes in a highly chemo- and enantioselective manner. This process enables efficient synthesis of various dihydrobenzofurans, indolines and indanes, which are of interest in pharmaceutical research and other areas. Late-stage modifications of the core structures of natural products are also well showcased. Moreover, synthetic transformations create a valuable platform for preparing a series of functionalized molecules. Several control experiments for mechanistic study are conducted to pursue a further understanding of the reaction.

Patient self-reported experience and satisfaction with golimumab and etanercept treatments for rheumatic diseases: A cohort study.

Golimumab and etanercept both exhibit good efficacy in treating rheumatic diseases, while the patient self-reported measurement of treatment improvement and injection experience lacks sufficient evidence. Hence, this study aimed to compare the satisfaction with disease improvement and injection experience and the level of injection site reactions (ISRs) between golimumab-treated and etanercept-treated patients with rheumatic diseases. A total of 312 patients with rheumatic diseases were serially enrolled. Among them, 158 patients received golimumab (golimumab group); the other 154 patients were treated with etanercept (etanercept group) according to the actual disease status, physician advice, and patient willingness. Satisfaction with disease improvement was assessed using the 7-point Likert scale; satisfaction with injection experience and level of ISRs were both determined by the 5-point Likert scale. Satisfaction degrees with global injection experience (P = .025), injection device (P = .008), injection frequency (P = .010), and injection convenience (P = .003) were superior in the golimumab group to the etanercept group, while satisfaction degrees with global disease improvement, symptom relief, and speed of action did not vary (all P > .050) between the 2 groups. Discomfort (P = .005), swelling (P < .001), pain (P = .028), and burning (P = .035) levels were lower in the golimumab group than in the etanercept group. In addition, among 56 patients with a history of tumor necrosis factor inhibitor treatment before golimumab, 40 (71.4%) patients preferred golimumab to other tumor necrosis factor inhibitor. After switching to golimumab treatment, the level of ISRs in most patients was reduced or comparable. Golimumab achieves a satisfying injection experience and relieves the level of ISRs over etanercept in patients with rheumatic diseases.

Preparation and Performance of Bitumen Modified by Melt-Blown Fabric of Waste Mask Based on Grey Relational and Radar Chart Analysis.

To effectively utilize waste mask materials in road engineering and minimize resource waste, the melt-blown fabric (MBF) of waste masks was utilized to modify the virgin bitumen. The preparation process of MBF-modified bitumen was investigated, and the physical and rheological properties of bitumen were measured. Subsequently, the blending mechanism during preparation and the dispersion morphology of the modifier were explored. Finally, the pavement performance of the mixture was investigated, and a radar chart analysis was performed to quantitatively assess the effects of MBF modification. Results suggested that the recommended preparation process of shear time, shear rate, and shear temperature was 170 °C, 4000 r/min, and 15 min, respectively. MBF enhanced the high-temperature stability of the binder and weakened the temperature susceptibility. The modification was primarily a physical process. No network structure and agglomeration formed in the bitumen after modification. The addition of MBF significantly improved the resistance of the asphalt mixture to a high-temperature deformation and water damage but harmed its low-temperature crack resistance. The comprehensive assessment results of 0% (f1), 1% (f2), 3% (f3), and 5% (f4) MBF to improve the properties of the mixture were in the following order: f3>f4>f2>f1, where the impact of 3% MBF was the most significant, followed by 5% and 1% MBF.

Recent advances in Pd-catalyzed asymmetric cyclization reactions.

Over the past few decades, there have been major developments in transition metal-catalyzed asymmetric cyclization reactions, enabling the convenient access to a wide spectrum of structurally diverse chiral carbo- and hetero-cycles, common skeletons found in fine chemicals, natural products, pharmaceuticals, agrochemicals, and materials. In particular, a plethora of enantioselective cyclization reactions have been promoted by chiral palladium catalysts owing to their outstanding features. This review aims to collect the latest advancements in enantioselective palladium-catalyzed cyclization reactions over the past eleven years, and it is organized into thirteen sections depending on the different types of transformations involved.

Long-term follow-up of children with carbamoyl phosphate synthase 1 deficiency detected in newborn screening. / æ–°ç”Ÿå„¿ç­›æŸ¥å‘çŽ°çš„æ°¨ç”²é °ç£·é ¸åˆæˆé ¶1ç¼ºä¹ç—‡æ‚£å„¿é•¿æœŸéšè®¿ç ”ç©¶.

OBJECTIVES: To investigate genotype-phenotype characteristics and long-term prognosis of neonatal carbamoyl phosphate synthetase 1 (CPS1) deficiency among children through newborn screening in Zhejiang province. METHODS: The clinical and follow-up data of children with CPS1 deficiency detected through neonatal screening and confirmed by tandem mass spectrometry and genetic testing in Zhejiang Province Newborn Disease Screening Center from September 2013 to August 2023 were retrospectively analyzed. RESULTS: A total of 4 056 755 newborns were screened and 6 cases of CPS1 deficiency were diagnosed through phenotypic and genetic testing. Ten different variations of CPS1 genewere identified in genetic testing, including 2 known pathogenic variations (c.2359C>T and c.1549+1G>T) and 8 unreported variations (c.3405-1G>T, c.2372C>T, c.1436C>T, c.2228T>C, c.2441G>A, c.3031G>A, c.3075T>C and c.390-403del). All patients had decreased citrulline levels (2.72-6.21 µmol/L), and varying degrees of elevated blood ammonia. The patients received restricted natural protein intake (special formula), arginine and supportive therapy after diagnosis, and were followed-up for a period ranging from 9 months to 10 years. Three patients experienced hyperammonemia, and one patient each had attention deficit hyperactivity disorder, transient facial twitching and increased muscle tone. One patient died, while the other five surviving patients had normal scores of the Ages & Stages Questionnaires (ASQ) and Griffiths Development Scales up to the present time; 4 cases had combined height or weight lag and one case was normal in height and weight. CONCLUSIONS: Low citrulline levels and hyperammonemia are common in CPS1 deficiency patients in Zhejiang. Most gene variants identified were specific to individual families, and no hotspot mutations were found. Early diagnosis through newborn screening and following standardized treatment can significantly improve the prognosis of the patients.

Study on the Performance and Mechanism of Cold-Recycled Asphalt Based on Permeable Recycling Agent.

In order to investigate the influence of recycling agent composition on the recycling effect of aged asphalt in the cold recycling process, the design and optimization of cold recycling agent composition were performed through the central composite design-response surface method combined with the dynamic shear rheometer (DSR) test and the bending beam rheometer (BBR) test. The molecular weight distribution and component changes in aged asphalt before and after the addition of a cold recycling agent were also analyzed by gel permeation chromatography (GPC) and hydrogen-flame ionization test. The results showed that the permeable cold recycling agent has a recycling effect on the aged asphalt, but its effectiveness is greatly affected by recycling agent composition. The best recycling effect was achieved when the ratio of aromatic oil and penetrant in the cold recycling agent was 61.2:38.8, respectively. In terms of the recycling agent and aromatic functional groups in the aromatic oil, the aromatics in the recycling agent are derived from the aromatic oils, and the penetrant is only fused and permeated with the aromatic oils. After the admixture of the cold recycling agent, the penetrant in the recycling agent allows the aromatic oil to enter the aged asphalt at room temperature. The light components volatilized by aging are replenished, allowing the aged asphalt to recover some of its properties.

Quantitative Proteomics of the CDK9 Interactome Reveals a Function of the HSP90-CDC37-P-TEFb Complex for BETi-Induced HIV-1 Latency Reactivation.

Brd4 has been intensively investigated as a promising drug target because of its implicated functions in oncogenesis, inflammation, and HIV-1 transcription. The formation of the Brd4-P-TEFb (CDK9/Cyclin T1) complex and its regulation of transcriptional elongation are critical for HIV latency reactivation and expression of many oncogenes. To further investigate the mechanism of the Brd4-P-TEFb complex in controlling elongation, mass spectrometry-based quantitative proteomics of the CDK9 interactome was performed. Upon treatment with the selective BET bromodomain inhibitor JQ1, 352 proteins were successfully identified with high confidence as CDK9-interacting proteins. Among them, increased bindings of HSP90 and CDC37 to CDK9 were particularly striking, and our data suggest that the HSP90-CDC37-P-TEFb complex is involved in controlling the dynamic equilibrium of the P-TEFb complex during BETi-induced reactivation of HIV-1 latency. Furthermore, the HSP90-CDC37-P-TEFb complex directly regulates HIV-1 transcription and relies on recruitment by heat shock factor 1 (HSF1) for binding to the HIV-1 promoter. These results advance the understanding of HSP90-CDC37-P-TEFb in HIV-1 latency reversal and enlighten the development of potential strategies to eradicate HIV-1 using a combination of targeted drugs.

Roxadustat, a HIF-PHD inhibitor with exploitable potential on diabetes-related complications.

Diabetes mellitus (DM) is a group of metabolic diseases caused by absolute or relative deficiency of insulin secretion and characterized by chronic hyperglycemia. Its complications affect almost every tissue of the body, usually leading to blindness, renal failure, amputation, etc. and in the final stage, it mostly develops into cardiac failure, which is the main reason why diabetes mellitus manifests itself as a high clinical lethality. The pathogenesis of diabetes mellitus and its complications involves various pathological processes including excessive production of mitochondrial reactive oxygen species (ROS) and metabolic imbalance. Hypoxia-inducible Factor (HIF) signaling pathway plays an important role in both of the above processes. Roxadustat is an activator of Hypoxia-inducible Factor-1α, which increases the transcriptional activity of Hypoxia-inducible Factor-1α by inhibiting hypoxia-inducible factor prolyl hydroxylase (HIF-PHD). Roxadustat showed regulatory effects on maintaining metabolic stability in the hypoxic state of the body by activating many downstream signaling pathways such as vascular endothelial growth factor (VEGF), glucose transporter protein-1 (GLUT1), lactate dehydrogenase (LDHA), etc. This review summarizes the current research findings of roxadustat on the diseases of cardiomyopathy, nephropathy, retinal damage and impaired wound healing, which also occur at different stages of diabetes and greatly contribute to the damage caused by diabetes to the organism. We attempts to uncover a more comprehensive picture of the therapeutic effects of roxadustat, and inform its expanding research about diabetic complications treatment.

Palladium/TY-Phos-Catalyzed Asymmetric Heck/Tsuji-Trost Reaction of o-Bromophenols with 1,3-Dienes.

2,3-Dihydrobenzofurans are crucial building blocks in the synthesis of natural products and pharmaceutical molecules. However, their asymmetric synthesis has been a long-standing formidable challenge so far. In this work, we developed a highly enantioselective Pd/TY-Phos-catalyzed Heck/Tsuji-Trost reaction of o-bromophenols with various 1,3-dienes, allowing expedient access to chiral substituted 2,3-dihydrobenzofurans. This reaction features excellent regio- and enantiocontrol, high functional group tolerance, and easy scalability. More importantly, the demonstration of this method as a highly valuable tool for the construction of optically pure natural products (R)-tremetone and fomannoxin is highlighted.

Recycling phosphogypsum in road construction materials and associated environmental considerations: A review.

Phosphogypsum (PG) is a major hazardous by-product of the phosphate industry. The whole world is facing the challenge of increasing stockpiles of PG, which significantly affect safety and the environment. Recycling this material may be an environmentally friendly and safe solution to this challenge. In this paper, we searched the Web of Science database for 2369 articles from 1975 to 2022 using "phosphogypsum" as the keyword. Using the VOSviewer as the literature visualisation tool, density visualisation was performed with keywords as the analysis units, and it was found that the researchers focused mainly on PG applications in construction and radionuclides. Over the years, different routes to PG valorisation have been developed in the agricultural, construction, environmental and energy sectors, and these topics are described in this review. As infrastructure projects, highway engineering is characterised by a large land area and high resource consumption. Therefore, applying PG to road materials can significantly increase the reuse and consumption of PG and reduce PG stockpiles. We hope that PG can be used for road construction on a large scale in the future. This paper focuses on the latest developments in PG as road materials. The most serious difficulty in using PG as road materials at present is that it contains radionuclides and heavy metal impurities, which can be purified by pretreatment methods. However, how to scale it up requires continuous research.

New Deferric Amine Compounds Efficiently Chelate Excess Iron to Treat Iron Overload Disorders and to Prevent Ferroptosis.

Excess iron accumulation occurs in organs of patients with certain genetic disorders or after repeated transfusions. No physiological mechanism is available to excrete excess iron and iron overload to promote lipid peroxidation to induce ferroptosis, thus iron chelation becomes critical for preventing ion toxicity in these patients. To date, several iron chelators have been approved for iron chelation therapy, such as deferiprone and deferoxamine, but the current iron chelators suffer from significant limitations. In this context, new agents are continuously sought. Here, a library of new deferric amine compounds (DFAs) with adjustable skeleton and flexibility is synthesized by adopting the beneficial properties of conventional chelators. After careful evaluations, compound DFA1 is found to have greater efficacy in binding iron through two molecular oxygens in the phenolic hydroxyl group and the nitrogen atom in the amine with a 2:1 stoichiometry. This compound remarkably ameliorates iron overload in diverse murine models through both oral and intravenous administration, including hemochromatosis, high iron diet-induced, and iron dextran-stimulated iron accumulation. Strikingly, this compound is found to suppress iron-induced ferroptosis by modulating the intracellular signaling that drives lipid peroxidation. This study opens a new approach for the development of iron chelators to treat iron overload.

Synthesis of W-Phos Ligand and Its Application in the Copper-Catalyzed Enantioselective Addition of Linear Grignard Reagents to Ketones.

The asymmetric catalytic addition of linear Grignard reagents to ketones has been a long-standing challenge in organic synthesis. Herein, a novel family of PNP ligands (W-Phos) was designed and applied in copper-catalyzed asymmetric addition of linear Grignard reagents to aryl alkyl ketones, allowing facile access to versatile chiral tertiary alcohols in good to high yields with excellent enantioselectivities (up to 94 % yield, 96 % ee). The process can also be used to synthesize chiral allylic tertiary alcohols from more challenging α,ß-unsaturated ketones. Notably, the potential utility of this method is demonstrated in the gram-scale synthesis and modification of various densely functionalized medicinally relevant molecules.

Enantioselective difunctionalization of alkenes by a palladium-catalyzed Heck/borylation sequence.

A palladium catalyzed enantioselective Heck/borylation reaction of alkene-tethered aryl iodides was realized, delivering a variety of 2,3-dihydrobenzofuranyl boronic esters in high yield with excellent enantioselectivity. Asymmetric synthesis of chromane boronic ester, indane boronic ester and indoline boronic ester was also accomplished. The protocol offers an efficient access to the corresponding chiral benzocyclic boronic esters, which are notably important chemical motifs in synthetic transformations.

Long-term prognosis of 35 patients with methionine adenosyltransferase deficiency based on newborn screening in China.

Methionine adenosyltransferase deficiency (MATD) is a rare metabolic disorder caused by mono- or biallelic MAT1A mutations that are not yet well understood. Of the 4,065,644 neonates screened between November 2010 and December 2021, 35 individuals have been diagnosed with an estimated incidence of 1: 116,161 by a cutoff value of methionine 82.7 µmol/L and follow-up over 11 years. MATD patients with autosomal recessive (AR) type had higher clinical and genetic heterogeneity than those with autosomal dominant (AD) type. Fifteen unrelated AD patients harbored one well-known dominant variant, c.791 G>A or c.776 C>T, and were clinically unaffected with a mean plasma methionine (Met) value <300 µmol/L. Twenty AR cases have unique genotypes and presented a wide range of clinical abnormalities from asymptomatic to white matter lesions. Of them, 10 AR patients displayed severe manifestations, such as verbal difficulty, motor delay, development delay, and white matter lesions, with mean Met >500 µmol/L and thereby were treated with a methionine-restricted diet alone or in combination with betaine, folate, or vitamin B6, and were healthy finally. Neurological abnormalities were evidenced in two patients (P16 and P27) with Met values >800 µmol/L by MRI scan. Neurological abnormalities were reversed here by liver transplantation or by the determination of S-adenosylmethionine supplementation. Additionally, 38 variants of MAT1A were distributed within patients and carriers, of which 24 were novel and mostly predicted to be damaged. Our findings with an extensive clinical and genetic dataset provided new insights into its diagnosis and treatment and will be helpful for its optimal management in the future.

Palladium-Catalyzed Asymmetric Cross-Coupling Reactions of Cyclobutanols and Unactivated Olefins.

Transition-metal-catalyzed activations of carbon-carbons bonds of small strained rings have widespread applications in synthetic and medicinal chemistry. However, coupling reactions of cyclobutanols involving ß-carbon elimination to construct C(sp3)-C(sp3) bonds have scarcely been developed. Here, we demonstrate a highly enantioselective Pd-catalyzed intermolecular C(sp3)-C(sp3) coupling reaction of a broad range of cyclobutanol derivatives and unactivated alkenes, allowing convenient access to a series of chiral benzene-fused cyclic compounds in a highly regio-, chemo-, and enantioselective manner.

Size-Controlled Synthesis of Pd Nanocatalysts on Defect-Engineered CeO2 for CO2 Hydrogenation.

The size effects of metal catalysts have been widely investigated to optimize their catalytic activity and selectivity. However, the size-controllable synthesis of uniform supported metal nanoparticles without surfactants and/or additives remains a great challenge. Herein, we developed a green, surfactant-free, and universal strategy to tailor the sizes of uniform Pd nanoparticles on metal oxides by an electroless chemical deposition method via defect engineering of supports. The nucleation and growth mechanism suggest a strong electrostatic interaction between the Pd precursor and low-defective CeO2 and a weak reducing capacity for low-defective CeO2, resulting in small Pd nanoparticles. Conversely, large Pd nanoparticles were formed on a highly defective CeO2 surface. Combined with various ex situ and in situ characterizations, a higher intrinsic activity of Pd for the CO2-to-CO hydrogenation was found on large Pd nanoparticles with higher electron density owing to their stronger H2 dissociation ability and H-spillover effects, as well as the larger number of oxygen vacancies generated in situ for CO2 activation under hydrogenation conditions.

Investigating the Effectiveness of Nano-Montmorillonite on Asphalt Binder from Rheological, Thermodynamics, and Chemical Perspectives.

In this research, the feasibility of using nano-montmorillonite (MMT) in asphalt binders was investigated in terms of rheological properties, thermomechanical properties, and chemical structure composition. Different doses of MMT were added to the base asphalt and styrene-butadiene-styrene (SBS) asphalt as test subjects. The effect of nanomaterials on the high-temperature resistance of asphalt binders to permanent deformation was analyzed from dynamic mechanical rheology using the multiple stress creep recovery (MSCR) test. The sessile drop method test based on surface free energy (SFE) theory was employed and thermodynamic parameters such as surface free energy, cohesive work, and adhesion work were calculated to analysis the change in energy of the asphalt binder. In addition, changes in the chemical structure and composition of the asphalt binder were examined by Fourier transform infrared (FTIR) and gel permeation chromatography (GPC) tests. The results showed that MMT can effectively enhance the high-temperature elastic recovery and plastic deformation resistance of the asphalt binder. The intercalation structure produced in the asphalt binder enhanced the overall cohesive power and adhesion to the aggregate. The anchoring effect of the intercalation structure resulted in an increase in the macromolecular weight of the binder was demonstrated, indicating that MMT enhanced the overall intermolecular forces of the binder. In addition, the molecular crystal structure was characterized by characteristic functional groups in the infrared spectra, while demonstrating that no chemical reaction occurs during the modification of the binder by the nanomaterials.

Effect of Phenolic Resin on the Rheological and Morphological Characteristics of Styrene-Butadiene Rubber-Modified Asphalt.

To improve the thermal-aging stability and rheological performance of styrene-butadiene rubber (SBR)-modified asphalt, phenolic resin (PF) was introduced in the process of preparing SBR-modified asphalt by melt blending. The effect of PF and SBR on the high and low-temperature rheological performance of the asphalt binder before and after aging was evaluated by a temperature and frequency sweep using a dynamic shear rheometer (DSR). Fourier transform infrared spectroscopy (FTIR), gel permeation chromatography (GPC), and fluorescence microscopy (FM) were used to further investigate the effect of PF and SBR on the thermal stability and morphological characteristics of the asphalt binder. The results showed that the addition of PF can enhance the high-temperature deformation resistance and short-term aging resistance of SBR-modified asphalt. Moreover, PF and SBR form an embedded network structure within the asphalt binder and alleviate the deterioration of the polymer during the aging process. Compared with SBR-modified asphalt, the chemical system of composite-modified asphalt is more stable, and it can remain stable with an aging time of less than 5 h.

Pd-Catalyzed Enantioselective Syntheses of Trisubstituted Allenes via Coupling of Propargylic Benzoates with Organoboronic Acids.

Enabled by the newly developed ligand, Ming-Phos, the first example of palladium-catalyzed highly enantioselective coupling of racemic propargylic benzoates with organoboronic acids for chiral allenes synthesis has been developed. Excellent asymmetric induction has been achieved with a decent substrate scope. Synthetic potentials for the construction of polycyclic compounds with multiple chiral centers have been demonstrated.