Ruthenium/η5-Phenoxo-Catalyzed Amination of Phenols with Amines.

Ruthenium(II) complexes are known to form η6-arene complexes with benzene-containing compounds through π-coordination, a property extensively utilized to initiate reactions not typically observed with free arenes. A prime example is nucleophilic aromatic substitution, where ruthenium-complexed aryl halides undergo nucleophilic attack, allowing the direct synthesis of diverse aromatic compounds by displacing halides with nucleophiles. However, this activation relies on the electron-withdrawing effect of the Ru(II) species, as well as is hindered by the resistance of η6-arenes to arene exchange. In the previous pursuit of catalysis, the emphasis of ligand design has centered on promoting arene exchange. In this study, we extended the ruthenium activation strategy to umpolung substitution reactions of phenols. The amination proceeds through a direct condensation between phenols and amines, with a key intermediate identified as [bis(η5-phenoxo)Ru], which is in situ generated from a commercially available ruthenium catalyst. In comparison with the well-studied cyclopentadienyl (Cp) type ligands, we demonstrated that an η5-phenoxo motif, as a superior alternative to Cp, contributes to the amination of phenols in two crucial ways: its less electron-donating nature enhances the withdrawing effect of the ruthenium unit, facilitating substitution on the phenol complex; its distinctive behavior in arene exchange allows for conducting the amination with a catalytic amount of metal. Additionally, hydrogen bonding, wherein the phenoxo serves as the acceptor, was found to be important for the substitution. The versatility of this ruthenium-catalyzed amination was validated by performing reactions with a diverse array of phenols exhibiting various electronic properties, in combination with a wide range of primary amines. This work exemplifies the expansion of the scope of π-coordination activation in catalysis through innovative ligand development.

Relationships between muscle strength, lung function, and cognitive function in Chinese middle-aged and older adults: A study based on the China health and retirement longitudinal study (CHARLS).

OBJECTIVE: As the population ages, concerns about cognitive decline have become increasingly relevant in medical consultations. This study aims to analyze the interaction between muscle strength, lung function, and cognitive function in Chinese middle-aged and older adults, providing a theoretical basis for better prevention of cognitive decline. METHODS: This study used data from the China Health and Retirement Longitudinal Study (CHARLS) wave 3, including 13 716 participants aged 45 years or older. Cognitive function was assessed through two dimensions, resulting in a total score ranging from 0 to 31 points, with higher scores indicating better cognitive function. Muscle strength was measured using normalized grip strength and chair-standing time, while lung function was evaluated using peak expiratory flow (PEF). RESULTS: Total cognitive function scores exhibited significant correlations with grip strength, chair-standing time, and PEF. Muscle strength and lung function demonstrated significant associations with cognitive function, with lung function emerging as a notable mediating factor. This relationship persisted even after adjusting for potential confounding variables. Specifically, PEF played a substantial mediating role in linking grip strength to cognitive function scores (estimated indirect effect = 0.0132, boot-strapped standard error = 0.0015, boot-strapped standard 95% confidence interval = 0.0104, 0.0162). Additionally, PEF served as a significant mediator in the association between chair-standing time and cognitive function scores (estimated indirect effect = -0.0204, boot-strapped standard error = 0.0023, boot-strapped standard 95% confidence interval = -0.0251, -0.0159). CONCLUSION: The study highlights the importance of addressing declines in muscle strength and lung function to identify risk factors associated with cognitive function. Understanding these relationships can provide insights into potential pathways linking these variables and may aid in better prevention of cognitive decline. Further long-term longitudinal cohort studies are needed to explore the causality between these factors.

A Unique Combination of Mn2+ and Aluminum Adjuvant Acted the Synergistic Effect.

Introduction: The development of combinatorial adjuvants is a promising strategy to boost vaccination efficiency. Accumulating evidence indicates that manganese exerts strong immunocompetence and will become an enormous potential adjuvant. Here, we described a novel combination of Mn2+ plus aluminum hydroxide (AH) adjuvant that significantly exhibited the synergistic immune effect. Methodology. Initially, IsdB3 proteins as the immune-dominant fragment of IsdB proteins derived from Staphylococcus aureus (S. aureus) were prepared. IsdB3 proteins were identified by western blotting. Furthermore, we immunized C57/B6 mice with IsdB3 proteins plus Mn2+ and AH adjuvant. After the second immunization, the proliferation of lymphocytes was measured by the cell counting kit-8 (CCK-8) and the level of IFN-γ, IL-4, IL-10, and IL-17 cytokine from spleen lymphocytes in mice and generation of the antibodies against IsdB3 in serum was detected with ELISA, and the protective immune response was assessed through S. aureus challenge. Results: IsdB3 proteins plus Mn2+ and AH obviously stimulated the proliferation of spleen lymphocytes and increased the secretion of IFN-γ, IL-4, IL-10, and IL-17 cytokine in mice, markedly enhanced the generation of the antibodies against IsdB3 in serum, observably decreased bacterial load in organs, and greatly improved the survival rate of mice. Conclusion: These data showed that the combination of Mn2+ and AH significantly acted a synergistic effect, reinforced the immunogenicity of IsdB3, and offered a new strategy to increase vaccine efficiency.

Transcriptome analysis provides insights into high fat diet-induced kidney injury and moderate intensity continuous training-mediated protective effects.

Although physics exercise has been utilized to prevent and treat a variety of metabolic diseases, its role in obesity-related kidney diseases remains poorly understood. In this study, we assessed the protective potential of moderate intensity continuous training (MICT) against high fat diet (HFD)-induced kidney injury and found that MICT could significantly reduce obesity indexes (body weight, serum glucose, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol) and kidney injury indexes (serum creatinine and the expression of Kim-1 mRNA) in HFD-fed mice. PAS staining and Masson staining displayed that MICT maintained the morphological structure of kidney subunits and reduced kidney fibrosis in HFD-fed mice. By kidney RNA-seq, we identified several genes and pathways (Cd9, Foxq1, Mier3, TGF-ß signaling pathway etc.) that might underlie HFD-induced kidney injury and MICT-mediated protective effects. In conclusion, this study revealed the protective role of MICT in HFD-induced kidney injury and suggested potential targets for the prevention and treatment of obesity-related kidney diseases.

Therapeutic Potential of Fingolimod in Diabetes Mellitus and Its Chronic Complications.

Diabetes mellitus is a metabolic disease characterized by elevated blood glucose due to a deficiency of insulin secretion and/or action. Long-term poor blood glucose control may lead to chronic damage and dysfunction of the heart, kidneys, eyes, and other organs. Therefore, it is important to develop treatments for diabetes and its chronic complications. Fingolimod is a structural sphingosine analogue and sphingosine-1-phosphate receptor modulator currently used for the treatment of relapsing-remitting multiple sclerosis. Several studies have shown that it has beneficial effects on the improvement of diabetes and its chronic complications. This paper reviews the therapeutic potential of Fingolimod in diabetes and its chronic complications, aiming to further guide future treatment strategies.

Sex differences in brain cell-type specific chromatin accessibility in schizophrenia.

Our understanding of the sex-specific role of the non-coding genome in serious mental illness remains largely incomplete. To address this gap, we explored sex differences in 1,393 chromatin accessibility profiles, derived from neuronal and non-neuronal nuclei of two distinct cortical regions from 234 cases with serious mental illness and 235 controls. We identified sex-specific enhancer-promoter interactions and showed that they regulate genes involved in X-chromosome inactivation (XCI). Examining chromosomal conformation allowed us to identify sex-specific cis- and trans-regulatory domains (CRDs and TRDs). Co-localization of sex-specific TRDs with schizophrenia common risk variants pinpointed male-specific regulatory regions controlling a number of metabolic pathways. Additionally, enhancers from female-specific TRDs were found to regulate two genes known to escape XCI, (XIST and JPX), underlying the importance of TRDs in deciphering sex differences in schizophrenia. Overall, these findings provide extensive characterization of sex differences in the brain epigenome and disease-associated regulomes.

Sex Matters-Insights from Testing Drug Efficacy in an Animal Model of Pancreatic Cancer.

Preclinical studies rarely test the efficacy of therapies in both sexes. The field of oncology is no exception in this regard. In a model of syngeneic, orthotopic, metastasized pancreatic ductal adenocarcinoma we evaluated the impact of sex on pathological features of this disease as well as on the efficacy and possible adverse side effects of a novel, small molecule-based therapy inhibiting KRAS:SOS1, MEK1/2 and PI3K signaling in male and female C57BL/6J mice. Male mice had less tumor infiltration of CD8-positive cells, developed bigger tumors, had more lung metastasis and a lower probability of survival compared to female mice. These more severe pathological features in male animals were accompanied by higher distress at the end of the experiment. The evaluated inhibitors BI-3406, trametinib and BKM120 showed synergistic effects in vitro. This combinatorial therapy reduced tumor weight more efficiently in male animals, although the drug concentrations were similar in the tumors of both sexes. These results underline the importance of sex-specific preclinical research and at the same time provide a solid basis for future studies with the tested compounds.

Manipulation of Glutamatergic Neuronal Activity in the Primary Motor Cortex Regulates Cardiac Function in Normal and Myocardial Infarction Mice.

Cardiac function is under neural regulation; however, brain regions in the cerebral cortex responsible for regulating cardiac function remain elusive. In this study, retrograde trans-synaptic viral tracing is used from the heart to identify a specific population of the excitatory neurons in the primary motor cortex (M1) that influences cardiac function in mice. Optogenetic activation of M1 glutamatergic neurons increases heart rate, ejection fraction, and blood pressure. By contrast, inhibition of M1 glutamatergic neurons decreased cardiac function and blood pressure as well as tyrosine hydroxylase (TH) expression in the heart. Using viral tracing and optogenetics, the median raphe nucleus (MnR) is identified as one of the key relay brain regions in the circuit from M1 that affect cardiac function. Then, a mouse model of cardiac injury is established caused by myocardial infarction (MI), in which optogenetic activation of M1 glutamatergic neurons impaired cardiac function in MI mice. Moreover, ablation of M1 neurons decreased the levels of norepinephrine and cardiac TH expression, and enhanced cardiac function in MI mice. These findings establish that the M1 neurons involved in the regulation of cardiac function and blood pressure. They also help the understanding of the neural mechanisms underlying cardiovascular regulation.

Exploring the effects of naringin on oxidative stress-impaired osteogenic differentiation via the Wnt/ß-catenin and PI3K/Akt pathways.

This study aimed to explore naringin's potential to promote the osteogenic differentiation of MC3T3-E1 under oxidative stress. It delved into Nar's connection with the Wnt/ß-catenin and PI3K/Akt signaling pathways. Initially, 2911 OP-related genes were analyzed, revealing close ties with the PI3K/Akt and Wnt pathways alongside oxidative stress. Nar's potential targets-ESR1, HSP90AA1, and ESR2-were identified through various databases and molecular docking studies confirmed Nar's affinity with ESR1 and HSP90AA1. Experiments established optimal concentrations for Nar and H2O2. H2O2 at 0.3 mmol/L damaged MC3T3-E1 cells, alleviated by 0.1 µmol/L Nar. Successful establishment of oxidative stress models was confirmed by DCFH-DA probe and NO detection. Nar exhibited the ability to enhance osteogenic differentiation, counteracting oxidative damage. It notably increased osteoblast-related protein expression in MC3T3-E1 cells under oxidative stress. The study found Nar's positive influence on GSK-3ß phosphorylation, ß-catenin accumulation, and pathway-related protein expression, all critical in promoting osteogenic differentiation. The research concluded that Nar effectively promotes osteogenic differentiation in MC3T3-E1 cells under oxidative stress. It achieved this by activating the Wnt/ß-catenin and PI3K/Akt pathways, facilitating GSK-3ß phosphorylation, and enhancing ß-catenin accumulation, pivotal in osteogenesis.

Resistance exercise upregulates Irisin expression and suppresses myocardial fibrosis following myocardial infarction via activating AMPK-Sirt1 and inactivating TGFß1-Smad2/3.

AIM: To reveal the contribution of Irisin in the beneficial effects of resistance exercise on myocardial fibrosis (MF) and cardiac function in the mice with myocardial infarction (MI). METHODS: The MI model was built by ligating the left anterior descending coronary artery in Fndc5 knockout mice (Fndc5-/-). Resistance exercise was started one week after surgery and continued for four weeks. In addition, H2O2, AICAR, recombinant human Irisin protein (rhIRISIN), and Sirt1 shRNA lentivirus (LV-Sirt1 shRNA) were used to intervene primary isolated cardiac fibroblasts (CFs). MF was observed through Masson staining, and apoptosis was assessed using TUNEL staining. MDA and T-SOD contents were detected by biochemical kits. The expression of proteins and genes was detected by Western blotting and RT-qPCR. RESULTS: Resistance exercise increased Fndc5 mRNA level, inhibited the activation of TGFß1-TGFßR2-Smad2/3 pathway, activated AMPK-Sirt1 pathway, reduced the levels of oxidative stress, apoptosis, and MF in the infarcted heart, and promoted cardiac function. However, Fndc5 knockout attenuated the protective effects of resistance exercise on the MI heart. Results of the in vitro experiments showed that AICAR and rhIRISIN intervention activated the AMPK-Sirt1 pathway and inactivated the TGFß1-Smad2/3 pathway, and promoted apoptosis in H2O2-treated CFs. Notably, these effects of rhIRISIN intervention, except for the TGFßR2 expression, were attenuated by LV-Sirt1 shRNA. CONCLUSION: Resistance exercise upregulates Fndc5 expression, activates AMPK-Sirt1 pathway, inhibits the activation of TGFß1-Smad2/3 pathway, attenuates MF, and promotes cardiac function after MI.

Alzheimer's disease transcriptional landscape in ex-vivo human microglia.

Microglia are resident immune cells of the brain and are implicated in the etiology of Alzheimer's Disease (AD) and other diseases. Yet the cellular and molecular processes regulating their function throughout the course of the disease are poorly understood. Here, we present the transcriptional landscape of primary microglia from 189 human postmortem brains, including 58 healthy aging individuals and 131 with a range of disease phenotypes, including 63 patients representing the full spectrum of clinical and pathological severity of AD. We identified transcriptional changes associated with multiple AD phenotypes, capturing the severity of dementia and neuropathological lesions. Transcript-level analyses identified additional genes with heterogeneous isoform usage and AD phenotypes. We identified changes in gene-gene coordination in AD, dysregulation of co-expression modules, and disease subtypes with distinct gene expression. Taken together, these data further our understanding of the key role of microglia in AD biology and nominate candidates for therapeutic intervention.

Activity-Dependent Transcriptional Program in NGN2+ Neurons Enriched for Genetic Risk for Brain-Related Disorders.

BACKGROUND: Converging evidence from large-scale genetic and postmortem studies highlights the role of aberrant neurotransmission and genetic regulation in brain-related disorders. However, identifying neuronal activity-regulated transcriptional programs in the human brain and understanding how changes contribute to disease remain challenging. METHODS: To better understand how the activity-dependent regulome contributes to risk for brain-related disorders, we profiled the transcriptomic and epigenomic changes following neuronal depolarization in human induced pluripotent stem cell-derived glutamatergic neurons (NGN2) from 6 patients with schizophrenia and 5 control participants. RESULTS: Multiomic data integration associated global patterns of chromatin accessibility with gene expression and identified enhancer-promoter interactions in glutamatergic neurons. Within 1 hour of potassium chloride-induced depolarization, independent of diagnosis, glutamatergic neurons displayed substantial activity-dependent changes in the expression of genes regulating synaptic function. Depolarization-induced changes in the regulome revealed significant heritability enrichment for schizophrenia and Parkinson's disease, adding to mounting evidence that sequence variation within activation-dependent regulatory elements contributes to the genetic risk for brain-related disorders. Gene coexpression network analysis elucidated interactions among activity-dependent and disease-associated genes and pointed to a key driver (NAV3) that interacted with multiple genes involved in axon guidance. CONCLUSIONS: Overall, we demonstrated that deciphering the activity-dependent regulome in glutamatergic neurons reveals novel targets for advanced diagnosis and therapy.

Insight into a natural novel histidine decarboxylase gene deletion in Enterobacter hormaechei RH3 from traditional Sichuan-style sausage.

Histamine (HIS) is primarily formed from decarboxylated histidine by certain bacteria with histidine decarboxylase (hdc) activity and is the most toxic biogenic amine. Hdc, which is encoded by the hdc gene, serves as a key enzyme that controls HIS production in bacteria. In this paper, we characterized the changes in microbial and biogenic amines content of traditional Sichuan-style sausage before and after storage and demonstrated that Enterobacteriaceae play an important role in the formation of HIS. To screen for Enterobacteriaceae with high levels of HIS production, we isolated strain RH3 which has a HIS production of 2.27 mg/mL from sausages stored at 37°C for 180 days, using selective media and high-performance liquid chromatography. The strain RH3 can produce a high level of HIS after 28 h of fermentation with a significant hysteresis. Analysis of the physicochemical factors revealed that RH3 still retained its ability to partially produce HIS in extreme environments with pH 3.5 and 10.0. In addition, RH3 exhibited excellent salt tolerance (6.0% NaCl and 1.0% NaNO2 ). Subsequently, RH3 was confirmed as Enterobacter hormaechei with hdc gene deletion by PCR, western blot, and whole-genome sequencing analysis. Furthermore, RH3 exhibited pathogenicity rate of 75.60% toward the organism, indicating that it was not a food-grade safe strain, and demonstrated a high level of conservation in intraspecific evolution. The results of this experiment provide a new reference for studying the mechanism of HIS formation in microorganisms. PRACTICAL APPLICATION: This study provides a new direction for investigating the mechanism of histamine (HIS) formation by microorganisms and provides new insights for further controlling HIS levels in meat products. Further research can control the key enzymes that form HIS to control HIS levels in food.