Role of Treg cell subsets in cardiovascular disease pathogenesis and potential therapeutic targets.

In the genesis and progression of cardiovascular diseases involving both innate and adaptive immune responses, inflammation plays a pivotal and dual role. Studies in experimental animals indicate that certain immune responses are protective, while others exacerbate the disease. T-helper (Th) 1 cell immune responses are recognized as key drivers of inflammatory progression in cardiovascular diseases. Consequently, the CD4+CD25+FOXP3+ regulatory T cells (Tregs) are gaining increasing attention for their roles in inflammation and immune regulation. Given the critical role of Tregs in maintaining immune-inflammatory balance and homeostasis, abnormalities in their generation or function might lead to aberrant immune responses, thereby initiating pathological changes. Numerous preclinical studies and clinical trials have unveiled the central role of Tregs in cardiovascular diseases, such as atherosclerosis. Here, we review the roles and mechanisms of Treg subsets in cardiovascular conditions like atherosclerosis, hypertension, myocardial infarction and remodeling, myocarditis, dilated cardiomyopathy, and heart failure. While the precise molecular mechanisms of Tregs in cardiac protection remain elusive, therapeutic strategies targeting Tregs present a promising new direction for the prevention and treatment of cardiovascular diseases.

Phosphorylation and O-GlcNAcylation at the same α-synuclein site generate distinct fibril structures.

α-Synuclein forms amyloid fibrils that are critical in the progression of Parkinson's disease and serves as the pathological hallmark of this condition. Different posttranslational modifications have been identified at multiple sites of α-synuclein, influencing its conformation, aggregation and function. Here, we investigate how disease-related phosphorylation and O-GlcNAcylation at the same α-synuclein site (S87) affect fibril structure and neuropathology. Using semi-synthesis, we obtained homogenous α-synuclein monomer with site-specific phosphorylation (pS87) and O-GlcNAcylation (gS87) at S87, respectively. Cryo-EM revealed that pS87 and gS87 α-synuclein form two distinct fibril structures. The GlcNAc situated at S87 establishes interactions with K80 and E61, inducing a unique iron-like fold with the GlcNAc molecule on the iron handle. Phosphorylation at the same site prevents a lengthy C-terminal region including residues 73 to 140 from incorporating into the fibril core due to electrostatic repulsion. Instead, the N-terminal half of the fibril (1-72) takes on an arch-like fibril structure. We further show that both pS87 and gS87 α-synuclein fibrils display reduced neurotoxicity and propagation activity compared with unmodified α-synuclein fibrils. Our findings demonstrate that different posttranslational modifications at the same site can produce distinct fibril structures, which emphasizes link between posttranslational modifications and amyloid fibril formation and pathology.

Phlorizin, an Important Glucoside: Research Progress on Its Biological Activity and Mechanism.

Phlorizin, as a flavonoid from a wide range of sources, is gradually becoming known for its biological activity. Phlorizin can exert antioxidant effects by regulating the IL-1ß/IKB-α/NF-KB signaling pathway. At the same time, it exerts its antibacterial activity by reducing intracellular DNA agglutination, reducing intracellular protein and energy synthesis, and destroying intracellular metabolism. In addition, phlorizin also has various pharmacological effects such as antiviral, antidiabetic, antitumor, and hepatoprotective effects. Based on domestic and foreign research reports, this article reviews the plant sources, extraction, and biological activities of phlorizin, providing a reference for improving the clinical application of phlorizin.

Swieteliacates S-U, phragmalin limonoids, from the leaves of Swietenia macrophylla.

Three novel phragmalin-type limonoids, swieteliacates S-U (1-3), were isolated from Swietenia macrophylla leaves, alongside four previously identified limonoids (4-7). The structures, encompassing absolute configurations, were delineated through 1D and 2D NMR analyses, high-resolution mass spectrometry (HR-MS), and NMR and ECD calculations. Swieteliacate S (1) is a distinctive cryptate comprising a tricyclo[4.2.110,30.11,4]decane fragment and an additional five-membered oxygen ring. Compounds 3 and 5 exhibited inhibition rates of 26.08 ± 2.26% and 15.42 ± 3.66%, respectively, on triglyceride (TG) production in Hep G2 cells at 40 µM.

Two new acorane-type sesquiterpenoids from an endophytic Trichoderma harzianum associated with Paeonia lactiflora Pall.

Two new acorane-type sesquiterpenoids, harzianes A and B (1 and 2), together with two known cyclonerodiol-type sesquiterpenoids (3-4) and four known sterols (5-8) were isolated from the endophytic Trichoderma harzianum, associated with the medicinal plant Paeonia lactiflora Pall. Compounds 1 and 2 were identified as a pair of heterotropic isomers by spectroscopic analysis (HR-ESI-MS, 1D and 2D NMR), and their absolute configurations were determined by ECD calculations. All compounds were tested for anti-inflammatory activity, however, none demonstrated such activity.

Anti-Inflammatory Lindenane Sesquiterpenoid Dimers from the Roots of Sarcandra glabra.

Sarglaroids A-H (1-8), eight new lindenane dimers, and a monomer sarglaroid I (9), along with fourteen known analogues (10-23), were isolated from the roots of Sarcandra glabra. The planar structures and the absolute configurations were elucidated by HR-MS, NMR, ECD calculations, and X-ray diffraction crystallography. Sarglaroid A (1) was identified as a rare 8,9-seco lindenane dimer with a unique 5/5/5 tricyclic system. The biological evaluation showed that compounds 1 and 13 potently inhibited NO production with IC50 values at 19.8 ± 1.06 and 10.7 ± 0.25 µM, respectively, and had no cytotoxicity to RAW264.7 cells. Compound 6 significantly inhibited the LPS-/ATP-induced IL-1ß release by inactivating the NLRP3 inflammasome through inhibiting the initiation and assembly by affecting the K+ efflux. Compounds 2 and 3 inhibited the proliferation of MCF-7 and MDA-MB-231 with IC50 values ranging from 5.4 to 10.2 µM.

Celastrol alleviated acute kidney injury by inhibition of ferroptosis through Nrf2/GPX4 pathway.

Ferroptosis is an important pathological process in acute kidney injury (AKI) which could lead to chronic kidney disease (CKD) and end-stage renal disease (ESRD). As an active ingredient of Chinese medicine Tripterygium wilfordii, celastrol has been reported to alleviate inflammation and preclinical studies have confirmed its anticancer effect. In the present study, we investigated the renal protective effects of celastrol against cisplatin induced AKI. Mice were administrated cisplatin by intraperitoneal injection and we found that celastrol reduced serum levels of BUN and creatinine, inhibited renal dysfunction, inflammation and oxidative stress. In addition, renal iron accumulation and ferroptosis were significantly reduced by celastrol treatment. Further mechanistic analyses suggested that Nrf2 is essential for celastrol upregulated GPX4 to alleviate ferroptosis and reduction of LDH release, intracellular iron accumulation and lipid peroxidation. These findings expand the potential uses of celastrol for treatment of various kinds of AKI associated with ferroptosis.

Development of an α-synuclein positron emission tomography tracer for imaging synucleinopathies.

Synucleinopathies are characterized by the accumulation of α-synuclein (α-Syn) aggregates in the brain. Positron emission tomography (PET) imaging of synucleinopathies requires radiopharmaceuticals that selectively bind α-Syn deposits. We report the identification of a brain permeable and rapid washout PET tracer [18F]-F0502B, which shows high binding affinity for α-Syn, but not for Aß or Tau fibrils, and preferential binding to α-Syn aggregates in the brain sections. Employing several cycles of counter screenings with in vitro fibrils, intraneuronal aggregates, and neurodegenerative disease brain sections from several mice models and human subjects, [18F]-F0502B images α-Syn deposits in the brains of mouse and non-human primate PD models. We further determined the atomic structure of the α-Syn fibril-F0502B complex by cryo-EM and revealed parallel diagonal stacking of F0502B on the fibril surface through an intense noncovalent bonding network via inter-ligand interactions. Therefore, [18F]-F0502B is a promising lead compound for imaging aggregated α-Syn in synucleinopathies.

CHI3L1 promotes myocardial fibrosis via regulating lncRNA TUG1/miR-495-3p/ETS1 axis.

Abnormal levels of CHI3L1 and lnc TUG1 are often associated with myocardial fibrosis, and their specific expressions may be closely related to the process of myocardial fibrosis. In addition, CHI3L1 was found to significantly up-regulate the expression of lncTUG1. Therefore, this study further explored the major role of CHI3L1 in regulating the progression of myocardial fibrosis. Myocardial fibrosis in mice was established using an angiotensin (Ang II) model, and the degree of myocardial fibrosis was assessed by qPCR, western blot and pathological techniques. HL-1 cells with overexpression and silencing of CHI3L1 were constructed, and the cell migration ability was detected using the Transwell method. Biological information was used to predict the potential target miRNA of lnc TUG1, and the interaction between them was verified by dual luciferase reporter assay. Using functional rescue assay and the rAAV9 technique, CHI3L1 was verified to affect the fibrotic process of myocardial cells by regulating the lnc TUG1/miR-495-3p/ETS1 axis in vitro and in vivo. The myocardial fibrosis index in the model group was significantly upregulated, and expression of both CHI3L1 and lnc TUG1 was upregulated. Pathological results revealed fibrosis and collagen deposition in the myocardium. Overexpression of lnc TUG1 reversed the inhibitory effect of CHI3L1 silencing on myocardial fibrosis. Mechanistically, CH3L1 upregulates the expression of lnc TUG1, and lnc TUG1 weakens the inhibition of ETS1 through sponge absorption of miR-495-3p, promoting the process of myocardial fibrosis.

Analysis of aerosol optical depth and relation to covariates during pre-monsoon season (2002-2019) over Pakistan using ARIMAX model and cross-wavelet analysis.

The pre-monsoon season heavily influences the precipitation amount in Pakistan. When hydrometeorological parameters interact with aerosols from multiple sources, a radiative climatic response is observed. In this study, aerosol optical depth (AOD) space-time dynamics were analyzed in relation to meteorological factors and surface parameters during the pre-monsoon season in the years 2002-2019 over Pakistan. Level-3 (L3) monthly datasets from Moderate Resolution Imaging Spectroradiometer (MODIS) and Multi-Angle Imaging Spectroradiometer (MISR) were used. Tropical Rainfall Measuring Mission (TRMM) derived monthly precipitation, Atmospheric Infrared Sounder (AIRS) derived air temperature, after moist relative humidity (RH) from Modern-Era Retrospective analysis for Research and Applications, Version-2 (MERRA-2), near-surface wind speed, and soil moisture data derived from Global Land Data Assimilation System (GLDAS) were also used on a monthly time scale. For AOD trend analysis, Mann-Kendall (MK) trend test was applied. Moreover, Autoregressive Integrated Moving Average with Explanatory variable (ARIMAX) technique was applied to observe the actual and predicted AOD trend, as well as test the multicollinearity of AOD with covariates. The periodicities of AOD were analyzed using continuous wavelet transformation (CWT) and the cross relationships of AOD with prevailing covariates on a time-frequency scale were analyzed by wavelet coherence analysis. A high variation of aerosols was observed in the spatiotemporal domain. The MK test showed a decreasing trend in AOD which was most significant in Baluchistan and Punjab, and the overall trend differs between MODIS and MISR datasets. ARIMAX model shows the correlation of AOD with varying meteorological and soil parameters. Wavelet analysis provides the abundance of periodicities in the 2-8 months periodic cycles. The coherency nature of the AOD time series along with other covariates manifests leading and lagging effects in the periodicities. Through this, a notable difference was concluded in space-time patterns between MODIS and MISR datasets. These findings may prove useful for short-term and long-term studies including oscillating features of AOD and covariates.

Green finance, renewable energy development, and climate change: evidence from regions of China.

In this study, using data from 2010 to 2021, and by utilizing the stochastic impacts by regression on population, affluence, and technology (STIRPAT) theory, and system generalized method of moments, the effect of green financing and deployment of renewable energy on carbon dioxide emissions in China and its provinces were analyzed. The results show that green financing reduces environmental pollution at the country level. Moreover, with a 1% increase in renewable energy consumption, carbon dioxide emission can be expected to decrease by 0.103%. It also demonstrates that green financing has a statistically significant coefficient only in provinces located in the eastern and western regions. Chinese policymakers should incentive policies for provinces in the eastern region of China in order to have a cleaner environment. The central region should be under supportive and pressure policies to move faster along the path to sustainable development.

Two new sesquiterpenoids from the roots of Sarcandra glabra.

Two new sesquiterpenoids, sarglanoids G and H (1 and 2), together with two known analogues (3-4) were isolated from the roots of Sarcandra glabra. Compound 2 was a rare elemene-type sesquiterpenoid with a furan ring fragment, which is mostly lactone ring in its analogues. The structures of new compounds were determined on the basis of extensive spectroscopic methods including HR-ESI-MS, 1D and 2D NMR, and the absolute configuration of 1 was established by ECD calculations. Their anti-inflammatory activities were also evaluated.

Financial performance of China's listed firms in presence of coronavirus: Evidence from corporate culture and corporate social responsibility.

Motivated from the shortage of the existing research studies on impacts of dangerously contagious diseases on firms' financial performance, this study sheds light on the impacts of Coronavirus (Covid-19) outbreak on financial performance upon on the quarterly data of 126 Chinese listed firms across 16 industries. Overall, the Covid-19 outbreak reduced Chinese listed firms' financial performance proxied by the revenue growth rate, ROA, ROE, and asset turnover. This outbreak's negative effects on Chinese firms' profitability were much smaller than that on their revenue growth rates. While this outbreak's negative effects on financial performance of Chinese listed firms were bigger for those that were seriously affected by this pandemic like airlines, travel, and entertainment (ATE), this pandemic's effects were positive for the medicine industry. In the meanwhile, Chinese listed firms that located in high-risk regions suffered a bigger financial loss during the outbreak, and especially there was a strong Hubei effect. The corporate culture and CSR moderated the inverse relationship between this outbreak and Chinese firms' financial performance. Findings of this study contribute to enrich the existing literature on impacts of the Covid-19 outbreak on firms' financial performance worldwide and suggest helpful practical and theoretical implications.

Conformational change of α-synuclein fibrils in cerebrospinal fluid from different clinical phases of Parkinson's disease.

α-Synuclein (α-syn) has been shown to form various conformational fibrils associated with different synucleinopathies. But whether the conformation of α-syn fibrils changes during disease progression is unclear. Here, we amplified α-syn aggregates from the cerebrospinal fluid (CSF) of patients with Parkinson's disease (PD) staged in preclinical PD (pre-PD), middle- to late-stage PD (mid-PD), and late-stage PD (late-PD). Our results show that α-syn fibrils derived from the late-PD patient are most potent in inducing endogenous α-syn aggregation in primary neurons, followed by the mid-PD and pre-PD fibrils. By using cryo-electron microscopy, we further determined the high-resolution structures of the CSF-amplified fibrils. The structures exhibit remarkable differences in a minor but significant population of conformational species in different staged samples. Our work demonstrates structural and pathological differences between α-syn fibrils derived from PD patients at a spectrum of clinical stages, which suggests potential conformational transition of α-syn fibrils during the progression of PD.

Rearranged Lindenane Sesquiterpenoid Trimers from Chloranthus fortunei: Target Discovery and Biomimetic Conversion.

Seven lindenane-type sesquiterpenoid trimers, including four new ones (1-4) and three known analogues (5-7), were isolated from Chloranthus fortunei guided by high-performance liquid chromatography with photodiode array detection with characteristic absorption at 210 and 350 nm. Their structures, including absolute configurations, were achieved by high-resolution mass spectrometry, nuclear magnetic resonance, electronic circular dichroism, and quantum chemical calculations. Compound 1 was the first example of two lindenane units connected by a C-15-C-15' bond. The 5/7/5-fused ring system in 2 was presumably formed biogenetically by key keto-enol tautomerism and Cope rearrangement from 5. The 5/3/6 carbon skeleton in 3-5 and epi-cyclopropane in 3 and 6 might have originated from trishizukaol A (7) with a normal 3/5/6-fused ring system through vinylcyclopropane rearrangement. The biomimetic conversion from 7 to 3-6 was successfully achieved by adding a 365 nm ultraviolet lamp and a free radical initiator, and 2 was also spontaneously converted to 5 in methanol and CDCl3, which proved the correctness of the structural identification and the speculation described above. Compounds 1-7 exhibited anti-inflammatory activity with IC50 values in the range of 2.90-22.80 µmol/L.

Somatic Mutation of PRKAR1A in Four Cases of Sporadic Cardiac Myxoma.

BACKGROUND: Inactivating mutations of the protein kinase A regulatory subunit 1 alpha (PRKAR1A) gene have been reported in familial cardiac myxoma. However, the role of PRKAR1A mutation in sporadic cardiac myxoma remains unknown. METHODS: Targeted next-generation sequencing (NGS) was performed to identify mutations with the PRKAR1A gene in seven cases of sporadic cardiac myxomas. Sanger sequencing of DNA from cardiac myxoma specimens and matched peripheral blood samples was performed to verify the identified mutations. RESULTS: Targeted NGS of myxoma DNA revealed 232 single nucleotide variants in 141 genes and 38 insertion-deletion mutations in 13 genes. Six PRKAR1A mutations were identified in four of the seven cardiac myxoma cases, and thus, the PRKAR1A inactivating mutation rate was 57.2% (4/7, 95% CI=0.44-0.58, P<0.05). The PRKAR1A variants identified by Sanger sequencing analysis were consistent with those from the NGS analysis for the four myxoma specimens. All of the pathogenic PRKAR1A mutations led to premature termination of PRKAR1A, except for one synonymous mutation. Moreover, none of the nonsense and missense mutations found in the myxoma specimens were found in the matched peripheral blood samples. CONCLUSION: Pathogenic mutations of the PRKAR1A gene were identified in tumor specimens from four cases of sporadic cardiac myxoma, and the absence of these mutations in peripheral blood samples demonstrated that they were somatic mutations.

Subtle change of fibrillation condition leads to substantial alteration of recombinant Tau fibril structure.

In vitro assembly of amyloid fibrils that recapitulate those in human brains is very useful for fundamental and applied research on the amyloid formation, pathology, and clinical detection. Recent success in the assembly of Tau fibrils in vitro enables the recapitulation of the paired helical filament (PHF) of Tau extracted from brains of patients with Alzheimer's disease (AD). However, following the protocol, we observed that Tau constructs including 297-391 and a mixture of 266-391 (3R)/297-391, which are expected to predominantly form PHF-like fibrils, form highly heterogeneous fibrils instead. Moreover, the seemingly PHF-like fibril formed by Tau 297-391 exhibits a distinctive atomic structure with a spindle-like fold, that is neither PHF-like or similar to any known Tau fibril structures revealed by cryo-electron microscopy (cryo-EM). Our work highlights the high sensitivity of amyloid fibril formation to subtle conditional changes and suggests high-resolution structural characterization to in vitro assembled fibrils prior to further laboratory use.

Sarcaglarone A, a lindenane-monoterpene heterodimer from the seeds of Sarcandra glabra.

Three novel lindenane-monoterpene heterodimers with different skeleton types (1-3), together with a known analogue (4), were obtained from the seeds of Sarcandra glabra. Their structures were elucidated on the basis of comprehensive spectroscopic analyses, single crystal X-ray diffraction, and calculations of ECD. Sarcaglarone A (1) displayed an unprecedented monocyclic monoterpene moiety formed by a free-radical-mediated C1'-C5' bond formation reaction. 6α-Hydroxysarglaperoxide A (2) and 7'-oxyisosarcaglabrin A (3) are C23 and C25 terpenes formed by [2 + 2 + 2] cycloaddition and the Diels-Alder reaction, respectively. Their inhibitory activities against nitric oxide (NO) production were evaluated.

Prediction of COVID-19 Data Using Hybrid Modeling Approaches.

A major emphasis is the dissemination of COVID-19 across the country's many regions and provinces. Using the present COVID-19 pandemic as a guide, the researchers suggest a hybrid model architecture for analyzing and optimizing COVID-19 data during the complete country. The analysis of COVID-19's exploration and death rate uses an ARIMA model with susceptible-infectious-removed and susceptible-exposed-infectious-removed (SEIR) models. The logistic model's failure to forecast the number of confirmed diagnoses and the snags of the SEIR model's too many tuning parameters are both addressed by a hybrid model method. Logistic regression (LR), Autoregressive Integrated Moving Average Model (ARIMA), support vector regression (SVR), multilayer perceptron (MLP), Recurrent Neural Networks (RNN), Gate Recurrent Unit (GRU), and long short-term memory (LSTM) are utilized for the same purpose. Root mean square error, mean absolute error, and mean absolute percentage error are used to show these models. New COVID-19 cases, the number of quarantines, mortality rates, and the deployment of public self-protection measures to reduce the epidemic are all outlined in the study's findings. Government officials can use the findings to guide future illness prevention and control choices.

Giant Cardiac Cavernous Hemangioma Diagnosed with Contrast-Enhanced Ultrasound: A Case Report.

Presently, there are few reports in the database about a contrast-enhanced ultrasound-assisted diagnosis of cardiac cavernous hemangioma. We report a case of giant cavernous hemangioma of the heart, which was diagnosed using contrast-enhanced ultrasound. Finally, it was confirmed by surgical pathology. This case demonstrates that contrast-enhanced ultrasound can play an important role in the diagnosis of cardiac cavernous hemangioma.