Regulation of optimized new Shengmai powder on cardiomyocyte apoptosis and ferroptosis in ischemic heart failure rats: The mediating role of phosphatidylinositol-3-kinase/protein kinase B/tumor protein 53 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Optimized New Shengmai Powder (ONSMP) is a sophisticated traditional Chinese medicinal formula renowned for bolstering vital energy, optimizing blood circulation, and mitigating fluid retention. After years of clinical application, ONSMP has shown a significant impact in improving myocardial injury and cardiac function and has a positive effect on treating heart failure. However, many unknowns exist about the molecular biological mechanisms of how ONSMP exerts its therapeutic effects, which require further research and exploration. AIM OF THE STUDY: Exploring the potential molecular biological mechanisms by which ONSMP ameliorates cardiomyocyte apoptosis and ferroptosis in ischemic heart failure (IHF). MATERIALS AND METHODS: First, we constructed a rat model of IHF by inducing acute myocardial infarction through surgery and using echocardiography, organ coefficients, markers of heart failure, antioxidant markers, and histopathological examination to assess the effects of ONSMP on cardiomyocyte apoptosis and ferroptosis in IHF rats. Next, we used bioinformatics analysis techniques to analyze the active components, signaling pathways, and core targets of ONSMP and calculated the interactions between core targets and corresponding elements. Finally, we detected the positive expression of apoptosis and ferroptosis markers and core indicators of signaling pathways by immunohistochemistry; detected the mean fluorescence intensity of core indicators of signaling pathways by immunofluorescence; detected the protein expression of signaling pathways and downstream effector molecules by western blotting; and detected the mRNA levels of p53 and downstream effector molecules by quantitative polymerase chain reaction. RESULTS: ONSMP can activate the Ser83 site of ASK by promoting the phosphorylation of the PI3K/AKT axis, thereby inhibiting the MKK3/6-p38 axis and the MKK4/7-JNK axis signaling to reduce p53 expression, and can also directly target and inhibit the activity of p53, ultimately inhibiting p53-mediated mRNA and protein increases in PUMA, SAT1, PIG3, and TFR1, as well as mRNA and protein decreases in SLC7A11, thereby inhibiting cardiomyocyte apoptosis and ferroptosis, effectively improving cardiac function and ventricular remodeling in IHF rat models. CONCLUSION: ONSMP can inhibit cardiomyocyte apoptosis and ferroptosis through the PI3K/AKT/p53 signaling pathway, delaying the development of IHF.

Strength-ductility materials by engineering a coherent interface at incoherent precipitates.

In the quest for excellent light-structural materials that can withstand mechanical extremes for advanced applications, design and control of microstructures beyond current material design strategies have become paramount. Herein, we design a coherent shell at incoherent precipitates in the 2195 aluminum alloy with multi-step metastable phase transitions. A high local strain rate via a neoteric deformation-driven metallurgy method facilitated the diffusion of Li. The original T1 (Al2CuLi) phases were transformed into coherent-shell (Li-rich) irregular-coated incoherent-core (Al2Cu) precipitates. The ultimate tensile strength and elongation reached 620 ± 18 MPa and 22.3 ± 2.2%, exhibiting excellent strength-ductility synergy. Grain boundaries, dislocation, solid solution atoms, and precipitates all contributed to the yield strength of the materials, among which precipitates occupied a dominant position, contributing approximately 56.07%. A new "incoherent-coherent interact" strain-hardening mechanism was also clarified, which was believed to be promoted in other heat-treatable alloy systems, especially with multi-step metastable phase transitions.

Phenotypic Characteristics and Occurrence Basis of Leaf Necrotic Spots in Response of Weedy Rice to Imazethapyr.

Weedy rice is the most challenging weed species to remove in rice production. We found a novel phenotype of seedling leaves which rapidly generates necrotic spots in response to imidazolinone herbicides in weedy rice, but its influencing factors and formation basis are still unknown. In this study, we used the leaf necrotic spot-producing type of weedy rice as the material. First, leaf necrotic spots were defined as physiological and vacuole-mediated cell necrosis by microscopic examination. The imazethapyr concentration was positively correlated with the degree of necrotic spots occurring, while the action site was in accordance with necrosis using herbicide stability tests combined with fluorescence parameters. Furthermore, transcriptome analysis revealed significant differences in the gene expression of endoplasmic reticulum stress and the lipid metabolism membrane structure damage pathway during necrosis, as confirmed by transmission electron microscopy. The light-temperature test also showed that high temperature and intense light could promote the appearance of necrotic spots. These experimental results are helpful in clarifying the process and basis of imazethapyr in inducing the rapid generation of necrotic spots in rice leaves and providing new insight into understanding the mechanism of response to imidazolinone herbicides and the control of weedy rice.

NIR-II light in clinical oncology: opportunities and challenges.

Novel strategies utilizing light in the second near-infrared region (NIR-II; 900-1,880 nm wavelengths) offer the potential to visualize and treat solid tumours with enhanced precision. Over the past few decades, numerous techniques leveraging NIR-II light have been developed with the aim of precisely eliminating tumours while maximally preserving organ function. During cancer surgery, NIR-II optical imaging enables the visualization of clinically occult lesions and surrounding vital structures with increased sensitivity and resolution, thereby enhancing surgical quality and improving patient prognosis. Furthermore, the use of NIR-II light promises to improve cancer phototherapy by enabling the selective delivery of increased therapeutic energy to tissues at greater depths. Initial clinical studies of NIR-II-based imaging and phototherapy have indicated impressive potential to decrease cancer recurrence, reduce complications and prolong survival. Despite the encouraging results achieved, clinical translation of innovative NIR-II techniques remains challenging and inefficient; multidisciplinary cooperation is necessary to bridge the gap between preclinical research and clinical practice, and thus accelerate the translation of technical advances into clinical benefits. In this Review, we summarize the available clinical data on NIR-II-based imaging and phototherapy, demonstrating the feasibility and utility of integrating these technologies into the treatment of cancer. We also introduce emerging NIR-II-based approaches with substantial potential to further enhance patient outcomes, while also highlighting the challenges associated with imminent clinical studies of these modalities.

Correction: Influence of Environmental Factors and Genome Diversity on Cumulative COVID-19 Cases in the Highland Region of China: Comparative Correlational Study.

[This corrects the article DOI: .].

Lenvatinib­based treatment regimens in conversion therapy of unresectable hepatocellular carcinoma: A systematic review and meta­analysis.

Hepatocellular carcinoma (HCC) is a malignancy associated with high morbidity and mortality rates. Conversion therapy provides patients with unresectable HCC (uHCC) the opportunity to undergo radical treatment and achieve long-term survival. Despite accumulating evidence regarding the efficacy of conversion therapy, the optimal treatment approach for such therapy remains uncertain. Lenvatinib (LEN) has shown efficacy and tolerable rates of adverse events (AEs) when applied in combination with immune checkpoint inhibitors (ICIs) or locoregional therapy (LRT) over the past decade. Therefore, the present meta-analysis was performed to systematically assess the safety and efficacy of LEN-based treatment regimens in conversion therapies for uHCC. Data on outcomes, including the conversion rate, objective response rate (ORR), disease control rate (DCR) and AE incidence in patients with uHCC, were collected. A systematic literature search was performed using MEDLINE, Embase, Web of Science and Cochrane Library databases, up to the date of September 1, 2023. In total, 16 studies, encompassing a total of 1,650 cases of uHCC, were included in the final meta-analysis. The pooled conversion rates for LEN alone, LEN + ICI, LEN + LRT and LEN + ICI + LRT were calculated to be 0.04 (95% CI, 0.00-0.07; I2=77%), 0.23 (95% CI, 0.16-0.30; I2=66%), 0.14 (95% CI, 0.10-0.18; I2=0%) and 0.35 (95% CI, 0.23-0.47; I2=88%), respectively. The pooled ORRs for LEN alone, LEN + ICI, LEN + LRT and LEN + ICI + LRT were found to be 0.45 (95% CI, 0.23-0.67; I2=96%), 0.49 (95% CI, 0.39-0.60; I2=78%), 0.43 (95% CI, 0.24-0.62; I2=88%) and 0.69 (95% CI, 0.56-0.82; I2=92%), respectively. The pooled DCRs for LEN alone, LEN + ICI, LEN + LRT and LEN + ICI + LRT were observed to be 0.77 (95% CI, 0.73-0.81; I2=23%), 0.82 (95% CI, 0.69-0.95; I2=90%), 0.67 (95% CI, 0.39-0.94; I2=94%) and 0.87 (95% CI, 0.82-0.93; I2=67%), respectively. The pooled grade ≥3 AEs for LEN alone, LEN + ICI, LEN + LRT and LEN + ICI + LRT were 0.25 (95% CI, 0.14-0.36; I2=89%), 0.43 (95% CI, 0.34-0.53; I2=23%), 0.42 (95% CI, 0.19-0.66; I2=81%) and 0.35 (95% CI, 0.17-0.54; I2=94%), respectively. These findings suggested that LEN-based combination strategies may confer efficacy and acceptable tolerability for patients with uHCC. In particular, LEN + ICI, with or without LRT, appears to represent a highly effective conversion regimen, with an acceptable conversion rate and well-characterized safety profile.

Assembly of Glycopeptides in Living Cells Resembling Viral Infection for Cargo Delivery.

Self-assembly in living cells represents one versatile strategy for drug delivery; however, it suffers from the limited precision and efficiency. Inspired by viral traits, we here report a cascade targeting-hydrolysis-transformation (THT) assembly of glycosylated peptides in living cells holistically resembling viral infection for efficient cargo delivery and combined tumor therapy. We design a glycosylated peptide via incorporating a ß-galactose-serine residue into bola-amphiphilic sequences. Co-assembling of the glycosylated peptide with two counterparts containing irinotecan (IRI) or ligand TSFAEYWNLLSP (PMI) results in formation of the glycosylated co-assemblies SgVEIP, which target cancer cells via ß-galactose-galectin-1 association and undergo galactosidase-induced morphological transformation. While GSH-reduction causes release of IRI from the co-assemblies, the PMI moieties release p53 and facilitate cell death via binding with protein MDM2. Cellular experiments show membrane targeting, endo-/lysosome-mediated internalization and in situ formation of nanofibers in cytoplasm by SgVEIP. This cascade THT process enables efficient delivery of IRI and PMI into cancer cells secreting Gal-1 and overexpressing ß-galactosidase. In vivo studies illustrate enhanced tumor accumulation and retention of the glycosylated co-assemblies, thereby suppressing tumor growth. Our findings demonstrate an in situ assembly strategy mimicking viral infection, thus providing a new route for drug delivery and cancer therapy in the future.

Resveratrol protects cardiomyocytes against ischemia/reperfusion-induced ferroptosis via inhibition of the VDAC1/GPX4 pathway.

The present study aimed to explore how resveratrol (Res) confers myocardial protection by attenuating ferroptosis. In vivo and in vitro myocardial ischemia/reperfusion injury (MIRI) models were established, with or without Res pretreatment. The results showed that Res pretreatment effectively attenuated MIRI, as evidenced by increased cell viability, reduced lactate dehydrogenase activity, decreased infarct size, and maintained cardiac function. Moreover, Res pretreatment inhibited MIRI-induced ferroptosis, as shown by improved mitochondrial integrity, increased glutathione level, decreased prostaglandin-endoperoxide synthase 2 level, inhibited iron overload, and abnormal lipid peroxidation. Of note, Res pretreatment decreased or increased voltage-dependent anion channel 1/glutathione peroxidase 4 (VDAC1/GPX4) expression, which was increased or decreased via anoxia/reoxygenation (A/R) treatment, respectively. However, the overexpression of VDAC1 via pAd/VDAC1 and knockdown of GPX4 through Si-GPX4 reversed the protective effect of Res in A/R-induced H9c2 cells, whereas the inhibition of GPX4 with RSL3 abolished the protective effect of Res on mice treated with ischemia/reperfusion.Interestingly, knockdown of VDAC1 by Si-VDAC1 promoted the protective effect of Res on A/R-induced H9c2 cells and the regulation of GPX4. Finally, the direct interaction between VDAC1 and GPX4 was determined using co-immunoprecipitation. In conclusion, Res pretreatment could protect the myocardium against MIRI-induced ferroptosis via the VDAC1/GPX4 signaling pathway.

Trajectory of COVID-19 response and management strategy in China: scientific rationale driven strategy adjustments.

The pneumonia caused by novel coronavirus SARS-CoV-2 infection in early December 2019, which was later named coronavirus disease 2019 (COVID-19) by the World Health Organization (WHO), rapidly spread across the world. China has made extraordinary efforts to this unprecedented pandemic, put its response and control at a very high level of infectious disease management (Category B but with measures for Category A), given top priority to the people and their lives, and balanced the pandemic control and socio-economic development. After more than three years' fighting against this disease, China downgraded the management of COVID-19 to Category B infectious disease on January 8, 2023 and the WHO declared the end of public health emergency on May 5, 2023. However, the ending of pandemic does not mean that the disease is no longer a health threat. Experiences against COVID-19 from China and the whole world should be learned to prepare well for the future public health emergencies. This article gives a systematic review of the trajectory of COVID-19 development in China, summarizes the critical policy arrangements and provides evidence for the adjustment during policy making process, so as to share experiences with international community and contribute to the global health for all humanity.

Sulfatase-Induced In Situ Formulation of Antineoplastic Supra-PROTACs.

Proteolysis targeting chimera (PROTAC) technology is an innovative strategy for cancer therapy, which, however, suffers from poor targeting delivery and limited capability for protein of interest (POI) degradation. Here, we report a strategy for the in situ formulation of antineoplastic Supra-PROTACs via intracellular sulfatase-responsive assembly of peptides. Coassembling a sulfated peptide with two ligands binding to ubiquitin VHL and Bcl-xL leads to the formation of a pro-Supra-PROTAC, in which the ratio of the two ligands is rationally optimized based on their protein binding affinity. The resulting pro-Supra-PROTAC precisely undergoes enzyme-responsive assembly into nanofibrous Supra-PROTACs in cancer cells overexpressing sulfatase. Mechanistic studies reveal that the pro-Supra-PROTACs selectively cause apparent cytotoxicity to cancer cells through the degradation of Bcl-xL and the activation of caspase-dependent apoptosis, during which the rationally optimized ligand ratio improves the bioactivity for POI degradation and cell death. In vivo studies show that in situ formulation enhanced the tumor accumulation and retention of the pro-Supra-PROTACs, as well as the capability for inhibiting tumor growth with excellent biosafety when coadministrating with chemodrugs. Our findings provide a new approach for enzyme-regulated assembly of peptides in living cells and the development of PROTACs with high targeting delivering and POI degradation efficiency.

High-Performance Broadband Image Sensing Photodetector Based on MnTe/WS2 van der Waals Epitaxial Heterostructures.

Two-dimensional transition metal dichalcogenide (TMDC) heterostructure is receiving considerable attention due to its novel electronic, optoelectronic, and spintronic devices with design-oriented and functional features. However, direct design and synthesis of high-quality TMDC/MnTe heterostructures remain difficult, which severely impede further investigations of semiconductor/magnetic semiconductor devices. Herein, the synthesis of high-quality vertically stacked WS2/MnTe heterostructures is realized via a two-step chemical vapor deposition method. Raman, photoluminescence, and scanning transmission electron microscopy characterizations reveal the high-quality and atomically sharp interfaces of the WS2/MnTe heterostructure. WS2/MnTe-based van der Waals field effect transistors demonstrate high rectification behavior with rectification ratio up to 106, as well as a typical p-n electrical transport characteristic. Notably, the fabricated WS2/MnTe photodetector exhibits sensitive and broadband photoresponse ranging from UV to NIR with a maximum responsivity of 1.2 × 103 A/W, a high external quantum efficiency of 2.7 × 105%, and fast photoresponse time of ∼50 ms. Moreover, WS2/MnTe heterostructure photodetectors possess a broadband image sensing capability at room temperature, suggesting potential applications in next-generation high-performance and broadband image sensing photodetectors.

PU.1 induces tumor-associated macrophages promoting glioma progression through BTK-mediated Akt/mTOR pathway activation.

Glioma, the most common primary malignant brain tumor, is characterized by infiltrating immune cells that contribute to tumor progression and therapeutic resistance. Tumor-associated macrophages (TAMs) constitute a significant proportion of these infiltrating immune cells and have been implicated in glioma progression. However, the underlying molecular mechanisms by which TAMs promote glioma progression remain elusive. In this study, we investigated the role of PU.1, a crucial transcription factor involved in myeloid cell development, in glioma-associated macrophage polarization and activation. First, bioinformatics and analysis of clinical glioma samples demonstrated a positive correlation between PU.1 expression in TAMs and disease severity. Further experiments using in vitro coculture systems revealed that the expression of PU.1 is increased in glioma cells vs. control cells. Importantly, PU.1-overexpressing macrophages exhibited a protumorigenic phenotype characterized by enhanced migration, invasion, and proliferation. Mechanistically, we found that PU.1-induced activation of the Bruton tyrosine kinase (BTK) signaling pathway led to Akt/mTOR pathway activation in macrophages, which further enhanced their protumorigenic functions. Furthermore, pharmacological inhibition of the BTK or Akt/mTOR pathway reversed the protumorigenic effects of macrophages in vitro and impaired their ability to promote glioma progression in vivo. In conclusion, our study elucidates a novel mechanism by which PU.1 induces the polarization and activation of TAMs in the glioma microenvironment. We highlight the significance of BTK-mediated Akt/mTOR pathway activation in driving the protumorigenic functions of TAMs. Targeting PU.1 and its downstream signaling pathways in TAMs may provide a promising therapeutic strategy to suppress glioma progression and improve patient outcomes.

Berberine inhibits excessive autophagy and protects myocardium against ischemia/reperfusion injury via the RhoE/AMPK pathway.

Several studies have shown that berberine (BBR) is effective in protecting against myocardial ischemia­reperfusion injury (MI/RI). However, the precise molecular mechanism remains elusive. The present study observed the mechanism and the safeguarding effect of BBR against hypoxia/reoxygenation (H/R) myocardial injury in H9c2 cells. BBR pretreatment significantly improved the decrease of cell viability, P62 protein, Rho Family GTPase 3 (RhoE) protein, ubiquinone subunit B8 protein, ubiquinol­cytochrome c reductase core protein U, the Bcl­2­associated X protein/B­cell lymphoma 2 ratio, glutathione (GSH) and the GSH/glutathione disulphide (GSSG) ratio induced by H/R, while reducing the increase in lactate dehydrogenase, microtubule­associated protein 1 light 3 protein, caspase­3 activity, reactive oxygen species, GSSG and malonaldehyde caused by H/R. Transmission electron microscopy and LysoTracker Red DND­99 staining results showed that BBR pretreatment inhibited H/R­induced excessive autophagy by mediating RhoE. BBR also inhibited mitochondrial permeability transition, maintained the stability of the mitochondrial membrane potential, reduced the apoptotic rate, and increased the level of caspase­3. However, the protective effects of BBR were attenuated by pAD/RhoE­small hairpin RNA, rapamycin (an autophagy activator) and compound C (an AMP­activated protein kinase inhibitor). These new findings suggested that BBR protects the myocardium from MI/RI by inhibiting excessive autophagy, maintaining mitochondrial function, improving the energy supply and redox homeostasis, and attenuating apoptosis through the RhoE/AMP­activated protein kinase pathway.

Self-assembly of peptides in living cells for disease theranostics.

The past few decades have witnessed substantial progress in biomedical materials for addressing health concerns and improving disease therapeutic and diagnostic efficacy. Conventional biomedical materials are typically created through an ex vivo approach and are usually utilized under physiological environments via transfer from preparative media. This transfer potentially gives rise to challenges for the efficient preservation of the bioactivity and implementation of theranostic goals on site. To overcome these issues, the in situ synthesis of biomedical materials on site has attracted great attention in the past few years. Peptides, which exhibit remarkable biocompability and reliable noncovalent interactions, can be tailored via tunable assembly to precisely create biomedical materials. In this review, we summarize the progress in the self-assembly of peptides in living cells for disease diagnosis and therapy. After a brief introduction to the basic design principles of peptide assembly systems in living cells, the applications of peptide assemblies for bioimaging and disease treatment are highlighted. The challenges in the field of peptide self-assembly in living cells and the prospects for novel peptide assembly systems towards next-generation biomaterials are also discussed, which will hopefully help elucidate the great potential of peptide assembly in living cells for future healthcare applications.

Epigallocatechin-3-gallate confers protection against myocardial ischemia/reperfusion injury by inhibiting ferroptosis, apoptosis, and autophagy via modulation of 14-3-3η.

Previous studies have demonstrated that the underlying mechanisms of myocardial ischemia/reperfusion injury (MIRI) are complex and involve multiple types of regulatory cell death, including ferroptosis, apoptosis, and autophagy. Thus, we aimed to identify the mechanisms underlying MIRI and validate the protective role of epigallocatechin-3-gallate (EGCG) and its related mechanisms in MIRI. An in vivo and in vitro models of MIRI were constructed. The results showed that pretreatment with EGCG could attenuate MIRI, as indicated by increased cell viability, reduced lactate dehydrogenase (LDH) activity and apoptosis, inhibited iron overload, abnormal lipid metabolism, preserved mitochondrial function, decreased infarct size, maintained cardiac function, decreased reactive oxygen species (ROS) level, and reduced TUNEL-positive cells. Additionally, EGCG pretreatment could attenuate ferroptosis, apoptosis, and autophagy induced by MIRI via upregulating 14-3-3η protein levels. Furthermore, the protective effects of EGCG could be abolished with pAd/14-3-3η-shRNA or Compound C11 (a 14-3-3η inhibitor) but not pAd/NC-shRNA. In conclusion, EGCG pretreatment attenuated ferroptosis, apoptosis, and autophagy by mediating 14-3-3η and protected cardiomyocytes against MIRI.

Mechanically Excellent, Notch-Insensitive, and Highly Conductive Double-Network Hydrogel for Flexible Strain Sensor.

A novel double-network conductive hydrogel based on lithium acetate/gelatin/polyacrylamide (PAAM) was synthesized by heating-cooling and subsequent γ-ray radiation-induced polymerization and cross-linking. Owing to the hydrogen bonding interaction between lithium acetate, physical cross-linked gelatin, and chemical cross-linked PAAM, the resultant hydrogel exhibited high tensile strength (1260 kPa), high ionic conductivity (35.2 mS cm-1), notch-insensitivity (tensile strength 415 kPa, elongation at break 872% with transverse notch), and extensive strain monitoring range (0.15-800%) under optimum conditions. The lithium acetate/gelatin/polyacrylamide hydrogel strain sensor attached to the skin can sensitively monitor the subtle movements of the human body. The strain sensor based on the resultant hydrogel with transverse notch can still work for 1200 cycles, due to that the covalent-cross-linked PAAm chain bridges the cracks and stabilizes the deformation, while the physical-cross-linked gelatin was unzipped to make the blunting of notch. The conductive hydrogel with high-sensitivity and high stability is expected to be used as materials for the preparation of flexible strain sensors in the future.

Metabolomics reveals factors affecting the radical reaction of sulfides during thermal processing for meaty aroma.

The effects of cysteine (Cys), glutathione (GSH) and cystine (GCys) on sulfides and meaty aroma were studied based on concentration monitoring and metabolomics. In multi-component models, Cys and GSH demonstrated a greater capacity to decrease dimethyl trisulfide (DMTS) levels and increase the proportion of 2-methyl-3-furanthiol (MFT), compared with GCys. Moreover, no discernible difference between Cys and GSH in dynamic profiles of volatiles to further analyze the synergistic effect of both. Results of single factor experiment and optimization revealed that the optimal thermal processing was a second-order thermal procedure. Aroma profiles revealed that the addition of Cys and GSH mixture increased the meaty intensity during the optimal thermal processing. Metabolomics based on Encyclopedia of Genes and Genomes pathway annotation confirmed that Cys and GSH significantly affected the degradation of methionine and thiamine in amino acid and protein metabolic pathways, resulting in various amounts of DMTS and MFT. Research on effect and potentially metabolic mechanisms revealed that the combination of Cys and GSH at ratio of 3:7 had higher and more effective control capacity for free radical reaction of sulfides than either one alone during second-order thermal processing, which would lay theoretical foundation for the development of high-quality thermal process products.

Targeting MAPK-ERK/JNK pathway: A potential intervention mechanism of myocardial fibrosis in heart failure.

Myocardial fibrosis is a significant pathological basis of heart failure. Overactivation of the ERK1/2 and JNK1/2 signaling pathways of MAPK family members synergistically promotes the proliferation of myocardial fibroblasts and accelerates the development of myocardial fibrosis. In addition to some small molecule inhibitors and Western drugs, many Chinese medicines can also inhibit the activity of ERK1/2 and JNK1/2, thus slowing down the development of myocardial fibrosis, and are generally safe and effective. However, the specific biological mechanisms of ERK1/2 and JNK1/2 signaling pathways in myocardial fibrosis still need to be fully understood, and there is no systematic review of existing drugs and methods to inhibit them from improving myocardial fibrosis. This study aims to summarize the roles and cross-linking mechanisms of ERK1/2 and JNK1/2 signaling pathways in myocardial fibrosis and to systematically sort out the small-molecule inhibitors, Western drugs, traditional Chinese medicines, and non-pharmacological therapies that inhibit ERK1/2 and JNK1/2 to alleviate myocardial fibrosis. In the future, we hope to conduct more in-depth research from the perspective of precision-targeted therapy, using this as a basis for developing new drugs that provide new perspectives on the prevention and treatment of heart failure.

Influence of Environmental Factors and Genome Diversity on Cumulative COVID-19 Cases in the Highland Region of China: Comparative Correlational Study.

BACKGROUND: The novel coronavirus SARS-CoV-2 caused the global COVID-19 pandemic. Emerging reports support lower mortality and reduced case numbers in highland areas; however, comparative studies on the cumulative impact of environmental factors and viral genetic diversity on COVID-19 infection rates have not been performed to date. OBJECTIVE: The aims of this study were to determine the difference in COVID-19 infection rates between high and low altitudes, and to explore whether the difference in the pandemic trend in the high-altitude region of China compared to that of the lowlands is influenced by environmental factors, population density, and biological mechanisms. METHODS: We examined the correlation between population density and COVID-19 cases through linear regression. A zero-shot model was applied to identify possible factors correlated to COVID-19 infection. We further analyzed the correlation of meteorological and air quality factors with infection cases using the Spearman correlation coefficient. Mixed-effects multiple linear regression was applied to evaluate the associations between selected factors and COVID-19 cases adjusting for covariates. Lastly, the relationship between environmental factors and mutation frequency was evaluated using the same correlation techniques mentioned above. RESULTS: Among the 24,826 confirmed COVID-19 cases reported from 40 cities in China from January 23, 2020, to July 7, 2022, 98.4% (n=24,430) were found in the lowlands. Population density was positively correlated with COVID-19 cases in all regions (ρ=0.641, P=.003). In high-altitude areas, the number of COVID-19 cases was negatively associated with temperature, sunlight hours, and UV index (P=.003, P=.001, and P=.009, respectively) and was positively associated with wind speed (ρ=0.388, P<.001), whereas no correlation was found between meteorological factors and COVID-19 cases in the lowlands. After controlling for covariates, the mixed-effects model also showed positive associations of fine particulate matter (PM2.5) and carbon monoxide (CO) with COVID-19 cases (P=.002 and P<.001, respectively). Sequence variant analysis showed lower genetic diversity among nucleotides for each SARS-CoV-2 genome (P<.001) and three open reading frames (P<.001) in high altitudes compared to 300 sequences analyzed from low altitudes. Moreover, the frequencies of 44 nonsynonymous mutations and 32 synonymous mutations were significantly different between the high- and low-altitude groups (P<.001, mutation frequency>0.1). Key nonsynonymous mutations showed positive correlations with altitude, wind speed, and air pressure and showed negative correlations with temperature, UV index, and sunlight hours. CONCLUSIONS: By comparison with the lowlands, the number of confirmed COVID-19 cases was substantially lower in high-altitude regions of China, and the population density, temperature, sunlight hours, UV index, wind speed, PM2.5, and CO influenced the cumulative pandemic trend in the highlands. The identified influence of environmental factors on SARS-CoV-2 sequence variants adds knowledge of the impact of altitude on COVID-19 infection, offering novel suggestions for preventive intervention.