[Down-regulation of miR-488 targeting to promote Jag1 expression inhibits hypoxia-reoxygenation myocardial H9c2 cell damage].

OBJECTIVE: To study the effect of down-regulating miR-488 targeting Jag1 on the injury of hypoxia-reoxygenation myocardial H9c2 cells. METHODS: A hypoxic-reoxygenated myocardial H9c2 cell injury model was constructed. miR-488 inhibitor was used to transfect the cells. CCK-8 method and flow cytometry were used to detect cell proliferation and apoptosis in each group. Lactate dehydrogenase (LDH), superoxide dismutase (SOD), malonaldehyde (MDA), catalase (CAT) levels were detected. Western blotting was used to detect the expression of Bcl-2 associated X Protein (Bax) and B cell lymphoma/lewkmia-2 (Bcl-2). Target genes of miR-488 were predicted, and a luciferase reporter system was used to verify the targeting relationship between the two. Myocardial H9c2 cells were co-transfected with miR-488 inhibitor and Jag1 siRNA, and treated with hypoxia and reoxygenation, cell proliferation, apoptosis, LDH, SOD, MDA, CAT levels, and Bax, Bcl-2 protein expression were detected. RESULTS: The expression of miR-488 in the hypoxia-reoxygenated myocardial H9c2 cells was increased, along with reduced cell proliferation, increased apoptosis, increased Bax protein expression, decreased Bcl-2 protein expression, increased MDA, decreased CAT and SOD, and increased LDH level in the supernatant of cell culture. When myocardial H9c2 cells were transfected with miR-488 inhibitor and treated with hypoxia and reoxygenation, the expression of miR-488 was decreased, along with increased cell proliferation, decreased apoptosis, decreased Bax protein expression, increased Bcl-2 protein expression, decreased MDA, increased CAT and SOD, and decreased LDH level in the supernatant of cell culture. Down-regulation of miR-488 could target and down-regulate Jag1 expression. And Jag1 siRNA could reverse the effect of miR-488 inhibitor on the proliferation, apoptosis, LDH, SOD, MDA, CAT levels and the expression of Bax and Bcl-2 of hypoxic-reoxygenated myocardial H9c2 cells. CONCLUSION: Down-regulating miR-488 targeted Jag1 can attenuate hypoxia-reoxygenation induced myocardial H9c2 cell injury.

A new species of the genus Soriculus (Soricidae, Eulipotyphla, Mammalia) from Medog in the eastern Himalaya.

Himalayan shrews of the genus Soriculus (Soricidae, Eulipotyphla), currently represented by four nominal species, are endemic to the Himalayas and the Gaoligong Mountains. In April 2022 and April 2023, a total of 10 specimens of Soriculus were collected from Beibeng and Damu, Medog County, Tibet, China. The morphology of the specimens was compared with the four recognised species of the genus Soriculus. Additionally, two mitochondrial (Cyt b and 12S) and three nuclear (APOB, BRCAI and RAG2) genes were sequenced to test the phylogenetic relationships of these specimens with the other species. Our results indicate that these specimens represent a distinct species, Soriculusbeibengensissp. nov., which is formally described here. The new species is distinguished from the other Soriculus species by the combination of darker pelages, smaller size, the relatively stubby nasal and the widened posterior processes of incisors. Phylogenetic analyses revealed the new species is sister to S.minor. The p-distance of Cyt b gene between S.beibengensis sp. nov. and other nominal Soriculus species ranges from 9.1-16.3%. This new species has a known distribution at an elevation of 1,500-2,125 m in Medog County, Tibet, China. The discovery of this new species from Medog County has important implications for interpreting small mammal biogeographic patterns in the eastern Himalaya and the mountain chains of south-west China.

LRRK2 deficiency protects the heart against myocardial infarction injury in mice via the P53/HMGB1 pathway.

LRRK2 is a Ser/Thr kinase with multiple functional domains. Studies have shown that LRRK2 mutations are closely related to hereditary Parkinson's disease. However, its role in cardiovascular disease, especially in myocardial infarction, is unclear. The aim of this study was to explore the functional role of LRRK2 in myocardial infarction. Wild-type and LRRK2-knockout mice were subjected to coronary artery ligation (left anterior descending) to establish a myocardial infarction model. Neonatal rat cardiomyocytes were subjected to hypoxia to induce hypoxic injury in vitro. We found increased LRRK2 expression levels in the infarct periphery in mouse hearts and hypoxic cardiomyocytes. LRRK2-deficient mice exhibited decreased death rates and reduced infarction areas compared to wild-type controls 14 days after infarction. LRRK2-deficient mice showed reduced left ventricular fibrosis and inflammatory responses, as well as improved cardiac function. In the in vitro study, LRRK2 silencing decreased cleaved caspase-3 activity, reduced cardiomyocyte apoptosis, and diminished hypoxia-induced inflammation. However, LRRK2 overexpression enhanced cleaved caspase-3 activity, increased the number of apoptotic cardiomyocytes, and caused remarkable hypoxia-induced inflammation. When examining the underlying mechanisms, we found that hypoxia increased HIFα expression, which enhanced LRRK2 expression. LRRK2 induced high expression of HMGB1 via P53. When HMGB1 was blocked using an anti-HMGB1 antibody, the deleterious effects caused by LRRK2 overexpression following hypoxia were inhibited in cardiomyocytes. In summary, LRRK2 deficiency protects the heart against myocardial infarction injury. The mechanism underlying this effect involves the P53-HMGB1 pathway.

Leucine-rich repeat kinase-2 deficiency protected against cardiac remodelling in mice via regulating autophagy formation and degradation.

Introduction: Leucine-rich repetitive kinase-2 (LRRK2) is a Parkinson's disease-related gene that also participates in many inflammatory diseases. However, the functional role of LRRK2 in cardiovascular disease is not clear. Objective: In this study, we aimed to elucidate the role of LRRK2 in cardiac remodelling under pressure overload. Methods: Aortic banding surgery was performed to induce cardiac remodelling in a LRRK2 knockout mouse model. A cardiomyocyte remodelling model was established by phenylephrine (PE) stimulation in neonatal rat cardiomyocytes. Results: LRRK2 was upregulated in remodelled mouse hearts and cardiomyocytes. Cardiac hypertrophy, fibrosis and dysfunction were ameliorated in LRRK2 knockout mice. LRRK2 silencing protected against the PE-induced cardiomyocyte hypertrophic response, while LRRK2 over-expression worsened the PE-induced hypertrophic response in cardiomyocytes. Decreased autophagy was observed in remodelled cardiomyocytes, whereas LRRK2 silencing increased autophagy levels and LRRK2 overexpression reduced autophagy levels. The autophagy inhibitors 3-MA, bafilomycin and chloroquine reversed the protective effects of LRRK2 deficiency. The autophagy activator rapamycin reversed the deleterious effects of LRRK2 overexpression. We found that LRRK2 inhibited Bcl-2 phosphorylation, thus decreasing the phosphorylation of Beclin1. The protective effects of LRRK2 knockout were partly counteracted by Beclin1(+/-) in vivo and Beclin1 silencing in vitro. We also observed an interaction between LRRK2 and Rab7, an autolysosome degradation-associated protein, which caused Rab7 downregulation. Rab7 knockdown almost completely reversed LRRK2 silencing-induced protection of cardiomyocytes. Conclusion: LRRK2 deficiency protected against cardiac remodelling under pressure overload by increasing Bcl-2/Beclin1 and Rab7-regulated autophagy levels in the heart.

Human Disturbance and Geometric Constraints Drive Small Mammal Diversity and Community Structure along an Elevational Gradient in Eastern China.

Understanding the mechanisms influencing patterns and processes of biological diversity is critical to protecting biodiversity, particularly in species-rich ecosystems such as mountains. Even so, there is limited knowledge of biodiversity patterns and processes in the mountains of eastern China, especially about small mammals. In this study, we examined the taxonomic, functional, and phylogenetic diversity of small mammal distribution and community structure along the elevational gradient of Qingliang Mountain, eastern China. We then evaluated how they are influenced by space (area and mid-domain effect (MDE)), environment (temperature, precipitation, and normalized difference vegetation index (NDVI)), and human disturbance. The results showed hump-shaped patterns of taxonomic and phylogenetic diversity along elevation gradients, peaking at 1000 m, unlike functional diversity, which peaked at lower elevations (600 m). The mean pairwise distance and mean nearest taxon distance of functional and phylogenetic variance (MFD and MPD, respectively) were also incongruent. The MFD and MPD showed hump-shaped patterns along elevations; however, unlike MFD, which peaked at lower elevations (600 m), MPD peaked at higher elevations (1200 m). The mean nearest functional taxon distance (MNFD) decreased, while the mean nearest phylogenetic taxon distance (MNTD) increased along the elevation gradient. The higher elevations were functionally more clustered, while the lower elevations were phylogenetically more clustered, suggesting that environmental filtering for traits was stronger at higher elevations. In comparison, phylogenetic conservatism of ecological niches had a stronger influence at lower elevations. The diversity and community structure indices were inconsistently explained, with human disturbance and MDE accounting for the biggest proportions of the model-explained variances. Overall, the results confirm that environmental filtering and human disturbance significantly influence small mammals' diversity and community structure. These findings also emphasize the need for increased conservation efforts in the middle and lower elevation regions of Qingliang Mountain.

A new species of Asiatic shrew of the genus Chodsigoa (Soricidae, Eulipotyphla, Mammalia) from the Dabie Mountains, Anhui Province, eastern China.

Asiatic shrews of the genus Chodsigoa (Soricidae, Eulipotyphla) currently comprise nine species, mostly occurring in southwest China. From May 2017 to August 2020, 11 specimens of Chodsigoa were collected from the Dabie Mountains in Anhui Province, eastern China. Their morphology was compared with other species within the genus and one mitochondrial (cytochrome b) and two nuclear (apolipoprotein B and breast cancer 1) genes were sequenced to estimate the phylogenetic relationships of these specimens. Based on morphological and molecular evidence, these specimens are recognized as a distinct species, Chodsigoadabieshanensis sp. nov., which is formally described here. Morphologically, the new species is most similar to Chodsigoahypsibia, but it is distinguishable from all known congeners by the combination of dark brownish pelage, small size, and relatively short tail. Phylogenetic analyses revealed that C.dabieshanensis sp. nov. forms a phylogenetic lineage sister to the clade containing C.parva + C.hypsibia. The-Kimura 2-parameter genetic distances of the cytochrome b (CYT B) gene between the new species and other nominal Chodsigoa species ranged between 8.6 and 17.6%. The new species is distributed at elevations from 750 to 1250 m in the Dabie Mountains and is geographically distant from other species in the genus.