Rynchopeterine inhibits the formation of hypertrophic scars by regulating the miR-21/HIF1AN axis.

Hypertrophic scar (HS) is a fibroproliferative skin disease characterized by abnormal wound healing and pathological excessive fibrosis of the skin. Currently, the molecular mechanism of the disease is still largely unknown, and there is no effective drug treatment. In this study, we explored the effect of Rynchopeterine on the formation of HS. HS fibroblasts (HSFs) were isolated from the HS tissues of patients recovering from severe burns. After treating HSFs with different concentrations of Rynchopeterine, CCK-8, EdU, and Annexin V-FITC/PI assays were used to detect the proliferation, apoptosis, and contractile ability of HSFs, respectively. RT-qPCR and Western blotting were performed to evaluate the effect of Rynchopeterine on the expression of miR-21 and hypoxia-inducible factor 1-alpha subunit suppressor (HIF1AN), respectively. The dual-luciferase reporter gene was used to verify the targeting relationship between miR-21 and HIF1AN. Rynchopeterine reduced the expression of Col1a2, Col3a1 and α-SMA, proliferation and contraction of HSFs, and increased apoptosis in a dose-dependent manner. miR-21 was highly expressed in HS tissues and HSFs, and Rynchopeterine could inhibit miR-21 expression. Overexpression of miR-21 and knockdown of HIF1AN increased proliferation, activation, contraction, and collagen synthesis of HSFs, and inhibited their apoptosis. In vivo, Rynchopeterine could reduce the collagen content of the dermis and the positive ratio of PCNA and α-SMA. Rynchopeterine is a good therapeutic agent for HS, which up-regulates the expression of HIF1AN by inhibiting miR-21, thereby inhibiting the formation of HS.

Angiotensin-(1-7) plays an important role in regulating spermatogenesis in Trachemys scripta elegans under salinity stress.

Elevation in water salinity can threaten the spermatogenesis and fertility of freshwater animals. The role of the renin-angiotensin system (RAS) in regulating spermatogenesis has attracted considerable attention. Our previous study found that red-eared sliders (Trachemys scripta elegans), could survive in 10 PSU water for over 1 year. To understand the chronic impact of salinity on testicular spermatogenesis and underlying mechanisms, male T. s. elegans were subjected to treatment with water of 5 PSU and 10 PSU for a year, and spermatogenesis and regulation of the RAS signal pathway was assessed. Results showed induced inflammation in the testes of T. s. elegans in the 10 PSU group, as evidenced by a decrease in the number of testicular germ cells from 1586 to 943. Compared with the control group, the levels of proinflammatory genes, including TNF-α, IL-12A and IL-6 were elevated 3.1, 0.3, and 1.4 times, respectively, in animals exposed to 10 PSU water. Testicular antiapoptotic processes of T. s. elegans might involve the vasoactive peptide angiotensin-(1-7) in the RAS, as its level was significantly increased from 220.2 ng ml-1 in controls to 419.2 ng ml-1 in the 10 PSU group. As expected, specific inhibitor (A-779) for the Ang-(1-7) acceptor effectively prevented the salinity-induced upregulation of genes encoding anti-inflammatory and antiapoptotic factors (TGF-ß1, Bcl-6) in the testis of the 10 PSU animals, whereas it promoted the upregulation of proinflammatory and proapoptotic factors (TNF-α, IL-12A, IL-6, Bax and caspase-3). Our data indicated that Ang-(1-7) attenuates the effect of salinity on inflammation and apoptosis of the testis in T. s. elegans. A new perspective to prevent salinity-induced testis dysfunction is provided.

Multi-elemental stoichiometric ratios of atmospheric wet deposition in Chinese terrestrial ecosystems.

Intense human activities have significantly altered the concentrations of atmospheric components that enter ecosystems through wet and dry deposition, thereby affecting elemental cycles. However, atmospheric wet deposition multi-elemental stoichiometric ratios are poorly understood, hindering systematic exploration of atmospheric deposition effects on ecosystems. Monthly precipitation concentrations of six elements-nitrogen (N), phosphorus (P), sulfur (S), potassium (K), calcium (Ca), and magnesium (Mg)-were measured from 2013 to 2021 by the China Wet Deposition Observation Network (ChinaWD). The multi-elemental stoichiometric ratio of atmospheric wet deposition in Chinese terrestrial ecosystems was N: K: Ca: Mg: S: P = 31: 11: 67: 5.5: 28: 1, and there were differences between vegetation zones. Wet deposition N: S and N: Ca ratios exhibited initially increasing then decreasing inter-annual trends, whereas N: P ratios did not exhibit significant trends, with strong interannual variability. Wet deposition of multi-elements was significantly spatially negatively correlated with soil nutrient elements content (except for N), which indicates that wet deposition could facilitate soil nutrient replenishment, especially for nutrient-poor areas. Wet N deposition and N: P ratios were spatially negatively correlated with ecosystem and soil P densities. Meanwhile, wet deposition N: P ratios were all higher than those of ecosystem components (vegetation, soil, litter, and microorganisms) in different vegetation zones. High input of N deposition may reinforce P limitations in part of the ecosystem. The findings of this study establish a foundation for designing multi-elemental control experiments and exploring the ecological effects of atmospheric deposition.

The mediting role of psychological resilience on the negative effect of pain in patients with rheumatoid arthritis: A cross-sectional study.

The objective of this study was to investigate the direct effects of pain-induced depression and anxiety, as well as the mediating role of psychological resilience, on the psychological distress associated with rheumatoid arthritis. The method involved a sample of 196 patients with rheumatoid arthritis and applied the Hospital Anxiety and Depression Scale, Connor-Davidson Resilience Scale, and visual analog scale for pain. Bivariate and path analyses were performed, and a multiple mediational model was utilized. Results showed that all correlations among study variables were significant (p < 0.01). A partial mediation effect of psychological resilience was observed, and direct effects among the variables (pain, psychological resilience, anxiety, and depression) were statistically significant, including the direct effect of psychological resilience on depression and anxiety. The indirect effects of pain through psychological resilience on depression and anxiety were also significant. Thus, the results suggest that psychological resilience partially mediates the effects of pain-induced anxiety and depression in patients with rheumatoid arthritis.

Toxicological effects of copper on bioaccumulation and mRNA expression of antioxidant, immune, and apoptosis-related genes in Chinese striped-necked turtle (Mauremys sinensis).

Heavy metals are among the most ubiquitous environmental pollutants of recent decades. Copper is commonly used to control algal blooms or macrophyte and waste infestations, its ambient concentration has increased significantly, indicating possible environmental risk. To investigate the effects of copper exposure on bioaccumulation, antioxidant defense, immune response, and apoptosis in the Chinese Striped-necked Turtle Mauremys sinensis, three experimental groups, control (0.0 mg/L), Cu2 (2 mg/L) and Cu4 (4 mg/L) were designed, and sampled at 14 and 28 days. Results showed that copper accumulates in different organs depending on the concentration and exposure time, Liver > Kidney > Gut > Heart > Brain > Muscle and the time order was 28 days > 14 days. The liver enzymes AST, ALT, and ALP decreased when the turtles were exposed to copper stress, while the contents of bilirubin TBIL, DBIL, IBIL, and LDH showed a significant upward trend. Similarly, the mRNA expression level of acetylcholinesterase AChE in the brain was significantly downregulated upon copper exposure. An upward trend was noticed in the liver Metallothionein MT mRNA expression levels compared to the control group. The mRNA expression levels of antioxidant enzymes CAT, SOD, MnSOD, and GSH-PX1 in the liver increased initially and then significantly decreased. Furthermore, the relative mRNA expression levels of inflammatory cytokines IL-1ß, IL-8, TNF-α, and IFN-γ involved in inflammatory response significantly upregulated. Copper significantly increased the hepatic mRNA transcription of heat shock proteins HSP70 and HSP90 at different exposure durations. In addition, the relative mRNA levels of caspase3, caspase8, and caspase9 related to the caspase-dependent apoptotic pathway significantly increased under copper stress. These results explain that copper toxicity causes bioaccumulation, promotes oxidative stress, obstructs immunity, and induces inflammation and apoptosis by altering their gene expression levels in M. sinensis.

Characterizations of the multi-kingdom gut microbiota in Chinese patients with gouty arthritis.

OBJECTIVE: The gut microbial composition has been linked to metabolic and autoimmune diseases, including arthritis. However, there is a dearth of knowledge on the gut bacteriome, mycobiome, and virome in patients with gouty arthritis (GA). METHODS: We conducted a comprehensive analysis of the multi-kingdom gut microbiome of 26 GA patients and 28 healthy controls, using whole-metagenome shotgun sequencing of their stool samples. RESULTS: Profound alterations were observed in the gut bacteriome, mycobiome, and virome of GA patients. We identified 1,117 differentially abundant bacterial species, 23 fungal species, and 4,115 viral operational taxonomic units (vOTUs). GA-enriched bacteria included Escherichia coli_D GENOME144544, Bifidobacterium infantis GENOME095938, Blautia_A wexlerae GENOME096067, and Klebsiella pneumoniae GENOME147598, while control-enriched bacteria comprised Faecalibacterium prausnitzii_G GENOME147678, Agathobacter rectalis GENOME143712, and Bacteroides_A plebeius_A GENOME239725. GA-enriched fungi included opportunistic pathogens like Cryptococcus neoformans GCA_011057565, Candida parapsilosis GCA_000182765, and Malassezia spp., while control-enriched fungi featured several Hortaea werneckii subclades and Aspergillus fumigatus GCA_000002655. GA-enriched vOTUs mainly attributed to Siphoviridae, Myoviridae, Podoviridae, and Microviridae, whereas control-enriched vOTUs spanned 13 families, including Siphoviridae, Myoviridae, Podoviridae, Quimbyviridae, Phycodnaviridae, and crAss-like. A co-abundance network revealed intricate interactions among these multi-kingdom signatures, signifying their collective influence on the disease. Furthermore, these microbial signatures demonstrated the potential to effectively discriminate between patients and controls, highlighting their diagnostic utility. CONCLUSIONS: This study yields crucial insights into the characteristics of the GA microbiota that may inform future mechanistic and therapeutic investigations.

Relationships of stomatal morphology to the environment across plant communities.

The relationship between stomatal traits and environmental drivers across plant communities has important implications for ecosystem carbon and water fluxes, but it has remained unclear. Here, we measure the stomatal morphology of 4492 species-site combinations in 340 vegetation plots across China and calculate their community-weighted values for mean, variance, skewness, and kurtosis. We demonstrate a trade-off between stomatal density and size at the community level. The community-weighted mean and variance of stomatal density are mainly associated with precipitation, while that of stomatal size is mainly associated with temperature, and the skewness and kurtosis of stomatal traits are less related to climatic and soil variables. Beyond mean climate variables, stomatal trait moments also vary with climatic seasonality and extreme conditions. Our findings extend the knowledge of stomatal trait-environment relationships to the ecosystem scale, with applications in predicting future water and carbon cycles.

Intestinal Cckbr-specific knockout mouse as a novel model of salt-sensitive hypertension via sodium over-absorption.

OBJECTIVES: To investigate the value of CCKBRfl/fl villin-Cre mice as a mouse model of salt-sensitive hypertension (SSH). METHODS: In the first part, 2-month-old CCKBRfl/fl villin-Cre mice (CKO) and control CCKBRfl/fl mice (WT) were fed with normal diet (0.4% NaCl) or high salt diet (4% NaCl), separately for 6 weeks. In the rescue study, one week of hydrochlorothiazide or saline injection were treated with the CKO mice fed high salt diet. The blood pressure, biochemical indexes, and the expression of small intestinal sodium transporters (NHE3, NKCC1, eNaC) was detected. The organ injury markers (MMP2/MMP9) and the histopathological changes of kidneys were observed, whereas the changes of duodenal sodium absorption were detected by small intestinal perfusion in vivo. RESULTS: The CCKBRfl/fl villin-Cre mice with high salt intake exhibited high blood pressure, increased duodenal sodium absorption and urinary sodium excretion, and with renal injury. The protein expression of NHE3, NKCC1 and eNaC were also significant increase in the intestine of CKO-HS mice. Treatment with hydrochlorothiazide remarkably attenuated the elevated blood pressure by high salt absorption in the CCKBRfl/fl villin-Cre mice, but no significant histopathological changes were observed. CONCLUSIONS: These results support a crucial role of intestinal Cckbr deficiency on SSH development and the diuretic antihypertension effect in CCKBRfl/fl villin-Cre mice. The CCKBRfl/fl villin-Cre mice with the high salt intake may serve as a stable model of salt-sensitive hypertensive induced by sodium overloading.

Co-Delivery of Methotrexate and Nanohydroxyapatite with Polyethylene Glycol Polymers for Chemotherapy of Osteosarcoma.

Neoadjuvant chemotherapy is an alternative treatment modality for tumors. Methotrexate (MTX) has been often used as a neoadjuvant chemotherapy reagent for osteosarcoma surgery. However, the large dosage, high toxicity, strong drug resistance, and poor improvement of bone erosion restricted the utilization of methotrexate. Here, we developed a targeted drug delivery system using nanosized hydroxyapatite particles (nHA) as the cores. MTX was conjugated to polyethylene glycol (PEG) through the pH-sensitive ester linkage and acted as both the folate receptor-targeting ligand and the anti-cancer drug due to the similarity to the structure of folic acid. Meanwhile, nHA could increase the concentration of calcium ions after being uptake by cells, thus inducing mitochondrial apoptosis and improving the efficacy of medical treatment. In vitro drug release studies of MTX-PEG-nHA in phosphate buffered saline at different pH values (5, 6.4 and 7.4) indicated that the system showed a pH-dependent release feature because of the dissolution of ester bonds and nHA under acidic conditions. Furthermore, the treatment on osteosarcoma cells (143B, MG63, and HOS) by using MTX-PEG-nHA was demonstrated to exhibit higher therapeutic efficacy. Therefore, the developed platform possesses the great potential for osteosarcoma therapy.

Atmospheric wet organic nitrogen deposition in China: Insights from the national observation network.

Organic nitrogen (N) is an important component of atmospheric reactive N deposition, and its bioavailability is almost as important as that of inorganic N. Currently, there are limited reports of national observations of organic N deposition; most stations are concentrated in rural and urban areas, with even fewer long-term observations of natural ecosystems in remote areas. Based on the China Wet Deposition Observation Network, this study regularly collected monthly wet deposition samples from 43 typical ecosystems from 2013 to 2021 and measured related N concentrations. The aim was to provide a more comprehensive assessment of the multi-component characteristics of atmospheric wet N deposition and reveal the influencing factors and potential sources of wet dissolved organic N (DON) deposition. The results showed that atmospheric wet deposition fluxes of NO3-, NH4+, DON and dissolved total N (DTN) were 4.68, 5.25, 4.32, and 13.05 kg N ha-1 yr-1, respectively, and that DON accounted for 30 % of DTN deposition (potentially up to 50 % in remote areas). Wet DON deposition was related to anthropogenic emissions (agriculture, biomass burning, and traffic), natural emissions (volatile organic compound emissions from vegetation), and precipitation processes. The wet DON deposition flux was higher in South, Central, and Southwest China, with more precipitation and intensive agricultural activities or more vegetation cover, and lower in Northwest China and Inner Mongolia, with less precipitation and human activities or vegetation cover. DON was the main contributor to DTN deposition in remote areas and was possibly related to natural emissions. In rural and urban areas, DON may have been more influenced by agricultural activities and anthropogenic emissions. This study quantified the long-term spatiotemporal patterns of wet N deposition and provides a reference for future N addition experiments and N cycle studies. Further consideration of DON deposition is required, especially in the context of anthropogenic control of NO2 and NH3.

High environmental costs behind rapid economic development: Evidence from economic loss caused by atmospheric acid deposition.

The rapid growth of energy-intensive and high-emission industries has propelled China's economy but has also led to massive levels of air pollutant emissions and ecological problems, such as acid deposition. Despite recent declines, atmospheric acid deposition in China is still severe. Long-term exposure to high levels of acid depositions has a substantial negative impact on the ecosystem. Evaluating these hazards and incorporating this issue into planning and decision-making processes is critical to achieving sustainable development goals in China. However, the long-term economic loss caused by atmospheric acid deposition and its temporal and spatial variation in China is unclear. Hence, the aim of this study was to assess the environmental cost of acid deposition in the agriculture, forestry, construction, and transportation industries from 1980 to 2019, using long-term monitoring, integrated data, and the dose-response method with localization parameters. The results showed that the estimated cumulative environmental cost of acid deposition was USD 230 billion, representing 0.27% of the gross domestic product (GDP) in China. This cost, was particularly high for building materials, followed by crops, forests, and roads. Temporally, the environmental cost and the ratio of environmental cost to GDP decreased from their peaks by 43% and 91%, respectively, because of emission controls targeting acidifying pollutants and promotion of clean energy. Spatially, the largest environmental cost occurred in developing provinces, indicating that more stringent emission reduction measures should be implemented in these regions. These findings highlight the huge environmental costs behind rapid development; however, the implementation of reasonable emission reduction measures can effectively reduce these environmental costs, providing a promising paradigm for other undeveloped and developing countries.

Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.

Apparent mineralocorticoid excess is an autosomal recessive form of monogenic disease characterized by juvenile resistant low-renin hypertension, marked hypokalemic alkalosis, low aldosterone levels, and high ratios of cortisol to cortisone metabolites. It is caused by defects in the HSD11B2 gene, encoding the enzyme 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2), which is primarily involved in the peripheral conversion of cortisol to cortisone. To date, over 50 deleterious HSD11B2 mutations have been identified worldwide. Multiple molecular mechanisms function in the lowering of 11ß-HSD2 activity, including damaging protein stability, lowered affinity for the substrate and cofactor, and disrupting the dimer interface. Genetic polymorphism, environmental factors as well as epigenetic modifications may also offer an implicit explanation for the molecular pathogenesis of AME. A precise diagnosis depends on genetic testing, which allows for early and specific management to avoid the morbidity and mortality from target organ damage. In this review, we provide insights into the molecular genetics of classic and non-classic apparent mineralocorticoid excess and aim to offer a comprehensive overview of this monogenic disease.

The Clinical Characteristics of Pheochromocytomas and Paragangliomas with Negative Catecholamines.

Pheochromocytomas and paragangliomas (PPGLs) associated with negative catecholamines are not uncommon. However, few studies have examined clinical features of patients with these tumors. In the absence of available data, it is difficult to identify characteristics of patients with potential PPGLs and normal serum and urine screens. Therefore, an analysis of patients with PPGLs was conducted retrospectively to compare the clinical features of patients with positive and negative catecholamines. This study included 214 patients, including 69 patients with negative catecholamines. Prevalence rates of diabetes (p < 0.001) and hypertension (p < 0.001) were lower and tumor diameter (p < 0.001) was smaller in the negative-catecholamine group compared with the positive-catecholamine group. Multivariable logistic regression analysis showed that extra-adrenal PPGLs were independently positively associated with negative catecholamines (p = 0.004); hypertension (p = 0.001) and tumor diameter (p = 0.016) were independently negatively associated with negative catecholamines. There was no significant difference in tumor recurrence between the two groups (mean follow-up, 20.54 ± 11.83 months) (p = 0.44). The results demonstrated that PPGL patients with negative catecholamines were more likely to have extra-adrenal tumors and less likely to have comorbidities, and these patients should also be closely monitored for tumor recurrence.

Atmospheric Wet Iron, Molybdenum, and Vanadium Deposition in Chinese Terrestrial Ecosystems.

Iron (Fe), molybdenum (Mo), and vanadium (V) are the main components of the three known biological nitrogenases, which constrain nitrogen fixation and affect ecosystem productivity. Atmospheric deposition is an important pathway of these trace metals into ecosystems. Here, we explored the deposition flux, spatiotemporal pattern, and influencing factors of atmospheric wet Fe, Mo, and V deposition based on China Wet Deposition Observation Network (ChinaWD) data from 2016 to 2020. Our results showed that atmospheric wet Fe, Mo, and V deposition was 7.77 ± 7.24, 0.16 ± 0.11, and 0.13 ± 0.12 mg m-2 a-1 in Chinese terrestrial ecosystems, respectively, and revealed obvious spatial patterns but no significant annual trends. Wet Fe deposition was significantly correlated with the soil Fe content. Mo and V deposition was more affected by anthropogenic activities than Fe deposition. Wet Mo deposition was significantly affected by Mo ore reserves and waste incineration. V deposition was significantly correlated with domestic biomass burning. This study quantified wet Fe, Mo, and V deposition in China for the first time, and the implications of atmospheric trace metal deposition on biological nitrogen fixation were discussed.

Atmospheric silicon wet deposition and its influencing factors in China.

Silicon (Si) is considered a "quasi-essential" nutrient element for plants and is also an essential nutrient for some phytoplankton. Except for the silicate provided by weathering, atmospheric deposition has gradually become an important supplementary method for Si nutrients to enter the ecosystem. However, national observational studies on atmospheric silicon deposition have not yet been reported. Herein, based on the China Wet Deposition Observation Network, we continuously collected monthly wet deposition samples from 43 typical ecosystems from 2013 to 2020 and measured the content of dissolved silica (dSi) in precipitation to quantify the spatiotemporal patterns of Si wet deposition in China. The results showed that the mean annual dSi wet deposition in China during 2013-2020 was approximately 2.07 ± 0.27 kg ha-1 yr-1. Atmospheric dSi deposition was higher in Southwest, North, and South China but lower in the Northwest and Northeast China, which was mainly regulated by precipitation and soil available Si content. There was no significant annual variation trend in dSi deposition during 2013-2020 in China, which showed disorderly fluctuations from year to year. This study revealed the spatiotemporal patterns of atmospheric dSi deposition in China for the first time, which can provide unique scientific data to explore the potential effect of dSi deposition on carbon sequestration in aquatic ecosystems. A comprehensive evaluation of the nutrient balance of aquatic ecosystems from the perspective of nitrogen, phosphorus, and silicon stoichiometry is required in the future.

A novel missense mutation in obscurin gene in a Chinese consanguineous family with left ventricular noncompaction.

BACKGROUND: Left ventricular noncompaction (LVNC) is an increasingly recognised cardiomyopathy of which a significant percentage are genetic in origin. The purpose of the present study was to identify potential pathogenic mutation leading to disease in a Chinese LVNC family. METHODS: A 3-generation family affected by LVNC was recruited. Clinical assessments were performed on available family members, with clinical examination, ECG, echocardiography and cardiac MRI. The proband (I-2), the proband's daughter (II-1, affected) and mother (III-1, unaffected) were selected for WGS. Sanger sequencing were performed in all of the 4 surviving family members. RESULTS: Combined whole genome sequencing with linkage analysis identified a novel missense mutation in the giant protein obscurin (OBSCN NM_001098623, c.C19063T), as the only plausible disease-causing variant that segregates with disease among the four surviving individuals, with interrogation of the entire genome excluding other potential causes. This c.C19063T missense mutation resulted in p.R6355W in the encoded OBSCN protein. It affected a highly conserved residue in the C terminus of the obscurin-B-like isoform between the PH and STKc domains, which was predicted to affect the function of the protein by different bioinformatics tools. CONCLUSIONS: Here we present clinical and genetic evidence implicating the novel R6355W missense mutation in obscurin as the cause of familial LVNC. This expands the spectrum of obscurin's roles in cardiomyopathies. It furthermore highlights that rare obscurin missense variants, currently often ignored or left uninterpreted, should be considered to be relevant for cardiomyopathies and can be identified by the approach presented here. This study also provided new insights into the molecular basis of OBSCN mutation positive LVNC.