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Ethnopharmacological Relevance: Radix et Rhizoma Salviae Miltiorrhizae (Salvia miltiorrhiza Bge., Lamiaceae, Danshen in Chinese) and Chuanxiong Rhizoma (rhizomes of Ligusticum chuanxiong Hort., Apiaceae, Chuanxiong in Chinese) both are important traditional Chinese medicine (TCM) for activating blood and eliminating stasis. Danshen-chuanxiong herb pair has been used for more than 600 years in China. Guanxinning injection (GXN) is a Chinese clinical prescription refined from aqueous extract of Danshen and Chuanxiong at the ratio of 1:1 (w/w). GXN has been mainly used in the clinical therapy of angina, heart failure (HF) and chronic kidney disease in China for almost twenty years., Aim of the Study: This study aimed to explore the role of GXN on renal fibrosis in heart failure mice and the regulation of GXN on SLC7A11/GPX4 axis., Matarials and Methods: The transverse aortic constriction model was used to mimic HF accompanied by kidney fibrosis model. GXN was administrated by tail vein injection in dose of 12.0, 6.0, 3.0 mL/kg, respectively. Telmisartan (6.1 mg/kg, gavage) was used as a positive control drug. Cardiac ultrasound indexes of ejection fraction (EF), cardiac output (CO), left ventricle volume (LV Vol), HF biomarker of pro-B type natriuretic peptide (Pro-BNP), kidney function index of serum creatinine (Scr), kidney fibrosis index of collagen volume fraction (CVF) and connective tissue growth factor (CTGF) were evaluated and contrasted. Metabolomic method was employed to analyze the endogenous metabolites changes in kidneys. Besides, contents of catalase (CAT), xanthine oxidase (XOD), nitricoxidesynthase (NOS), glutathione peroxidase 4 (GPX4), the x(c)(-) cysteine/glutamate antiporter (SLC7A11) and ferritin heavy chain (FTH1) in kidney were quantitatively analyzed. In addition, ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to analyze the chemical composition of GXN and network pharmacology was used to predict possible mechanisms and the active ingredients of GXN., Results: The cardiac function indexes of EF, CO and LV Vol, kidney functional indicators of Scr, the degree of kidney fibrosis indicators CVF and CTGF were all relieved to different extent for the model mice treated with GXN. 21 differential metabolites involved in redox regulation, energy metabolism, organic acid metabolism, nucleotide metabolism, etc were identified. Aspartic acid, homocysteine, glycine, and serine, methionine, purine, phenylalanine and tyrosine metabolism were found to be the core redox metabolic pathways regulated by GXN. Furthermore, GXN were found to increase CAT content, upregulate GPX4, SLC7A11 and FTH1 expression in kidney significantly. Not only that, GXN also showed good effect in down-regulating XOD and NOS contents in kidney. Besides, 35 chemical constituents were initially identified in GXN. Active ingredients of GXN-targets-related enzymes/transporters-metabolites network was established to find out that GPX4 was a core protein for GXN and the top 10 active ingredients with the most relevant to renal protective effects of GXN were rosmarinic acid, caffeic acid, ferulic acid, senkyunolide E, protocatechualdehyde, protocatechuic acid, danshensu, L-Ile, vanillic acid, salvianolic acid A., Conclusion: GXN could significantly maintain cardiac function and alleviate the progression of fibrosis in the kidney for HF mice, and the mechanisms of action were related to regulating redox metabolism of aspartate, glycine, serine, and cystine metabolism and SLC7A11/GPX4 axis in kidney. The cardio-renal protective effect of GXN may be attributed to multi-components like rosmarinic acid, caffeic acid, ferulic acid, senkyunolide E, protocatechualdehyde, protocatechuic acid, danshensu, L-Ile, vanillic acid, salvianolic acid A et al., Competing Interests: Declaration of competing interest All authors declare no conflict of interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The NOD-like receptor protein 3 (NLRP3) inflammasome is a protein complex that regulates innate immune responses by activating caspase-1 and the inflammatory cytokines interleukin (IL)-1β and IL-18. Multiple studies have demonstrated the importance of the NLRP3 inflammasome in the development of immune and inflammation-related diseases, including arthritis, Alzheimer's disease, inflammatory bowel disease, and other autoimmune and autoinflammatory diseases. This review first explains the activation and regulatory mechanism of the NLRP3 inflammasome. Secondly, we focus on the role of the NLRP3 inflammasome in various inflammation-related diseases. Finally, we look forward to new methods for targeting the NLRP3 inflammasome to treat inflammation-related diseases, and provide new ideas for clinical treatment., (© 2023. The Author(s).)

Cancer is a multi-step disease caused by the accumulation of genetic mutations and/or epigenetic changes, and is the biggest challenge around the world. Cytokines, including chemokines, exhibit expression changes and disorders in all human cancers. These cytokine abnormalities can disrupt homeostasis and immune function, and make outstanding contributions to various stages of cancer development such as invasion, metastasis, and angiogenesis. Chemokines are a superfamily of small molecule chemoattractive cytokines that mediate a variety of cellular functions. Importantly, the interactions of chemokine members CXCL12 and its receptors CXCR4 and CXCR7 have a broad impact on tumor cell proliferation, survival, angiogenesis, metastasis, and tumor microenvironment, and thus participate in the onset and development of many cancers including leukemia, breast cancer, lung cancer, prostate cancer and multiple myeloma. Therefore, this review aims to summarize the latest research progress and future challenges regarding the role of CXCL12-CXCR4/CXCR7 signaling axis in cancer, and highlights the potential of CXCL12-CXCR4/CXCR7 as a biomarker or therapeutic target for cancer, providing essential strategies for the development of novel targeted cancer therapies., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: High altitude pulmonary edema (HAPE) is a high-altitude idiopathic disease with serious consequences due to hypoxia at high altitude, and there is individual genetic susceptibility. Whole-exome sequencing (WES) is an effective tool for studying the genetic etiology of HAPE and can identify potentially novel mutations that may cause protein instability and may contribute to the development of HAPE., Materials and Methods: A total of 50 unrelated HAPE patients were examined using WES, and the available bioinformatics tools were used to perform an analysis of exonic regions. Using the Phenolyzer program, disease candidate gene analysis was carried out. SIFT, PolyPhen-2, Mutation Taster, CADD, DANN, and I-Mutant software were used to assess the effects of genetic variations on protein function., Results: The results showed that rs368502694 (p. R1022Q) located in NOS3, rs1595850639 (p. G61S) located in MYBPC3, and rs1367895529 (p. R333H) located in ITGAV were correlated with a high risk of HAPE, and thus could be regarded as potential genetic variations associated with HAPE., Conclusion: WES was used in this study for the first time to directly screen genetic variations related to HAPE. Notably, our study offers fresh information for the subsequent investigation into the etiology of HAPE., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Near-infrared light (NIR) driven lanthanide-doped upconversion nanoparticle (UCNP) based photo-dynamic therapy (PDT) holds a great promise for the non-invasive treatment of deep-seated tumors. However, it has also been highly hindered by the low upconversion luminescence (UCL) efficiency, hypoxia nature of solid tumors, and low therapeutic efficiency using single modality. Herein, we present a novel Nd 3+ → Yb 3+ → Tm 3+ → Er 3+ cascade-sensitized red-emitting UCNP with tandem hydrophobic hydration-shell (HHS) and metal-phenolic network (Fe-tannic acid, Fe-TA) decoration (UCNP@HHS@Fe-TA, denoted as UCFS@Fe-TA) for single 808 nm triggered simultaneous tumor PDT and photothermal therapy (PTT) enhanced chemo-dynamic therapy (CDT). The UCNP can supply intense red emission under high tissue penetrating/minimized tissue overheating 808 nm excitation, and their HHS coating with perfluorocarbon/photosensitizer Ce6 co-doping can not only realize UCL-based PDT, but also strengthen PDT of as-formed UCFS via O 2 -carrying/UCL protection capacity of the HHS. Fe-TA coating can supply 808 nm triggered PTT, and the rise in temperature during PTT leads to enhanced Fenton catalytic activity of Fe-TA and faster ˙OH production rate of CDT to match with the real-timely released 1 O 2 in PDT. The as-designed UCFS@Fe-TA thus can achieve a single 808 nm triggered simultaneous PDT and PTT enhanced CDT, leading to a PTT-assisted reactive oxygen species storm for efficient tumor suppression. Such a design also renders the nanoplatform lower cell dark toxicity. In addition, the single excitation-triggered multimodal therapy mode might address the excitation wavelength mismatch issue in dual laser-triggered PTT/PDT mode. This study has therefore presented an efficient nanotherapeutic platform enabling synergistic multimodal tumor therapies with high biocompatibility.

Background: HCC characterizes malignant metastasis with high incidence and recurrence. Thus, it is pivotal to discover the mechanisms of HCC metastasis. TATA-box-binding protein (TBP), a general transcriptional factor (TF), couples with activators and chromatin remodelers to sustain the transcriptional activity of target genes. Here, we investigate the key role of TBP in HCC metastasis., Methods: TBP expression was measured by PCR, western blot, and immunohistochemistry. RNA-sequencing was performed to identify downstream proteins. Functional assays of TBP and downstream targets were identified in HCC cell lines and xenograft models. Luciferase reporter and chromatin immunoprecipitation assays were used to demonstrate the mechanism mediated by TBP., Results: HCC patients showed high expression of TBP, which correlated with poor prognosis. Upregulation of TBP increased HCC metastasis in vivo and in vitro, and muscleblind-like-3 (MBNL3) was the effective factor of TBP, positively related to TBP expression. Mechanically, TBP transactivated and enhanced MBNL3 expression to stimulate exon inclusion of lncRNA-paxillin (PXN)-alternative splicing (AS1) and, thus, activated epithelial-mesenchymal transition for HCC progression through upregulation of PXN., Conclusions: Our data revealed that TBP upregulation is an HCC enhancer mechanism that increases PXN expression to drive epithelial-mesenchymal transition., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Gypsophila huashanensis Y. W. Tsui & D. Q. Lu (Caryophyllaceae) is an endemic herb species to the Qinling Mountains in China. In this study, we characterized its whole plastid genome using the Illumina sequencing platform. The complete plastid genome of G. huashanensis is 152,457 bp in length, including a large single-copy DNA region of 83,476 bp, a small single-copy DNA region of 17,345 bp, and a pair of inverted repeat DNA sequences of 25,818 bp. The genome contains 130 genes comprising 85 protein-coding genes, 37 tRNA genes, and eight rRNA genes. Evolutionary analysis showed that the non-coding regions of Caryophyllaceae exhibit a higher level of divergence than the exon regions. Gene site selection analysis suggested that 11 coding protein genes ( accD , atpF , ndhA , ndhB , petB , petD , rpoCl , rpoC2 , rps16 , ycfl , and ycf2 ) have some sites under protein sequence evolution. Phylogenetic analysis showed that G. huashanensis is most closely related to the congeneric species G. oldhamiana . These results are very useful for studying phylogenetic evolution and species divergence in the family Caryophyllaceae., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: The current study probed prognosis-related potential for m6A-related lncRNAs signatures within colon tumor immune microenvironment (TIM)., Methods: After downloading transcriptomic datasets for colon cancer (CC) patients from The Cancer Genome Atlas (TCGA), they were divided, in a 1:1 ratio, within training or test datasets. m6A-related lncRNAs were then scrutinized across such dataset using Pearson correlation assessment before generating a m6A-related lncRNAs prognosis-related model using the training dataset. The latter was then validated with the test and the whole dataset. In addition, we compared the differences of TIM and the estimated IC50 of drug response between the high- and low-risk groups., Results: Overall survival (OS) resulted as linked with 11 m6A-related lncRNAs, while within the developed prognosis-related model, areas-under-curves were as follows: within training dataset, values at 3-, 4-, and 5-years were 0.777, 0.819, and 0.805, accordingly, and for test one, they were 0.697, 0.682, and 0.706, respectively. Finally, the values for the whole dataset were 0.675 (3-year), 0.682 (4-years), and 0.679 (5-years), accordingly. Moreover, CC cases categorized within low-risk cohort demonstrated enhanced OS (p < .0001), lower metastasis (p = 2e-06) and lower T stage (p = .0067), more instability for microsatellite status (p = .012), and downregulation for PD-L1, PD-1, CTLA-4, LAG3, and HAVCR2 (p < .05). In addition, risk scorings were significantly linked to the degree of infiltrative intensity for CD8 and CD4 (memory resting) T-cells, T-regulatory (Tregs), and Mast cells triggering (p < .05). Patients with low infiltrative propensity for CD4 T-cells also had better OS (p = .016). Moreover, six representative drugs were found to be sensitive for treating CC patients., Conclusion: A robust m6A-related prognostic model with great performances was developed before exploring the TIM characteristics and its potential therapeutic drugs, which might improve the prognosis and therapeutic efficacy., (© 2023 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Decitabine (5-aza-2-deoxycytidine, DAC), a DNA-hypomethylating agent, has been one of the frontline therapies for clonal hematopoietic stem cell disorders, such as myelodysplastic syndrome and acute myeloid leukemia, but DAC-resistance often occurs and leads to treatment failure. Therefore, elucidating the mechanisms of DAC resistance is important for improving its therapeutic efficacy. The extracellular vesicles and particles (EVPs) have been reported to be involved in mediating drug resistance by transporting diverse bioactive components. In this study, we established the DAC-resistant cell line (KG1a-DAC) from its parental human leukemia-derived cell line KG1a and observed that EVPs released from KG1a-DAC can promote DAC-resistant in KG1a cells. Moreover, treatment with KG1a-DAC EVPs reduced the expression of cyclin-dependent kinase inhibitor 2B (CDKN2B) in KG1a cells. miRNA-Seq analysis revealed that miR-4755-5p is overexpressed in EVPs from KG1a-DAC. Dual-luciferase reporter assay and flow cytometry analysis confirmed that miR-4755-5p rendered KG1a cells resistant to the DAC by targeting CDKN2B gene. Taken together, miR-4755-5p in EVPs released from the DAC-resistant cells plays an essential role in inducing DAC-resistance, and is a potential therapeutic target for suppression of DAC resistance., (© 2023 Wiley Periodicals LLC.)

After tissue damage, a series of molecular and cellular events are initiated to promote tissue repair and regeneration to restore its original structure and function. These events include inter-cell communication, cell proliferation, cell migration, extracellular matrix differentiation, and other critical biological processes. Glycosylation is the crucial conservative and universal post-translational modification in all eukaryotic cells [1], with influential roles in intercellular recognition, regulation, signaling, immune response, cellular transformation, and disease development. Studies have shown that abnormally glycosylation of proteins is a well-recognized feature of cancer cells, and specific glycan structures are considered markers of tumor development. There are many studies on gene expression and regulation during tissue repair and regeneration. Still, there needs to be more knowledge of complex carbohydrates' effects on tissue repair and regeneration, such as glycosylation. Here, we present a review of studies investigating protein glycosylation in the tissue repair and regeneration process., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A novel tri-functional probe HEX-OND was developed for detecting Pb(II), cysteine (Cys), and K(I) by fluorescence quenching, recovery, and amplification strategies respectively, based on Pb(II)-induced chair-type G-quadruplex (CGQ) and K(I)-induced parallel G-quadruplex (PGQ). The thermodynamic mechanism was illustrated as that HEX-OND transformed into CGQ by associating equimolar Pb(II) (K 1  = 1.10 ± 0.25 × 10 6 L/mol), forcing (G) 2 spontaneously approaching and static-quenching HEX (5'-hexachlorofluorescein phosphoramidite) in the photo-induced electron transfer (PET) way by the van der Waals force and hydrogen bond (K 2  = 5.14 ± 1.65 × 10 7 L/mol); the additional Cys recovered fluorescence in the molecular ratio of 2:1 via Pb(II)-precipitation induced CGQ destruction (K 3  = 3.03 ± 0.77 × 10 9 L/mol); the equimolar K(I) induced HEX-OND transforming into PGQ (K 4  = 3.53 ± 0.30 × 10 4 L/mol) and specifically associating with the equimolar N-methyl mesoporphyrin IX (NMM) by hydrophobic force (K 5  = 3.48 ± 1.08 × 10 5 L/mol), leading to the fluorescence enhancement. Moreover, the practicability results showed that the detection limits reached a nanomolar level for Pb(II) and Cys and micromolar for K(I), with mere disturbances for 6, 10, and 5 kinds of other substances, respectively; no significant deviations of the real sample detection results were found between the well-understood methods with ours in detecting Pb(II) and Cys, and K(I) could be recognized and quantified even in the presence of Na(I) with 5000 and 600 fold respectively. The results demonstrated the triple-function, sensitivity, selectivity, and tremendous application feasibility of the current probe in sensing Pb(II), Cys, and K(I)., (© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.)

Loss of bone mass can occur in mammals after prolonged disuse but the situation for hibernators that are in a state of torpor for many months of the year is not yet fully understood. The present study assesses the bone remodeling mechanisms present in Daurian ground squirrels (Spermophilus dauricus) during hibernation as compared with a model of hindlimb disuse. Differences in microstructure, mechanical properties, bone remodeling-related proteins (Runx2, OCN, ALP, RANKL, CTK and MMP-9) and key proteins of Wnt/β-catenin signaling pathway (GSK-3β and phospho-β-catenin) were evaluated in ground squirrels under 3 conditions: summer active (SA) vs. hibernation (HIB) vs. hindlimb unloaded (HLU). The results indicated that the body weight in HLU ground squirrels was lower than the SA group, and the middle tibia diameter in the HLU group was lower than that in SA and HIB groups. The thickness of cortical and trabecular bone in femurs from HLU ground squirrels was lower than in SA and HIB groups. Most parameters of the tibia in the HLU group were lower than those in SA and HIB groups, which indicated cortical bone loss in ground squirrels. Moreover, our data showed that the changes in microscopic parameters in the femur were more obvious than those in the tibia in HLU and HIB ground squirrels. The levels of Runx2 and ALP were lower in HLU ground squirrels than SA and HIB groups. The protein levels of OCN were unchanged in the three groups, but the protein levels of ALP were lower in the HLU group than in SA and HIB groups. RANKL, CTK and MMP-9 protein levels were significantly decreased in tibia of HLU ground squirrels as compared with SA and HIB groups. In addition, the protein expression levels of RANKL, CTK and MMP-9 showed no statistical difference between SA and HIB ground squirrels. Thus, the mechanisms involved in the balance between bone formation and resorption in hibernating and hindlimb unloading ground squirrels may be different. The present study showed that in femur, the Wnt signaling pathway was inhibited, the protein level of GSK-3β was increased, and the protein expression of phospho-β-catenin was decreased in the HIB group as compared with the SA group, which indicates that the Wnt signaling pathway has a great influence on the femur of the HIB group. In conclusion, the natural anti-osteoporosis properties of Daurian ground squirrels are seasonal. The squirrels do not experience bone loss when they are inactive for a long time during hibernation, but the mechanisms of anti-osteoporosis did not work in HLU summer active squirrels., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Fibrosis is a universal aging-related pathological process in the different organ, but is actually a self-repair excessive response. To date, it still remains a large unmet therapeutic need to restore injured tissue architecture without detrimental side effects, due to the limited clinical success in the treatment of fibrotic disease. Although specific organ fibrosis and the associated triggers have distinct pathophysiological and clinical manifestations, they often share involved cascades and common traits, including inflammatory stimuli, endothelial cell injury, and macrophage recruitment. These pathological processes can be widely controlled by a kind of cytokines, namely chemokines. Chemokines act as a potent chemoattractant to regulate cell trafficking, angiogenesis, and extracellular matrix (ECM). Based on the position and number of N-terminal cysteine residues, chemokines are divided into four groups: the CXC group, the CX3C group, the (X)C group, and the CC group. The CC chemokine classes (28 members) is the most numerous and diverse subfamily of the four chemokine groups. In this Review, we summarized the latest advances in the understanding of the importance of CC chemokine in the pathogenesis of fibrosis and aging and discussed potential clinical therapeutic strategies and perspectives aimed at resolving excessive scarring formation., Competing Interests: Conflicts of interest The authors declare that they do not have any conflicts of interest to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Stroke is a common cerebrovascular disease. The purpose of this study was to explore the association between LIPC single nucleotide polymorphisms (SNPs) and the risk of stroke in the Chinese population., Methods: This study recruited 710 stroke patients and 701 healthy controls. The four SNPs (rs690, rs6083, rs3829461, and rs6074) in LIPC were genotyped by the Agena MassARRAY. The correlation between LIPC polymorphisms and stroke risk was measured by odds ratio (OR) and 95% confidence interval (CI). In addition, multifactor dimensionality reduction (MDR) analysis was used to evaluate the impact of SNP-SNP interaction on stroke risk., Results: Overall analysis showed that rs690 was associated with an increased risk of stroke (T vs. G: OR = 1.19, 95% CI: 1.01-1.40, p = 0.041; additive: OR = 1.20, 95% CI: 1.01-1.42, p = 0.036). The stratified analysis revealed that rs690 was associated with an increased risk of stroke in subjects aged ≤ 64 years, male patients, and smokers, and rs6074 was associated with an increased risk of stroke in subjects aged > 64 years, male patients, drinkers, and non-smokers ( p < 0.05). The results of the MDR analysis suggested the four-locus model as the most favorable model for assessing the risk of stroke. The analysis of clinical parameters of stroke patients showed that rs690 was correlated with platelet distribution width (PDW) ( p = 0.014) and hematocrit levels ( p = 0.004), and rs6074 was correlated with low-density lipoprotein cholesterol (LDL-C) level ( p = 0.033). Furthermore, bioinformatics analysis results demonstrated that the expression levels of LIPC and its related genes ( APOB, CETP, PNPLA2 , and LMF1 ) were significantly different between the control and stroke groups ( p < 0.05), and LIPC -related proteins were mainly related to lipid metabolism., Conclusion: This study indicated that rs690 and rs6074 in LIPC were significantly associated with increased risk of stroke in the Chinese population, possibly by regulating the levels of PDW, HCT, and LDL-C., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pan, Zhuo, Chen, Huang, Shen, Yang, Luo, Wang and Jin.)

Opisthopappus is a perennial, endemic herb of the Taihang Mountains in China. Two species of this genus ( O. longilobus and O. taihangensis ) are important wild genetic resources for Asteraceae; however, their reproductive biology has been lacking until now. This study is the first detailed report on the reproductive biology and breeding systems of two Opisthopappus species. Through field observations, the floral syndromes of O. longilobus and O. taihangensis were found to possess a similar pattern, although O. taihangensis has a relatively larger capitulum, more ray ligules, and disc florets. The flowers of both O. longilobus and O. taihangensis are protandrous, a character that can prevent autogamy at the single-flower level, and insects are required for pollination. Further, brightly ligules, brightly bisexual florets, unique fragrance, and amount of nectar suggest that these species propagate via an entomophilous pollination system. Hymenopteran and Diptera species were observed as the effective pollinators for these two species. The outcrossing index, pollen/ovule ratio and the results of hand pollination indicated that these Opisthopappus species might have a mixed mating system that combines cross-fertilization and partial self-fertilization for O. longilobus and O. taihangensis , outcrossing predominated in the breeding system, while self-pollination played an important role in seed production when insect pollination was unavailable, particularly in a harsh environment, such as the Taihang Mountains cliffs. Meanwhile, O. taihangensis might better adapt to severe surroundings with relatively complex floral syndromes, specifically through the attraction of visiting insects and a high seed set rate. The above results not only provide reference information toward a better understanding of the survival strategies of O. longilobus and O. taihangensis in the Taihang Mountains but also lay a solid foundation for further exploring the molecular mechanisms that underly their adaptation under cliff environments.

Assessing plant diversity during community succession based on plant trait and phylogenetic features within a community (alpha scale) and among communities (beta scale) could improve our understanding of community succession mechanism. However, whether changes of community functional diversity at alpha and beta scale are structured by different traits and whether integrating plant traits and phylogeny can enhance the ability in detecting diversity pattern have not been studied in detail. Thirty plots representing different successional stages were established on the Loess Plateau of China and 15 functional traits were measured for all coexisting species. We first analyzed the functional alpha and beta diversity along succession by decomposing species trait into alpha and beta components and then integrated key traits with phylogenetic information to explore their roles in shaping species turnover during community succession. We found that functional alpha diversity increased along successional stages and was structured by morphological traits, while beta diversity decreased during succession and was more structured by stoichiometry traits. Phylogenetic alpha diversity showed congruent pattern with functional alpha diversity because of phylogenetic conservation of trait alpha components (variation within community), while beta diversity showed incongruent pattern due to phylogenetic randomness of trait beta components (variation among communities). Furthermore, only integrating relatively conserved traits (plant height and seed mass) and phylogenetic information can raise the detecting ability in assessing diversity change. Overall, our results reveal the increasing niche differentiation within community and functional convergence among communities with succession process, indicating the importance of matching traits with scale in studying community functional diversity and the asymmetry of traits and phylogeny in reflecting species ecological differences under long-term selection pressures., Competing Interests: All of the undersigned authors participated actively in the study, and none has any potential conflict of interest. All of authors have read and approved the manuscript in its present form., (© 2023 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

A typical angiosperm flower is usually bisexual, with entomophilous plants having four whorls of organs: the calyx, corolla, stamens, and gynoecium. The flower is usually colorful, and thus, distinct from the dull-colored reproductive organs of gymnosperms; however, this formula is not applicable to all flowers. For example, the male flower of Sarcobatus baileyi is reduced into only a single stamen. Such unusual flowers are largely poorly documented and underappreciated. To fill such a lacuna in our knowledge of the male reproductive organ of S. baileyi , we collected and studied materials of the male inflorescence of S. baileyi (Sarcobataceae). The outcomes of our Micro-CT (micro computed tomography), SEM (scanning electron microscopy), and paraffin sectioning indicate that a male inflorescence of S. baileyi is more comparable with the cone of conifers; its male flowers lack the perianth, are directly attached to a central axis and sheltered by peltate indusium-like shields. To understand the evolutionary logic underlying such a rarely seen male inflorescence, we also studied and compared it with a female cone of Cupressus sempervirens . Although the genera Sarcobatus and Cupressus belong to two distinct major plant groups (angiosperms and gymnosperms), they apply the same propagule-protecting strategy.

As a famous traditional Chinese formula, Danshen Decoction has the potential to relieve the pain of pulmonary arterial hypertension patients, however, the functional components remain unknown. Herein, we reported a method to screen the functional components in Danshen Decoction targeting endothelin receptor A, an accepted target for the treatment of the disease. The receptor was functionalized on the macroporous silica gel through an epidermal growth factor receptor fusion tag and its covalent inhibitor. Using the affinity gel as the stationary phase, the bioactive compound was identified as salvianolic acid B by mass spectrometry. The binding kinetic parameter (dissociation rate constants k d ) of salvianolic acid B with the receptor was determined via peak profiling. Using the specific ligands of the receptor as probes, the binding configuration prediction of salvianolic acid B with the receptor was performed by molecular dynamics simulation. Our results indicated that salvianolic acid B is a potential bioactive compound in Danshen Decoction targeting the receptor. This work showed that receptor chromatography in combination with molecular dynamics simulation is applicable to predicting the binding kinetics and configuration of a ligand to a receptor, providing crucial insight for the rational design of drugs that recognize functional proteins., (© 2023 Wiley-VCH GmbH.)

Hybridization is recognized as a major force in species evolution and biodiversity formation, generally leading to the origin and differentiation of new species. Multiple hybridization events cannot easily be reconstructed, yet they offer the potential to study a number of evolutionary processes. Here, we used nuclear expressed sequence tag-simple sequence repeat and large-scale single nucleotide polymorphism variation data, combined with niche analysis, to investigate the putative independent hybridization events in Notopterygium, a group of perennial herb plants endemic to China. Population genomic analysis indicated that the four studied species are genetically well-delimited and that N. forrestii and N. oviforme have originated by hybridization. According to Approximate Bayesian Computation, the best-fit model involved the formation of N. forrestii from the crossing of N. franchetii and N. incisum, with N. forrestii further backcrossing to N. franchetii to form N. oviforme. The niche analyses indicated that niche divergence [likely triggered by the regional climate changes, particularly the intensification of East Asian winter monsoon, and tectonic movements (affecting both Qinghai-Tibetan Plateau and Qinling Mountains)] may have promoted and maintained the reproductive isolation among hybrid species. N. forrestii shows ecological specialization with respect to their parental species, whereas N. oviforme has completely shifted its niche. These results suggested that the climate and environmental factors together triggered the two-step hybridization of the East Asia herb plants. Our study also emphasizes the power of genome-wide SNPs for investigating suspected cases of hybridization, particularly unravelling old hybridization events., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The stress-and-coping theory of forgiveness posits that forgiveness and aggression are alternative ways of coping with stress of interpersonal offences. Inspired by the link between aggression and MAOA-uVNTR (a genetic variant involving in catabolism of monoamines), we investigated the relationship between this variant and forgiveness with two studies. Study 1 examined the relationship between the MAOA-uVNTR and trait forgiveness in students, and study 2 examined the effect of this variant on third-party forgiveness in response to situational offences in male inmates. The results showed that the MAOA-H (a high activity allele) was associated with higher trait forgiveness in male students and greater third-party forgiveness to accidentally committed harm and attempted but failed harm in male inmates than the MAOA-L. These findings highlight the bright side of MAOA-uVNTR on trait and situational forgiveness., Competing Interests: Conflict of Interest The authors declared that they had no conflicts of interest concerning their authorship or the publication of this article., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Isopropyl 3-(3,4-dihydroxyphenyl)-2-hydroxypropanoate (IDHP) is the core active substance of salvia miltiorrhiza in disease treatment. The significance of our work lies in evaluating the ameliorating effects of IDHP on hypoxia-induced injury and investigating its mechanisms. We examined the morphology, dopamine neurons (DANs), cerebral vessels, and behavior of zebrafish larvae administrated by IDHP/VHC after hypoxia-induction. We next sought to explore its anti-hypoxic mechanisms via transcriptome analysis and qPCR experiments. The results indicated that hypoxia-induced injuries, including decreased length of DANs, number of cereal vessels, total swimming distance, and average swimming speed, were all alleviated by IDHP. Furthermore, transcriptome analysis provided a sign that IDHP most likely played the anti-hypoxic role through the neuroactive ligand-receptor interaction (NLRI) signaling pathway. Consistently, expression of related genes, such as f2rl1.1, p2ry10, npy1r, ptger2b, ptger2b, pth2rb, and nmur1a, was downregulated by hypoxia induction and recovered after IDHP administration. Therefore, we speculated that, via regulating NLRI, IDHP reduced inflammation, promoted angiogenesis, modulated blood pressure and flow, and inhibited cell apoptosis, and eventually played an anti-hypoxic role., Competing Interests: Conflict of Interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The basic fibroblast growth factor (bFGF) plays a significant role in promoting the process of bone repair, but bFGF cannot keep its biological activity stable under normal physiological conditions. Therefore, the development of better biomaterials to carry bFGF remains a challenge for bone repair and regeneration. Here we designed a novel recombinant human collagen (rhCol), which could be cross-linked by transglutaminase (TG) and loaded bFGF to prepare rhCol/bFGF hydrogels. The rhCol hydrogel possessed a porous structure and good mechanical properties. The assays, including cell proliferation, migration, and adhesion assay, were performed to evaluate the biocompatibility of rhCol/bFGF and the results demonstrated that the rhCol/bFGF promoted cell proliferation, migration and adhesion. The rhCol/bFGF hydrogel degraded and released bFGF controllably, enhancing utilization rate of bFGF and allowing osteoinductive activity. The results of RT-qPCR and immunofluorescence staining also proved that rhCol/bFGF promoted expression of bone-related proteins. The rhCol/bFGF hydrogels were applied in the cranial defect in rats and the results confirmed that it accelerates bone defect repair. In conclusion, rhCol/bFGF hydrogel has excellent biomechanical properties and can continuously release bFGF to promote bone regeneration, suggesting that rhCol/bFGF hydrogel is a potential scaffold in clinic application., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Hyperinsulinemia is a critical risk factor for the pathogenesis of insulin resistance (IR) in metabolic tissues, including the liver. Ethanolamine phosphate phospholyase (ETNPPL), a newly discovered metabolic enzyme that converts phosphoethanolamine (PEA) to ammonia, inorganic phosphate, and acetaldehyde, is abundantly expressed in liver tissue. Whether it plays a role in the regulation of hyperinsulinemia-induced IR in hepatocytes remains elusive. Here, we established an in vitro hyperinsulinemia-induced IR model in the HepG2 human liver cancer cell line and primary mouse hepatocyte via a high dose of insulin treatment. Next, we overexpressed ETNPPL by using lentivirus-mediated ectopic to investigate the effects of ETNPPL per se on IR without insulin stimulation. To explore the underlying mechanism of ETNPPL mediating hyperinsulinemia-induced IR in HepG2, we performed genome-wide transcriptional analysis using RNA sequencing (RNA-seq) to identify the downstream target gene of ETNPPL. The results showed that ETNPPL expression levels in both mRNA and protein were significantly upregulated in hyperinsulinemia-induced IR in HepG2 and primary mouse hepatocytes. Upon silencing ETNPPL, hyperinsulinemia-induced IR was ameliorated. Under normal conditions without IR in hepatocytes, overexpressing ETNPPL promotes IR, reactive oxygen species (ROS) generation, and AKT inactivation. Transcriptome analysis revealed that salt-inducible kinase 1 (SIK1) is markedly downregulated in the ETNPPL knockdown HepG2 cells. Moreover, disrupting SIK1 prevents ETNPPL-induced ROS accumulation, damage to the PI3K/AKT pathway and IR. Our study reveals that ETNPPL mediates hyperinsulinemia-induced IR through the SIK1/ROS-mediated inactivation of the PI3K/AKT signaling pathway in hepatocyte cells. Targeting ETNPPL may present a potential strategy for hyperinsulinemia-associated metabolic disorders such as type 2 diabetes., (© 2023 Wiley Periodicals LLC.)

Background: Heart failure is a common complication of sepsis with a high mortality rate. It has been reported that melatonin can attenuate septic injury due to various properties. On the basis of previous reports, this study will further explore the effects and mechanisms of melatonin pretreatment, posttreatment, and combination with antibiotics in the treatment of sepsis and septic myocardial injury., Methods and Results: Our results showed that melatonin pretreatment showed an obvious protective effect on sepsis and septic myocardial injury, which was related to the attenuation of inflammation and oxidative stress, the improvement of mitochondrial function, the regulation of endoplasmic reticulum stress (ERS), and the activation of the AMPK signaling pathway. In particular, AMPK serves as a key effector for melatonin-initiated myocardial benefits. In addition, melatonin posttreatment also had a certain degree of protection, while its effect was not as remarkable as that of pretreatment. The combination of melatonin and classical antibiotics had a slight but limited effect. RNA-seq detection clarified the cardioprotective mechanism of melatonin., Conclusion: Altogether, this study provides a theoretical basis for the application strategy and combination of melatonin in septic myocardial injury., (© 2023. The Author(s).)

Our previous studies found that the H1-50 monoclonal antibody (mAb) of influenza A virus hemagglutinin (HA) cross-reacted with pancreatic tissue and islet β-cells, and further studies showed that H1-50 mAb binds to prohibitin (PHB) protein of islet β-cells. These suggest that there are heterophilic epitopes between influenza virus HA and pancreatic tissue, which may be involved in the pathogenesis of type 1 diabetes. To further investigate these heterophilic epitopes, we screened binding epitopes of H1-50 mAb using a phage 12-peptide library. DNA sequencing and comparative analysis were performed on specific positive phage clones, and the sequence of 12-peptide binding to H1-50 mAb was obtained. The binding epitopes of H1-50 mAb in influenza virus HA were determined by sequence analysis and experimental verification, and their distribution within the three-dimensional structure was assessed by PyMOL. The results showed that H1-50 mAb specifically binds to polypeptides (306-SLPFQNIHPITIGK-319) of influenza A virus HA, located in the stem of the HA protein. However, there is no specific binding sequence between H1-50 mAb and the PHB protein of islet β-cells in the primary structure, and we speculate that the binding of H1-50 mAb to islet β-cells may depend on the spatial conformation. The identification of the heterophilic epitopes of H1N1 influenza virus hemagglutinin provides a new perspective on type 1 diabetes that may be caused by influenza virus infection, which may contribute to the prevention and control of influenza., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Despite its increasing application in pursing potential ligands, the capacity of receptor affinity chromatography is greatly challenged as most current research studies lack a comprehensive characterization of the ligand-receptor interaction, particularly when simultaneously determining their binding thermodynamics and kinetics. This work developed an immobilized M3 muscarinic receptor (M3R) affinity column by fixing M3R on amino polystyrene microspheres via the interaction of a 6-chlorohexanoic acid linker with haloalkane dehalogenase. The efficiency of the immobilized M3R was tested by characterizing the binding thermodynamics and kinetics of three known drugs to immobilized M3R using a frontal analysis and the peak profiling method, as well as by analyzing the bioactive compounds in Daturae Flos (DF) extract. The data showed that the immobilized M3R demonstrated good specificity, stability, and competence for analyzing drug-protein interactions. The association constants of (-)-scopolamine hydrochloride, atropine sulfate, and pilocarpine to M3R were determined to be (2.39 ± 0.03) × 10 4 , (3.71 ± 0.03) × 10 4 , and (2.73 ± 0.04) × 10 4 M -1 , respectively, with dissociation rate constants of 27.47 ± 0.65, 14.28 ± 0.17, and 10.70 ± 0.35 min -1 , respectively. Hyoscyamine and scopolamine were verified as the bioactive compounds that bind to M3R in the DF extract. Our results suggest that the immobilized M3R method was capable of determining drug-protein binding parameters and probing specific ligands in a natural plant, thus enhancing the effectiveness of receptor affinity chromatography in diverse stages of drug discovery.

Introduction: The modernized lifestyle has been paralleled by an epidemic of inflammatory bowel disease (IBD). Excessive consumption of cold beverages is especially common among the modern humans. However, whether cold stress contributes directly to the gut barrier and gut-brain axis is not clear., Methods: We conducted a cold stress model induced by cold water. The mice were treated with 14 consecutive days of intragastric cold or common water administration. We observed changes in gut transit and gut barrier in the colon. We also employed RNA sequencing-based transcriptomic analysis to identify the genes potentially driving gut injury, and simultaneously examined the gut microbiota and metabolites in the feces., Results: We found that cold stress disturbed the intestinal function and increased gut permeability. A set of core genes related to immune responses were consistently overexpressed in the cold stress group. Additionally, cold stress induced decreased bacterial diversity, ecological network, and increased pathogens mainly belonging to Proteobacteria. The dopamine signaling pathway-related metabolites were largely reduced in the cold stress group., Conclusion: This study revealed that cold stress could trigger an IBD-like phenotype in mice, implying that cold stress is a possible risk factor for IBD development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sun, Wang, Zou, He, Liang, Li, Li and Zhang.)

Introduction: Zebrafish is a suitable animal model for molecular genetic tests and drug discovery due to its characteristics including optical transparency, genetic manipulability, genetic similarity to humans, and cost-effectiveness. Mobility of the zebrafish reflects pathological conditions leading to brain disorders, disrupted motor functions, and sensitivity to environmental challenges. However, it remains technologically challenging to quantitively assess zebrafish's mobility in a flowing environment and simultaneously monitor cellular behavior in vivo ., Methods: We herein developed a facile fluidic device using mechanical vibration to controllably generate various flow patterns in a droplet housing single zebrafish, which mimics its dynamically flowing habitats., Results: We observe that in the four recirculating flow patterns, there are two equilibrium stagnation positions for zebrafish constrained in the droplet, i.e., the "source" with the outward flow and the "sink" with the inward flow. Wild-type zebrafish, whose mobility remains intact, tend to swim against the flow and fight to stay at the source point. A slight deviation from streamline leads to an increased torque pushing the zebrafish further away, whereas zebrafish with motor neuron dysfunction caused by lipin-1 deficiency are forced to stay in the "sink," where both their head and tail align with the flow direction. Deviation angle from the source point can, therefore, be used to quantify the mobility of zebrafish under flowing environmental conditions. Moreover, in a droplet of comparable size, single zebrafish can be effectively restrained for high-resolution imaging., Conclusion: Using the proposed methodology, zebrafish mobility reflecting pathological symptoms can be quantitively investigated and directly linked to cellular behavior in vivo ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jia, Feng, Ma, Zhao, Liu, Jing, Tian, Yang and Zhang.)

Most sepsis deaths are due to the development of multiple organ failure, in which heart failure is a recognized manifestation of sepsis. To date, the role of liver X receptors α (NR1H3) in sepsis is still uncertain. Here, we hypothesized that NR1H3 mediates multiple essential sepsis-related signalings to attenuate septic heart failure. Adult male C57BL/6 or Balbc mice and HL-1 myocardial cell line were performed for in vivo and in vitro experiments, respectively. NR1H3 knockout mice or NR1H3 agonist T0901317 was applied to evaluate the impact of NR1H3 on septic heart failure. We found decreased myocardial expression levels of NR1H3-related molecules while increased NLRP3 level in septic mice. NR1H3 knockout worsensed cardiac dysfunction and injury in mice subjected to cecal ligation and puncture (CLP), in association with exacerbated NLRP3-mediated inflammation, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis-related markers. The administration of T0901317 reduced systemic infection and improve cardiac dysfunction in septic mice. Moreover, Co-IP assays, luciferase reporter assays, and chromatin immunoprecipitation analysis, confirmed that NR1H3 directly repressed NLRP3 activity. Finally, RNA-seq detection further clarified an overview of the roles of NR1H3 in sepsis. In general, our findings indicate that NR1H3 had a significant protective effect against sepsis and sepsis-induced heart failure., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of American Institute of Chemical Engineers.)

Disuse atrophy of skeletal muscle is associated with a severe imbalance in cellular Ca 2+ homeostasis and marked increase in nuclear apoptosis. Nuclear Ca 2+ is involved in the regulation of cellular Ca 2+ homeostasis. However, it remains unclear whether nuclear Ca 2+ levels change under skeletal muscle disuse conditions, and whether changes in nuclear Ca 2+ levels are associated with nuclear apoptosis. In this study, changes in Ca 2+ levels, Ca 2+ transporters, and regulatory factors in the nucleus of hindlimb unloaded rat soleus muscle were examined to investigate the effects of disuse on nuclear Ca 2+ homeostasis and apoptosis. Results showed that, after hindlimb unloading, the nuclear envelope Ca 2+ levels ([Ca 2+ ] NE ) and nucleocytoplasmic Ca 2+ levels ([Ca 2+ ] NC ) increased by 78% ( p < 0.01) and 106% ( p < 0.01), respectively. The levels of Ca 2+ -ATPase type 2 (Ca 2+ -ATPase2), Ryanodine receptor 1 (RyR1), Inositol 1,4,5-tetrakisphosphate receptor 1 (IP 3 R1), Cyclic ADP ribose hydrolase (CD38) and Inositol 1,4,5-tetrakisphosphate (IP 3 ) increased by 470% ( p < 0.001), 94% ( p < 0.05), 170% ( p < 0.001), 640% ( p < 0.001) and 12% ( p < 0.05), respectively, and the levels of Na + /Ca 2+ exchanger 3 (NCX3), Ca 2+ /calmodulin dependent protein kinase II (CaMK II) and Protein kinase A (PKA) decreased by 54% ( p < 0.001), 33% ( p < 0.05) and 5% ( p > 0.05), respectively. In addition, DNase X is mainly localized in the myonucleus and its activity is elevated after hindlimb unloading. Overall, our results suggest that enhanced Ca 2+ uptake from cytoplasm is involved in the increase in [Ca 2+ ] NE after hindlimb unloading. Moreover, the increase in [Ca 2+ ] NC is attributed to increased Ca 2+ release into nucleocytoplasm and weakened Ca 2+ uptake from nucleocytoplasm. DNase X is activated due to elevated [Ca 2+ ] NC , leading to DNA fragmentation in myonucleus, ultimately initiating myonuclear apoptosis. Nucleocytoplasmic Ca 2+ overload may contribute to the increased incidence of myonuclear apoptosis in disused skeletal muscle.

C1q/tumor necrosis factor (TNF) related proteins (CTRPs) is a newly discovered adipokine family with conservative structure and ubiquitous distribution and is secreted by adipose tissues. Recently, CTRPs have attracted increasing attention due to the its wide-ranging effects upon inflammation and metabolism. To-date, 15 members of CTRPs (CTRP1-15) with the characteristic C1q domain have been characterized. Earlier in-depth phenotypic analyses of mouse models of CTRPs deficiency have also unveiled ample function of CTRPs in inflammation and metabolism. This review focuses on the rise of CTRPs, with a special emphasis on the latest discoveries with regards to the effects of the CTRP family on inflammation and metabolism as well as related diseases. We first introduced the structure of characteristic domain and polymerization of CTRPs to reveal its pleiotropic biological functions. Next, intimate association of CTRP family with inflammation and metabolism, as well as the involvement of CTRPs as nodes in complex molecular networks, were elaborated. With expanding membership of CTRP family, the information presented here provides new perspectives for therapeutic strategies to improve inflammatory and metabolic abnormalities., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Ample evidence suggests that estrogen replacement therapy is associated with beneficial effects with regard to cardiovascular diseases when the therapy is initiated temporally close to menopause but not when it is initiated later. Little is known about the complex interactions between hormone receptors after menopause. Coronary artery function and cardiac function were measured in rats that had either received no treatment or had been pretreated with an androgen receptor (AR) antagonist and/or a GPER agonist G-1. ICI 182,780 was used to block the classical estrogen receptors (ERs) to investigate their complex interactions with GPER. The beneficial effects of GPER were only observed by blocking ARs and classical ERs in aged female rats. The results demonstrate that GPER activation is a potential therapeutic target for the inhibition of age-dependent coronary artery dysfunction and cardiac dysfunction under the condition of blocking ARs and classical ERs after menopause. CLINICAL RELEVANCE: The risk of cardiovascular disease in postmenopausal women significantly increased. The role of sex hormones and their receptors during this process is still complicated. Our present study demonstrated that the imbalance of androgen and estrogen may contribute to the impairment of vascular reactivity and subsequent cardiac function. Treatment with GPER agonist G1 combined with the inhibition of ERα and ERβ could improve vascular function and reduce the myocardial ischemia reperfusion injury. These findings may provide the novel and effective strategy for the treatment of cardiovascular diseases in postmenopausal women., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Oxidative stress plays a key part in cardiovascular event. Growth arrest-specific gene 6 (GAS6) is a vitamin K-dependent ligand which has been shown to exert important effects in heart. The effects of GAS6 were evaluated against hydrogen peroxide (H 2 O 2 ) ‑induced oxidative stress injury in HL-1 cardiomyocytes. A series of experimental methods were used to analyze the effects of GAS6 on cell viability, apoptosis, oxidative stress, mitochondrial function and AMPK/ACC signaling in H 2 O 2 ‑injured HL-1 cells. In this study, we found that H 2 O 2 reduced cell viability, increased apoptotic rate and intracellular reactive oxygen species (ROS). Meanwhile, H 2 O 2 decreased the protein levels of GAS6, and increased the protein level of p-AMPK/AMPK, p-ACC/ACC. Then, we observed that overexpression of GAS6 significantly reduced cell death, manifested as increased cell viability, improved oxidative stress, apoptosis and upregulated the levels of GAS6, p-Axl/Axl, Nrf2, NQO1, HO-1, Bcl-2/Bax, PGC-1α, NRF1, TFAM, p-AMPK/AMPK, and p-ACC/ACC-related protein expression in HL-1 cells and H 2 O 2 ‑injured cardiomyocytes. To further verify the results, we successfully constructed GAS6 lentiviral vectors, and found GAS6 shRNA partially reversed the above results. These data suggest that AMPK/ACC may be a downstream effector molecule in the antioxidant action of GAS6. In summary, our findings indicate that activation GAS6/Axl-AMPK signaling protects H 2 O 2 ‑induced oxidative stress which is accompanied by the amelioration of oxidative stress, apoptosis, and mitochondrial function., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Endothelial senescence due to increased age or oxidative stress can cause endothelial dysfunction, which is strongly associated with the pathogenesis of cardiovascular diseases (CVDs)., Research Design and Methods: Hydrogen peroxide (H 2 O 2 ) was used to induced human umbilical vein endothelial cells (HUVECs) senescence model. Cell senescence and cell proliferation were assessed by SA-β-gal staining and PCNA staining. Nitric oxide (NO) and reactive oxygen species (ROS) levels were detected by DAF-2 DA and DCFH-DA. Inflammatory indicators were quantified by qPCR. Meanwhile, western blot was used to examine the ARG2 protein. Finally, an aging mice model induced by H 2 O 2 was established to confirm the role of OIP5-AS1/miR-4500/ARG2 in endothelial dysfunction in vivo., Results: ARG2 was upregulated and miR-4500 was reduced in H 2 O 2 -induced HUVECs. MiR-4500 negatively regulates ARG2 expression, meanwhile ameliorating H 2 O 2 -induced ECs senescence and dysfunction. Targeted interactions among OIP5-AS1, miR-4500, and ARG2 were confirmed by dual-luciferase reporter assays. OIP5-AS1 as miR4500 sponge negatively mediates miR-4500 expression, and is upregulated upon H 2 O 2 stimulation in HUVECs. OIP5-AS1 depletion shows the protective effects on H 2 O 2 -induced ECs senescence, dysfunction, and SASP. In vivo, a higher expression of OIP5-AS1 and ARG2 in the aortas of aged mice., Conclusions: We disclosed a regulatory mechanism for OIP5-AS1/miR-4500/ARG2 in the regulation of oxidative stress-related ECs senescence and vascular aging.

Excessive free fatty acids (FFAs) accumulation is a leading risk factor for the pathogenesis of insulin resistance (IR) in metabolic tissues, including the liver. Ethanolamine-phosphate phospho-lyase (ETNPPL), a newly identified metabolic enzyme, catalyzes phosphoethanolamine (PEA) to ammonia, inorganic phosphate, and acetaldehyde and is highly expressed in hepatic tissue. Whether it plays a role in regulating FFA-induced IR in hepatocytes has yet to be understood. In this study, we established an in vitro palmitic acid (PA)-induced IR model in human HepG2 cells and mouse AML12 cells with chronic treatment of PA. Next, we overexpressed ETNPPL by using lentivirus-mediated ectopic to investigate the effects of ETNPPL per se on IR without PA stimulation. We show that ETNPPL expression is significantly elevated in PA-induced IR and that silencing ETNPPL ameliorates this IR in hepatocytes. Inversely, overexpressing ETNPPL under normal conditions without PA promotes IR, reactive oxygen species generation, and ARG2 activation in both HepG2 and AML12 cells. Moreover, ETNPPL depletion markedly down-regulates ARG2 expression in hepatocytes. Besides, silencing ARG2 prevents ETNPPL-induced ROS accumulation and inhibition of autophagic flux and IR in hepatocytes. Finally, we found that phytopharmaceutical disruption of ETNPPL by quercetin ameliorates PA-induced IR in hepatocytes. Our study discloses that ETNPPL inhibiting autophagic flux mediates insulin resistance triggered by PA in hepatocytes via ARG2/ROS signaling cascade. Our findings provide novel insights into elucidating the pathogenesis of obesity-associated hepatic IR, suggesting that targeting ETNPPL might represent a potential approach for T2DM therapy., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The normal colorectal mucosa undergoes precancerous lesions that can develop over time into colorectal cancer (CRC). In the stage of precancerous lesions, DNA replication stress may lead to genome instability. We have performed whole-exome sequencing on genomic DNA obtained from three cases of CRC tissues and identified a novel frameshift mutation of DNA damage inducible 1 homolog 2 gene (DDI2, c. 854 del T). To date, there is no direct evidence that DDI2 is involved in the carcinogenesis of CRC. In this study, we demonstrated that DDI2 is upregulated in the early stage of CRC based on clinical samples and public databases. We also found that 5FU, a standard chemotherapeutic agent for CRC treatment, increased DDI2 mRNA levels in a dose-dependent manner. Depression of DDI2 inhibited CRC cell proliferation, migration and invasion both in vitro and in vivo. Transcriptome sequencing revealed that DDI2 was involved in the mitogen-activated protein kinase (MAPK) pathway. Furthermore, DDI2 resists a MAPK kinase (MEK) inhibitor (trametinib) and a PolyADP-ribose polymerase 1 (PARP1) inhibitor (talazoparib) induced apoptosis in CRC cells. Thus, our results indicate that DDI2 may play a vital role in the carcinogenesis of CRC and could serve as a promising therapeutic target for CRC., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: Taurohyodeoxycholic acid (THDCA), a natural 6α-hydroxylated bile acid, exhibits intestinal anti-inflammatory effects. This study aimed to explore the efficacy of THDCA on ulcerative colitis and to reveal its mechanisms of action., Main Methods: Colitis was induced by intrarectal administration of trinitrobenzene sulfonic acid (TNBS) to mice. Mice in the treatment group were gavage THDCA (20, 40, and 80 mg/kg/day) or sulfasalazine (500 mg/kg/day) or azathioprine (10 mg/kg/day). The pathologic markers of colitis were comprehensively assessed. The levels of Th1-/Th2-/Th17-/Treg-related inflammatory cytokines and transcription factors were detected by ELISA, RT-PCR, and Western blotting. The balance of Th1/Th2 and Th17/Treg cells was analyzed by Flow cytometry., Key Findings: THDCA significantly alleviated colitis by improving the body weight, colon length, spleen weight, histological characteristics, and MPO activity of colitis mice. THDCA reduced the secretion of Th1-/Th17-related cytokines (IFN-γ, IL-12p70, IL-6, IL-17A, IL-21, IL-22, and TNF-α) and the expressions of transcription factors (T-bet, STAT4, RORγt, and STAT3), but increase the production of Th2-/Treg-related cytokines (IL-4, IL-10, and TGF-β1) and the expressions of transcription factors (GATA3, STAT6, Foxp3, and Smad3) in the colon. Meanwhile, THDCA inhibited the expressions of IFN-γ, IL-17A, T-bet, and RORγt, but improved the expression of IL-4, IL-10, GATA3, and Foxp3 in the spleen. Furthermore, THDCA restored the proportion of Th1, Th2, Th17, and Treg cells, and balanced the Th1/Th2 and Th17/Treg immune response of colitis mice., Significance: THDCA can alleviate TNBS-induced colitis via regulating Th1/Th2 and Th17/Treg balance, which may represent a promising treatment for patients with colitis., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The uneven distribution of species diversity on earth, with mountainous regions housing half of the high species diversity areas, makes mountain ecosystems vital to biodiversity conservation. The Panorpidae are ecological indicators, ideal for studying the impact of climate change on potential insect distribution. This study examines the impact of environmental factors on the distribution of the Panorpidae and analyzes how their distribution has changed over three historical periods, the Last Interglacial (LIG), the Last Glacial Maximum (LGM), and Current. The MaxEnt model is used to predict the potential distribution area of Panorpidae based on global distribution data. The results show that precipitation and elevation are the primary factors affecting species richness, and the suitable areas for Panorpidae are distributed in southeastern North America, Europe, and southeastern Asia. Throughout the three historical periods, there was an initial increase followed by a decrease in the area of suitable habitats. During the LGM period, there was a maximum range of suitable habitats for cool-adapted insects, such as scorpionflies. Under the scenarios of global warming, the suitable habitats for Panorpidae would shrink, posing a challenge to the conservation of biodiversity. The study provides insights into the potential geographic range of Panorpidae and helps understand the impact of climate change on their distribution.

Biomimetic materials have emerged as attractive and competitive alternatives for tissue engineering (TE) and regenerative medicine. In contrast to conventional biomaterials or synthetic materials, biomimetic scaffolds based on natural biomaterial can offer cells a broad spectrum of biochemical and biophysical cues that mimic the in vivo extracellular matrix (ECM). Additionally, such materials have mechanical adaptability, microstructure interconnectivity, and inherent bioactivity, making them ideal for the design of living implants for specific applications in TE and regenerative medicine. This paper provides an overview for recent progress of biomimetic natural biomaterials (BNBMs), including advances in their preparation, functionality, potential applications and future challenges. We highlight recent advances in the fabrication of BNBMs and outline general strategies for functionalizing and tailoring the BNBMs with various biological and physicochemical characteristics of native ECM. Moreover, we offer an overview of recent key advances in the functionalization and applications of versatile BNBMs for TE applications. Finally, we conclude by offering our perspective on open challenges and future developments in this rapidly-evolving field., (© 2023. The Author(s).)

In this study, 21 species of the leaf-beetle genus Aplosonyx in China are described, including three new species, Aplosonyxancorella sp. nov. and Aplosonyxnigricornis , and 1 new record, sp. nov. and Aplosonyxwudangensis Chen, 1964 is elevated to species. A key to the Chinese species of sp. nov. , and 1 new record, Aplosonyxduvivieri Jacoby, 1900. Additionally, Aplosonyxancorafulvescens Chen, 1964 is elevated to species. A key to the Chinese species of Aplosonyx is provided., (Chuan Feng, Xing-Ke Yang, Yang Liu, Zhi-Qiang Li.)

Rhizoma Drynariae (RD) was used clinically to treat osteoporosis in China due to stimulating bone formation and inhibiting bone resorption, however, the bioactive constituents with the dual effect on bone are still unknown exactly. Disease-causing mutations in calcium sensing receptor (CaSR) can alter parathyroid hormone secretion and affect Ca 2+ release from bone and Ca 2+ reabsorption from kidney, which gives an indication that CaSR is a potential target for developing therapeutics to manage osteoporosis. Herein, a chromatographic approach was established, by immobilizing the mutant CaSR onto the surface of silica gels as stationary phase in a one-step procedure and then adding the different amino acids into mobile phase as competitors, for exploring the binding features of the known agonists and further screening ligands from RD. The mutant CaSR-coated column was prepared rapidly without the complicated purification and separation of the receptor, which had the large capacity of 13.1 mg CaSR /g silica gels and kept a good stability and specificity for at least 35 days. The CaSR mutation can weaken the binding affinities for three agonists, and the largest decreases occurred on the mutational site Thr151Met for neomycin, on the two sites of Asn118Lys and Glu191Lys for gentamicin-C, and on the site Phe612Ser for kanamycin, which gained new insights into their structure-function relationship. The potential bioactive compounds from RD were screened using the mutant CaSR-coated column and were recognized as coumaric acid 4-O-β-D-glucopyranoside, caffeic acid, and naringin using UPLC-MS. Among them, naringin targeting CaSR gives a possible explanation that RD could manage osteoporosis. These results indicated that, such a rapid and simple method, utilizing disease-associated mutation in CaSR to alter the binding affinity for agonists, can be applied in capturing the potential bioactive compounds efficiently from complex matrices like herb medicines., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Pharmacogenomics has been widely used to study the very important pharmacogenetic (VIP) variants among different populations. However, there is little pharmacogenomic information about the Chinese Hui population. Our research aimed to reveal the outstandingly different loci in the Hui population, and provide a theoretical foundation for personalized drug use in the Hui population, so as to facilitate more effective treatment of diseases. This study genotyped 53 VIP variants of 26 genes in 200 independent Hui individuals based on the Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB). Remarkable differences in the genotype and allele frequencies between the Hui and 26 other populations from the 1000 Genomes Project were assessed using the χ 2 test. The genotype and allele frequencies of single nucleotide polymorphisms (SNPs) in PTGS2 (rs20417), NAT2 (rs1801280), NAT2 (rs1208), ACE (rs4291), and CYP2D6 (rs1065852) were considerably different in the Hui population compared with those in the other 26 populations. Besides, using the PharmGKB database, we identified several VIP variants that may alter the drug metabolism of ibuprofen, rofecoxib (PTGS2), captopril (ACE), citalopram, and escitalopram (CYP2D6). We also discovered other variants associated with adverse reactions to cisplatin and cyclophosphamide (NAT2). Our study indicated that the loci of PTGS2 (rs20417), NAT2 (rs1801280 and rs1208), ACE (rs4291), and CYP2D6 (rs1065852) in the Hui population were obviously different from those in the other 26 populations, which provides reliable information for predicting drug efficacy. Besides, it supplements the pharmacogenomic knowledge of the Hui population and lays the foundation for the individualized treatment for the Hui population., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Lung cancer is one of the malignant tumors, and genetic background is a risk factor in lung cancer that cannot be neglected. In this study, we aimed to find out the effect of MRPS30-DT and NINJ2 variants on lung cancer risk. In this study, the seven selected single-nucleotide polymorphisms (SNPs) of MRPS30-DT and NINJ2 were genotyped in 509 lung cancer patients and 501 healthy controls based on the Agena MassARRAY platform. Odds ratios and 95% confidence intervals were calculated by logistic regression analysis to evaluate association between gene polymorphisms and lung cancer risk. False-positive report probability was also used to assess false-positive results. Furthermore, the interaction between SNPs was analyzed by multifactor dimensionality reduction to predict lung cancer risk. We identified the genotype TA of rs16901963 (T < A) in MRPS30-DT as a protective factor against lung cancer, while rs16901963-TT was significantly associated with an increased risk of lung cancer. We also revealed that the effect of MRPS30-DT and NINJ2 variants on the risk of lung cancer was dependent on age, gender, smoking, and drinking status. In conclusion, this study first proved that MRPS30-DT and NINJ2 variants played important roles in affecting the susceptibility to lung cancer., Competing Interests: Conflict of interest: All authors declared no conflict of interest., (© 2023 the author(s), published by De Gruyter.)

The mechanism of sex differentiation in androdioecy is of great significance for illuminating the origin and evolution of dioecy. Tapiscia sinensis Oliv. is a functionally androdioecious species with both male and hermaphroditic individuals. Male flowers of T. sinensis lack the ovules of gynoecia compared with hermaphrodites. To identify sex simply and accurately, and further find the potential determinants of sex differentiation in T. sinensis, we found that TsRPL10a', a duplicate of TsRPL10a, was a male-linked gene. The promoter (5' untranslated region and the first intron) of TsRPL10a' can be used to accurately identify sex in T. sinensis. TsRPL10a is a ribosomal protein that is involved in gynoecium development, and sufficient ribosomal levels are necessary for female gametogenesis. The expression level of TsRPL10a was significantly downregulated in male flower primordia compared with hermaphrodites. The RNA fluorescence in situ hybridization (FISH) assay demonstrated that TsRPL10a was almost undetectable in male gynoecia at the gynoecial ridge stage, which was a key period of ovule formation by scanning electron microscope observation. In male flowers, although the promoter activity of TsRPL10a was significantly higher than TsRPL10a' verified by transgenic Arabidopsis thaliana, the transcriptional expression ratio of TsRPL10a was obviously lower than TsRPL10a' and reached its lowest at the gynoecial ridge stage, indicating the existence of a female suppressor. The promoter similarity of TsRPL10a and TsRPL10a' was only 45.29%; the genomic sequence similarity was 89.8%; four amino acids were altered in TsRPL10a'. The secondary structure of TsRPL10a' was different from TsRPL10a, and TsRPL10a' did not exhibit FISH and GUS expression in the gynoecium the way TsRPL10a did. From the perspective of RT-qPCR, its high expression level, followed by the low expression level of TsRPL10a in male flowers, indicates its antagonism function with TsRPL10a. The evolutionary analysis, subcellular localization and flower expression pattern suggested that TsRPL10a might be functionally conserved with AtRPL10aA, AtRPL10aB and AtRPL10aC in A. thaliana. Overall, we speculated that TsRPL10a and its duplicate TsRPL10a' might be involved in sex differentiation by influencing gynoecium development in T. sinensis., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The deficient catalytic activity of nanozymes and insufficient endogenous H 2 O 2 in the tumor microenvironment (TME) are major obstacles for nanozyme-mediated catalytic tumor therapy. Since electron transfer is the basic essence of catalysis-mediated redox reactions, we explored the contributing factors of enzymatic activity based on positive and negative charges, which are experimentally and theoretically demonstrated to enhance the peroxidase (POD)-like activity of a MoS 2 nanozyme. Hence, an acidic tumor microenvironment-responsive and ultrasound-mediated cascade nanocatalyst (BTO/MoS 2 @CA) is presented that is made from few-layer MoS 2 nanosheets grown on the surface of piezoelectric tetragonal barium titanate (T-BTO) and modified with pH-responsive cinnamaldehyde (CA). The integration of pH-responsive CA-mediated H 2 O 2 self-supply, ultrasound-mediated charge-enhanced enzymatic activity, and glutathione (GSH) depletion enables out-of-balance redox homeostasis, leading to effective tumor ferroptosis with minimal side effects., (© 2022 Wiley-VCH GmbH.)

Isopropyl 3-(3,4-dihydroxyphenyl)-2-hydroxypropanoate (IDHP) is one of the main bioactive metabolites of the Chinese medicinal herb Danshen, which can be absorbed into blood compounds by oral administration of Compound Danshen dripping pills (CDDPs). Previous study showed that IDHP exerted anti-inflammatory effects by abolishing the secretion of proinflammatory factors stimulated by lipopolysaccharide (LPS). However, the effects of IDHP on LPS-induced acute lung injury (ALI) are not fully understood. In the present study, we observed the effects of IDHP on mortality and lung injury in LPS-treated mice and on LPS-induced THP-1 macrophages. Pretreatment with high dose of IDHP was found to reduce the mortality of ALI mice, significantly improve LPS-induced pathological changes, and reduce protein leakage and inhibited myeloperoxidase (MPO) activity in lung tissue. IDHP also inhibited the release of inflammatory factors in bronchoalveolar lavage fluid (BALF) and lung tissue. Meanwhile, IDHP treatment significantly reduced the expression of active-caspase1, Nlrp3, Asc speck formation, Gsdmd (part of the canonical pyroptosis pathway), caspase4 (part of the non-canonical pyroptosis pathway), therefore decreasing IL-1β, IL-18, and ROS secretion in LPS-stimulated THP-1 macrophages. Moreover, after co-culturing endothelial/epithelial cells with conditioned medium (CM) from LPS-stimulated THP-1 macrophages, we found that the protein levels of occludin and Zonula occludens-1 (Zo-1) were increased in IDHP CM-treated endothelial cells compared to those that were LPS CM-treated. Lactic dehydrogenase (LDH) assay shows that IDHP also alleviated LPS-induced endothelial/epithelial cell injury. These findings indicate that the protective effect of IDHP on LPS-induced lung injury may be partly due to the inhibition of pyroptosis pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Cardiac dysfunction is a common complication in patients with sepsis triggering high morbidity and mortality. Lycorine (LYC), the main effective monomer component extracted from Lycoris bulbs, possesses antiviral, anti-inflammatory, analgesic, liver protection properties. In this study, the effect of LYC pre- and post-treatment as well as the underlying mechanism were evaluated in the cecal ligation and puncture (CLP) model of Balb/c mice. The survival rate, anal temperature, sepsis score, blood biochemical/routine indicators, cardiac function, sepsis-related pathophysiological processes, and AMPK signaling in septic mice were observed by echocardiography, histological staining, western blot, qPCR, and etc. LYC pretreatment attenuated myocardial injury in septic mice by improving survival rate, sepsis score, blood biochemical/routine indicators, cardiac function and structure, inhibiting inflammation and oxidative stress, improving mitochondrial function, modulating endoplasmic reticulum stress, and activating AMPK pathway. In particular, AMPK deficiency and AMPK inhibitor (Compound C) partially reversed the protective effects of LYC in septic mice. In addition, LYC posttreatment also has slight protective phenotypes on septic myocardial injury, but the effect is not as ideal as pretreatment. Taken together, these findings suggest that LYC may be a potential drug for the treatment of sepsis., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Hepatobiliary magnetic resonance imaging (MRI) can inform the diagnosis of liver tumours in patients with liver cirrhosis and hepatitis. However, its clinical utility has been hampered by the lack of sensitive and specific contrast agents, partly because hepatocyte-specific nanoparticles, regardless of their surface ligands, are readily sequestered by Kupffer cells. Here we show, in rabbits, pigs and macaques, that the performance of hepatobiliary MRI can be enhanced by an ultrasmall nanoparticle composed of a manganese ferrite core (3 nm in diameter) and poly(ethylene glycol)-ethoxy-benzyl surface ligands binding to hepatocyte-specific transmembrane metal and anion transporters. The nanoparticle facilitated faster, more sensitive and higher-resolution hepatobiliary MRI than the clinically used contrast agent gadoxetate disodium, a substantial enhancement in the detection rate (92% versus 48%) of early-stage liver tumours in rabbits, and a more accurate assessment of biliary obstruction in macaques. The nanoparticle's performance and biocompatibility support the further translational development of liver-specific MRI contrast agents., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)