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1.
Expert Opin Ther Pat ; 34(5): 297-313, 2024 May.
Article in English | MEDLINE | ID: mdl-38849323

ABSTRACT

INTRODUCTION: Stimulator of Interferon Genes (STING) is an innate immune sensor. Activation of STING triggers a downstream response that results in the expression of proinflammatory cytokines (TNF-α, IL-1ß) via nuclear factor kappa-B (NF-κB) or the expression of type I interferons (IFNs) via an interferon regulatory factor 3 (IRF3). IFNs can eventually result in promotion of the adaptive immune response including activation of tumor-specific CD8+ T cells to abolish the tumor. Consequently, activation of STING has been considered as a potential strategy for cancer treatment. AREAS COVERED: This article provides an overview on structures and pharmacological data of CDN-like and non-nucleotide STING agonists acting as anticancer agents (January 2021 to October 2023) from a medicinal chemistry perspective. The data in this review come from EPO, WIPO, RCSB PDB, CDDI. EXPERT OPINION: In recent years, several structurally diverse STING agonists have been identified. As an immune enhancer, they are used in the treatment of tumors, which has received extensive attention from scientific community and pharmaceutical companies. Despite the multiple challenges that have appeared, STING agonists may offer opportunities for immunotherapy.


Subject(s)
Antineoplastic Agents , Membrane Proteins , Neoplasms , Patents as Topic , Humans , Animals , Neoplasms/drug therapy , Neoplasms/pathology , Antineoplastic Agents/pharmacology , Membrane Proteins/agonists , Membrane Proteins/metabolism , Membrane Proteins/genetics , Immunity, Innate/drug effects , Immunotherapy/methods
2.
BMC Genomics ; 25(1): 572, 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38844832

ABSTRACT

KNOXs, a type of homeobox genes that encode atypical homeobox proteins, play an essential role in the regulation of growth and development, hormonal response, and abiotic stress in plants. However, the KNOX gene family has not been explored in sweet potato. In this study, through sequence alignment, genomic structure analysis, and phylogenetic characterization, 17, 12 and 11 KNOXs in sweet potato (I. batatas, 2n = 6x = 90) and its two diploid relatives I. trifida (2n = 2x = 30) and I. triloba (2n = 2x = 30) were identified. The protein physicochemical properties, chromosome localization, phylogenetic relationships, gene structure, protein interaction network, cis-elements of promoters, tissue-specific expression and expression patterns under hormone treatment and abiotic stresses of these 40 KNOX genes were systematically studied. IbKNOX4, -5, and - 6 were highly expressed in the leaves of the high-yield varieties Longshu9 and Xushu18. IbKNOX3 and IbKNOX8 in Class I were upregulated in initial storage roots compared to fibrous roots. IbKNOXs in Class M were specifically expressed in the stem tip and hardly expressed in other tissues. Moreover, IbKNOX2 and - 6, and their homologous genes were induced by PEG/mannitol and NaCl treatments. The results showed that KNOXs were involved in regulating growth and development, hormone crosstalk and abiotic stress responses between sweet potato and its two diploid relatives. This study provides a comparison of these KNOX genes in sweet potato and its two diploid relatives and a theoretical basis for functional studies.


Subject(s)
Diploidy , Gene Expression Regulation, Plant , Ipomoea batatas , Multigene Family , Phylogeny , Plant Proteins , Stress, Physiological , Ipomoea batatas/genetics , Ipomoea batatas/growth & development , Ipomoea batatas/metabolism , Stress, Physiological/genetics , Plant Proteins/genetics , Plant Proteins/metabolism , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Genome, Plant , Gene Expression Profiling , Promoter Regions, Genetic
3.
Sci Rep ; 14(1): 13586, 2024 06 12.
Article in English | MEDLINE | ID: mdl-38866898

ABSTRACT

Hyperglycemia is prevalent and closely associated with pulmonary tuberculosis (PTB). This study aimed to investigate the effects of hyperglycemia on the outcomes of PTB treatment. This study comprised 791 patients with PTB in total. Patients with fasting plasma glucose levels of ≥ 6.1 mmol/L were diagnosed with hyperglycemia. Anthropometric and baseline demographic data were also collected. The treatment response was assessed based on clinical symptoms (sputum production, cough, chest pain, fever, hemoptysis, night sweats, loss of appetite, and fatigue), sputum smear, chest computed tomography (CT), and adverse gastrointestinal responses (vomiting, nausea, abdominal distension, diarrhea, and constipation). A generalized estimating equation (GEE) was used to evaluate these relationships. Hyperglycemia affected 266 (33.6%) of the 791 patients with PTB. In GEE analyses, patients with hyperglycemia exhibited a greater incidence of elevated tuberculosis (TB) scores (odds ratio (OR) 1.569; 95% CI 1.040-2.369), cough (OR 1.332; 95% CI 1.050-1.690), and night sweats (OR 1.694; 95% CI 1.288-2.335). Hyperglycemia was linked with a higher risk of positive sputum smears (OR 1.941; 95% CI 1.382-2.727). During therapy, hyperglycemia was also associated with an increased incidence of vomiting (OR 2.738; 95% CI 1.041-7.198), abdominal distension (OR 2.230; 95% CI 1.193-4.171), and constipation (OR 2.372; 95% CI 1.442-3.902). However, the CT results indicated that hyperglycemia did not affect pulmonary lesions in patients with TB. Patients with TB and hyperglycemia are at a higher risk of severe clinical manifestations, positive sputum smears, and adverse gastrointestinal effects and, therefore, the special situation of hyperglycemic patients should be considered in the prevention and treatment of TB.


Subject(s)
Hyperglycemia , Tuberculosis, Pulmonary , Humans , Female , Male , Hyperglycemia/complications , Middle Aged , Tuberculosis, Pulmonary/drug therapy , Tuberculosis, Pulmonary/complications , Treatment Outcome , Adult , Cohort Studies , Antitubercular Agents/therapeutic use , Aged , Blood Glucose/metabolism , Blood Glucose/analysis , Sputum/microbiology
4.
Nat Commun ; 15(1): 5139, 2024 Jun 17.
Article in English | MEDLINE | ID: mdl-38886388

ABSTRACT

Although it is well documented that mountains tend to exhibit high biodiversity, how geological processes affect the assemblage of montane floras is a matter of ongoing research. Here, we explore landform-specific differences among montane floras based on a dataset comprising 17,576 angiosperm species representing 140 Chinese mountain floras, which we define as the collection of all angiosperm species growing on a specific mountain. Our results show that igneous bedrock (granitic and karst-granitic landforms) is correlated with higher species richness and phylogenetic overdispersion, while the opposite is true for sedimentary bedrock (karst, Danxia, and desert landforms), which is correlated with phylogenetic clustering. Furthermore, we show that landform type was the primary determinant of the assembly of evolutionarily older species within floras, while climate was a greater determinant for younger species. Our study indicates that landform type not only affects montane species richness, but also contributes to the composition of montane floras. To explain the assembly and differentiation of mountain floras, we propose the 'floristic geo-lithology hypothesis', which highlights the role of bedrock and landform processes in montane floristic assembly and provides insights for future research on speciation, migration, and biodiversity in montane regions.


Subject(s)
Biodiversity , Magnoliopsida , Phylogeny , China , Magnoliopsida/growth & development , Altitude , Geological Phenomena , Ecosystem
6.
World J Diabetes ; 15(4): 735-757, 2024 Apr 15.
Article in English | MEDLINE | ID: mdl-38680704

ABSTRACT

BACKGROUND: The cognitive impairment in type 2 diabetes mellitus (T2DM) is a multifaceted and advancing state that requires further exploration to fully comprehend. Neuroinflammation is considered to be one of the main mechanisms and the immune system has played a vital role in the progression of the disease. AIM: To identify and validate the immune-related genes in the hippocampus associated with T2DM-related cognitive impairment. METHODS: To identify differentially expressed genes (DEGs) between T2DM and controls, we used data from the Gene Expression Omnibus database GSE125387. To identify T2DM module genes, we used Weighted Gene Co-Expression Network Analysis. All the genes were subject to Gene Set Enrichment Analysis. Protein-protein interaction network construction and machine learning were utilized to identify three hub genes. Immune cell infiltration analysis was performed. The three hub genes were validated in GSE152539 via receiver operating characteristic curve analysis. Validation experiments including reverse transcription quantitative real-time PCR, Western blotting and immunohistochemistry were conducted both in vivo and in vitro. To identify potential drugs associated with hub genes, we used the Comparative Toxicogenomics Database (CTD). RESULTS: A total of 576 DEGs were identified using GSE125387. By taking the intersection of DEGs, T2DM module genes, and immune-related genes, a total of 59 genes associated with the immune system were identified. Afterward, machine learning was utilized to identify three hub genes (H2-T24, Rac3, and Tfrc). The hub genes were associated with a variety of immune cells. The three hub genes were validated in GSE152539. Validation experiments were conducted at the mRNA and protein levels both in vivo and in vitro, consistent with the bioinformatics analysis. Additionally, 11 potential drugs associated with RAC3 and TFRC were identified based on the CTD. CONCLUSION: Immune-related genes that differ in expression in the hippocampus are closely linked to microglia. We validated the expression of three hub genes both in vivo and in vitro, consistent with our bioinformatics results. We discovered 11 compounds associated with RAC3 and TFRC. These findings suggest that they are co-regulatory molecules of immunometabolism in diabetic cognitive impairment.

7.
Cell Mol Biol (Noisy-le-grand) ; 70(3): 174-181, 2024 Mar 31.
Article in English | MEDLINE | ID: mdl-38650145

ABSTRACT

Ovarian cancer is a prevalent malignancy in the female reproductive system, representing a significantly fatal and incurable tumor. Chelerythrine (CHE), a natural benzopyridine alkaloid, has demonstrated a broad spectrum of anticancer activities. Nevertheless, the ovarian cancer inhibitory impact of CHE remains unclear. In this study, we investigated the cytotoxic mechanism and potential targets of CHE on in vitro cultures of A2780 and SKOV3 cells derived from ovarian cancer. Additionally, in vivo experiments were conducted to confirm the suppressive impact of CHE on tumor growth in nude mice. The findings revealed that CHE impeded the growth of A2780 and SKOV3 cells in a concentration-time-dependent manner and significantly suppressed the development of tumors in nude mice. CHE elevated the level of oxidative stress in tumor cells, prompted cell cycle halt in the S phase, and increased their mitochondrial membrane potential. Western blotting results demonstrated that CHE could modulate the expression of proteins associated with apoptotic and ferroptosis processes in A2780 and SKOV3 cells. Nrf2 was verified to be an upstream key target mediating the inhibitory impact of CHE on ovarian cancer cells. In summary, CHE exerts its anti-cancer effects on ovarian cancer by modulating Nrf2, inhibiting cellular proliferation, and promoting apoptosis and ferroptosis.


Subject(s)
Apoptosis , Benzophenanthridines , Cell Proliferation , Ferroptosis , Mice, Nude , NF-E2-Related Factor 2 , Ovarian Neoplasms , Female , Benzophenanthridines/pharmacology , Humans , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Ovarian Neoplasms/drug therapy , NF-E2-Related Factor 2/metabolism , Animals , Cell Line, Tumor , Ferroptosis/drug effects , Apoptosis/drug effects , Cell Proliferation/drug effects , Membrane Potential, Mitochondrial/drug effects , Mice , Xenograft Model Antitumor Assays , Mice, Inbred BALB C , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism
8.
Heliyon ; 10(7): e27989, 2024 Apr 15.
Article in English | MEDLINE | ID: mdl-38590878

ABSTRACT

Purpose: The aim of this study is to investigate abdominal aortic aneurysm (AAA), a disease characterised by inflammation and progressive vasodilatation, for novel gene-targeted therapeutic loci. Methods: To do this, we used weighted co-expression network analysis (WGCNA) and differential gene analysis on samples from the GEO database. Additionally, we carried out enrichment analysis and determined that the blue module was of interest. Additionally, we performed an investigation of immune infiltration and discovered genes linked to immune evasion and mitochondrial fission. In order to screen for feature genes, we used two PPI network gene selection methods and five machine learning methods. This allowed us to identify the most featrue genes (MFGs). The expression of the MFGs in various cell subgroups was then evaluated by analysis of single cell samples from AAA. Additionally, we looked at the expression levels of the MFGs as well as the levels of inflammatory immune-related markers in cellular and animal models of AAA. Finally, we predicted potential drugs that could be targeted for the treatment of AAA. Results: Our research identified 1249 up-regulated differential genes and 3653 down-regulated differential genes. Through WGCNA, we also discovered 44 genes in the blue module. By taking the point where several strategies for gene selection overlap, the MFG (ITGAL and SELL) was produced. We discovered through single cell research that the MFG were specifically expressed in T regulatory cells, NK cells, B lineage, and lymphocytes. In both animal and cellular models of AAA, the MFGs' mRNA levels rose. Conclusion: We searched for the AAA novel targeted gene (ITGAL and SELL), which most likely function through lymphocytes of the B lineage, NK cells, T regulatory cells, and B lineage. This analysis gave AAA a brand-new goal to treat or prevent the disease.

9.
Seizure ; 116: 93-99, 2024 Mar.
Article in English | MEDLINE | ID: mdl-37643945

ABSTRACT

OBJECTIVES: Variants in NEXMIF had been reported associated with intellectual disability (ID) without epilepsy or developmental epileptic encephalopathy (DEE). It is unkown whether NEXMIF variants are associated with epilepsy without ID. This study aims to explore the phenotypic spectrum of NEXMIF and the genotype-phenotype correlations. MATERIALS AND METHODS: Trio-based whole-exome sequencing was performed in patients with epilepsy. Previously reported NEXMIF variants were systematically reviewed to analyze the genotype-phenotype correlations. RESULTS: Six variants were identified in seven unrelated cases with epilepsy, including two de novo null variants and four hemizygous missense variants. The two de novo variants were absent in all populations of gnomAD and four hemizygous missense variants were absent in male controls of gnomAD. The two patients with de novo null variants exhibited severe developmental epileptic encephalopathy. While, the patients with hemizygous missense variants had mild focal epilepsy with favorable outcome. Analysis of previously reported cases revealed that males with missense variants presented significantly higher percentage of normal intellectual development and later onset age of seizure than those with null variants, indicating a genotype-phenotype correlation. CONCLUSION: This study suggested that NEXMIF variants were potentially associated with pure epilepsy with or without intellectual disability. The spectrum of epileptic phenotypes ranged from the mild epilepsy to severe developmental epileptic encephalopathy, where the epileptic phenotypes variability are potentially associated with patients' gender and variant type.


Subject(s)
Epilepsy, Generalized , Epilepsy , Intellectual Disability , Humans , Male , Intellectual Disability/complications , Intellectual Disability/genetics , Epilepsy/complications , Epilepsy/genetics , Seizures/complications , Epilepsy, Generalized/complications , Epilepsy, Generalized/genetics , Phenotype
10.
Seizure ; 116: 37-44, 2024 Mar.
Article in English | MEDLINE | ID: mdl-36941137

ABSTRACT

PURPOSE: The FAT1 gene encodes FAT atypical cadherin 1, which is essential for foetal development, including brain development. This study aimed to investigate the relationship between FAT1 variants and epilepsy. METHODS: Trio-based whole-exome sequencing was performed on a cohort of 313 patients with epilepsy. Additional cases with FAT1 variants were collected from the China Epilepsy Gene V.1.0 Matching Platform. RESULTS: Four pairs of compound heterozygous missense FAT1 variants were identified in four unrelated patients with partial (focal) epilepsy and/or febrile seizures, but without intellectual disability/developmental abnormalities. These variants presented no/very low frequencies in the gnomAD database, and the aggregate frequencies in this cohort were significantly higher than those in controls. Two additional compound heterozygous missense variants were identified in two unrelated cases using the gene-matching platform. All patients experienced infrequent (yearly/monthly) complex partial seizures or secondary generalised tonic-clonic seizures. They responded well toantiseizure medication, but seizures relapsed in three cases when antiseizure medication were decreased or withdrawn after being seizure-free for three to six years, which correlated with the expression stage of FAT1. Genotype-phenotype analysis showed that epilepsy-associated FAT1 variants were missense, whereas non-epilepsy-associated variants were mainly truncated. The relationship between FAT1 and epilepsy was evaluated to be "Strong" by the Clinical Validity Framework of ClinGen. CONCLUSIONS: FAT1 is a potential causative gene of partial epilepsy and febrile seizures. Gene expression stage was suggested to be one of the considerations in determining the duration ofantiseizure medication. Genotype-phenotype correlation helps to explain the mechanisms underlying phenotypic variation.


Subject(s)
Epilepsies, Partial , Epilepsy , Seizures, Febrile , Humans , Anticonvulsants/therapeutic use , Seizures, Febrile/genetics , Seizures, Febrile/drug therapy , Epilepsies, Partial/drug therapy , Epilepsy/drug therapy , Recurrence , Gene Expression , Cadherins/genetics
11.
Chinese Journal of Pathology ; (12): 52-57, 2024.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-1012424

ABSTRACT

Objective: To investigate the clinicopathological features and treatment of gastric alpha-fetoprotein (AFP)-producing adenocarcinoma with SWI/SNF complex deletion. Methods: Four cases of gastric AFP-producing adenocarcinoma with SWI/SNF complex deletion diagnosed in Zhongshan Hospital of Fudan University from January 2021 to December 2022 were collected, and their histomorphological characteristics, immunohistochemical (IHC), in situ hybridization of Epstein-Barr virus-encoded RNA (EBER), next-generation sequencing results, clinicopathological features and treatment were summarized, and literature review was conducted. Results: Among the 4 patients, there were three males and one female. They presented with abdominal pain, belching and melena. Serum AFP was significantly elevated in three patients, and endoscopy showed ulcerative lesions. Microscopically, the tumor cells showed mainly diffuse flaky or nest-like growth and typical characteristics of hepatoid adenocarcinoma. In two cases there were adenoid growth, and the tumor cells in these areas possessed clear cytoplasm, suggesting enteroblastic differentiation. The tumor cell nuclei were pleomorphic with large nucleoli and brisk mitoses. The IHC results showed that the tumor cells expressed AFP, GPC3 and SALL4, and there was retained expression of broad-spectrum keratin (CKpan) and E-cadherin. IHC detection of SWI/SNF complex subunits, namely INI1 (SMARCB1), BRG1 (SMARCA4), BRM (SMARCA2), ARID1A protein was performed. In all four cases the hepatoid adenocarcinoma region and enteroblastic differentiation region showed SMARCA2 deletion, and one case with enteroblastic differentiation also showed ARID1A deletion. SMARCB1 and SMARCA4 deletions were not seen. All the four cases were diffusely positive for p53 protein, and the Ki-67 proliferation index was 80%-90%. There were no mismatch repair deletion detected; one cases showed HER2 was strongly positive (3+), and EBER was negative. None of the four cases had mutations in the SWI/SNF complex-related subunits detected by next-generation sequencing. Among the four patients, two underwent palliative surgery due to distant metastasis at the time of surgery, two underwent radical resection. Postoperative adjuvant chemotherapy was given to three patients. Conclusions: AFP-producing adenocarcinoma is a rare subtype of gastric cancer, which can be combined with SWI/SNF complex deletion, and the pathomorphological manifestations are different from the classical SWI/SNF complex deletion of undifferentiated carcinoma with rhabdoid phenotype.


Subject(s)
Male , Humans , Female , alpha-Fetoproteins , Stomach Neoplasms/genetics , Epstein-Barr Virus Infections , Herpesvirus 4, Human , Adenocarcinoma/pathology , Biomarkers, Tumor/genetics , DNA Helicases/genetics , Nuclear Proteins , Transcription Factors/genetics , Glypicans
12.
J Transl Med ; 21(1): 921, 2023 12 19.
Article in English | MEDLINE | ID: mdl-38115075

ABSTRACT

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is one of the most prevalent metabolic syndromes worldwide. However, no approved pharmacological treatments are available for MAFLD. Chenpi, one kind of dried peel of citrus fruits, has traditionally been utilized as a medicinal herb for liver diseases. Didymin is a newly identified oral bioactive dietary flavonoid glycoside derived from Chenpi. In this study, we investigated the therapeutic potential of Didymin as an anti-MAFLD drug and elucidated its underlying mechanisms. METHODS: High-fat diet (HFD)-induced MAFLD mice and alpha mouse liver 12 (AML12) cells were utilized to evaluate the effects and mechanisms of Didymin in the treatment of MAFLD. Liver weight, serum biochemical parameters, and liver morphology were examined to demonstrate the therapeutic efficacy of Didymin in MAFLD treatment. RNA-seq analysis was performed to identify potential pathways that could be affected by Didymin. The impact of Didymin on Sirt1 was corroborated through western blot, molecular docking analysis, microscale thermophoresis (MST), and deacetylase activity assay. Then, a Sirt1 inhibitor (EX-527) was utilized to confirm that Didymin alleviates MAFLD via Sirt1. Western blot and additional assays were used to investigate the underlying mechanisms. RESULTS: Our results suggested that Didymin may possess therapeutic potential against MAFLD in vitro and in vivo. By promoting Sirt1 expression as well as directly binding to and activating Sirt1, Didymin triggers downstream pathways that enhance mitochondrial biogenesis and function while reducing apoptosis and enhancing lipophagy. CONCLUSIONS: These suggest that Didymin could be a promising medication for MAFLD treatment. Furthermore, its therapeutic effects are mediated by Sirt1.


Subject(s)
Non-alcoholic Fatty Liver Disease , Sirtuin 1 , Animals , Mice , Sirtuin 1/metabolism , Organelle Biogenesis , Molecular Docking Simulation , Flavonoids/pharmacology , Flavonoids/therapeutic use , Glycosides/pharmacology , Non-alcoholic Fatty Liver Disease/metabolism , Liver/metabolism
13.
Huan Jing Ke Xue ; 44(10): 5649-5656, 2023 Oct 08.
Article in Chinese | MEDLINE | ID: mdl-37827781

ABSTRACT

The supplementation of soil amendments may not only improve the soil physical and chemical properties but also lead to the accumulation of heavy metals in soil. This experiment included six treatments:control (CK), organic manure (OM), polyacrylamide+organic manure (PAM+OM), straw mulching+organic manure (SM+OM), buried straw+organic manure (BS+OM), and bio-organic manure+organic manure (BM+OM) to explore the effects of different soil amendments on heavy metals and soil enzyme activities in coastal saline land and the relationship between them. The results revealed that compared with that in the CK treatment, the contents of soil Cr, Cu, Ni, and Pb exhibited an upward trend after the supplementation of soil amendments, among which the SM+OM and PAM+OM treatments had the most significant effects on the contents of soil Cr and Cu, respectively, whereas the BM+OM treatment had the most significant effects on the contents of soil Ni and Pb. Compared with those in the CK treatment, the activities of soil invertase and urease increased significantly following supplementation of soil amendments, and the BM+OM treatment had the best effect. The alkaline phosphatase activity exhibited a slightly upward trend after the supplementation of soil amendments, whereas the catalase activity did not change significantly. The redundancy analysis revealed that the first two axes cumulatively accounted for 70.3% of the variability in enzyme activities, and the importance of single soil heavy metals on soil enzyme activity was as follows:Ni>Cu>Cr>Pb.


Subject(s)
Metals, Heavy , Soil Pollutants , Soil/chemistry , Manure/analysis , Lead/analysis , Soil Pollutants/analysis , Metals, Heavy/analysis , Dietary Supplements/analysis
14.
Molecules ; 28(19)2023 Oct 09.
Article in English | MEDLINE | ID: mdl-37836830

ABSTRACT

Osteoporosis (OP) is distinguished by a reduction in bone mass and degradation of bone micro-structure, frequently resulting in fractures. As the geriatric demographic expands, the incidence of affected individuals progressively rises, thereby exerting a significant impact on the quality of life experienced by individuals. The flavonoid compound hesperidin has been subject to investigation regarding its effects on skeletal health, albeit the precise mechanisms through which it operates remain ambiguous. This study utilized network pharmacology to predict the core targets and signaling pathways implicated in the anti-OP properties of hesperidin. Molecular docking and molecular dynamics simulations were employed to confirm the stability of the interaction between hesperidin and the core targets. The effects of hesperidin on osteoblastic cells MC3T3-E1 were assessed using MTT, ELISA, alkaline phosphatase assay, and RT-qPCR techniques. Furthermore, in vivo experiments were conducted to determine the potential protective effects of hesperidin on zebrafish bone formation and oxidative stress response. The results demonstrate that network pharmacology has identified 10 key target points, significantly enriched in the estrogen signaling pathway. Hesperidin exhibits notable promotion of MC3T3-E1 cell proliferation and significantly enhances ALP activity. ELISA measurements indicate an elevation in NO levels and a reduction in IL-6 and TNF-α. Moreover, RT-qPCR analysis consistently reveals that hesperidin significantly modulates the mRNA levels of ESR1, SRC, AKT1, and NOS3 in MC3T3-E1 cells. Hesperidin promotes osteogenesis and reduces oxidative stress in zebrafish. Additionally, we validate the stable and tight binding of hesperidin with ESR1, SRC, AKT1, and NOS3 through molecular dynamics simulations. In conclusion, our comprehensive analysis provides evidence that hesperidin may exert its effects on alleviating OP through the activation of the estrogen signaling pathway via ESR1. This activation leads to the upregulation of SRC, AKT, and eNOS, resulting in an increase in NO levels. Furthermore, hesperidin promotes osteoblast-mediated bone formation and inhibits pro-inflammatory cytokines, thereby alleviating oxidative stress associated with OP.


Subject(s)
Hesperidin , Osteoporosis , Animals , Humans , Aged , Hesperidin/pharmacology , Hesperidin/metabolism , Zebrafish , Cell Differentiation , Molecular Docking Simulation , Quality of Life , Signal Transduction , Osteogenesis , Osteoblasts , Estrogens/pharmacology , Osteoporosis/metabolism
15.
Ying Yong Sheng Tai Xue Bao ; 34(6): 1713-1720, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37694434

ABSTRACT

The core of scientific greening in arid areas is 'greening based on water'. One of its preconditions is the potential causal relationship between vegetation construction and habitat drought. However, the causal relationship between factors or processes in ecology is generally difficult to accurately define and describe, especially for complex ecosystems. To scientifically carry out 'greening based on water', it is necessary to clarify the relationship between vegetation construction and hydrological cycle in drylands, and clarify the basis and conditions for habitat drought. Taking the construction of scientific greening pilot demonstration province in Ningxia as an example, we started with the theoretical connotation and application model of ecological causality of 'greening based on water', and empirically analyzed the causal relationship between vegetation construction and habitat drought at the regional, landscape, and ecosystem scale, respectively. The contradictions and problems in relevant understanding and practice were pointed out, and the principles and suggestions of scientific practice of 'greening based on water' were put forward.


Subject(s)
Droughts , Ecosystem , Water , Water Cycle
16.
Am J Cancer Res ; 13(6): 2732-2750, 2023.
Article in English | MEDLINE | ID: mdl-37424811

ABSTRACT

Drug resistance is a major cause of treatment failure and post-treatment disease progression in patients with cancer. This study aimed to investigate the mechanisms of chemoresistance to gemcitabine (GEM) plus cisplatin (cis-diamminedichloroplatinum, DDP) combination therapy in stage IV lung squamous cell carcinoma (LSCC). It also examined the functional role of lncRNA ASBEL and lncRNA Erbb4-IR in the malignant progression of LSCC. The expression of lncRNA ASBEL, lncRNA Erbb4-IR, miR-21, and LZTFL1 mRNA was examined in human stage IV LSCC tissues and adjacent normal tissues, human LSCC cells and normal human bronchial epithelial cells using qRT-PCR. Furthermore, LZTFL1 protein levels were also examined using western blots. Cell proliferation, cell migration and invasion, and cell cycle progression and apoptosis were evaluated in vitro using the CCK-8, transwell, and flow cytometry assays, respectively. Based on the treatment response, LSCC tissues were classified as GEM-, DDP-, and GEM+DDP-sensitive/resistant. The MTT assay was performed to assess the chemoresistance of human LSCC cells to GEM, DDP, and GEM+DDP following transfection experiments. The results showed that lncRNA ASBEL, lncRNA Erbb4-IR, and LZTFL1 were down-regulated in human LSCC tissues and cells, whereas miR-21 was up-regulated. In stage IV human LSCC tissues, miR-21 levels were negatively correlated with those of lncRNA ASBEL, lncRNA Erbb4-IR, and LZTFL1 mRNA. The overexpression of lncRNA ASBEL and lncRNA Erbb4-IR inhibited cell proliferation, migration, and invasion. It also blocked cell cycle entry and accelerated apoptosis. These effects were mediated by the miR-21/LZTFL1 axis and reduced chemoresistance to GEM+DDP combination therapy in stage IV human LSCC. These findings indicate that lncRNA ASBEL and lncRNA Erbb4-IR function as tumor suppressors in stage IV LSCC and attenuate chemoresistance to GEM+DDP combination therapy via the miR-21/LZTFL1 axis. Hence, lncRNA ASBEL, lncRNA Erbb4-IR, and LZTFL1 may be targeted to enhance the efficacy of GEM+DDP combination chemotherapy against LSCC.

17.
Chem Biodivers ; 20(8): e202300754, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37401658

ABSTRACT

Magnolol and Honokiol are the primary active components that have been identified and extracted from Magnolia officinalis, and several investigations have demonstrated that they have significant pharmacological effects. Despite their therapeutic benefits for a wide range of illnesses, research on and the implementation of these compounds have been hindered by their poor water solubility and low bioavailability. Researchers are continually using chemical methods to alter their structures to make them more effective in treating and preventing diseases. Researchers are also continuously developing derivative drugs with high efficacy and few adverse effects. This article summarizes and analyzes derivatives with significant biological activities reported in recent research obtained by structural modification. The modification sites have mainly focused on the phenolic hydroxy groups, benzene rings, and diene bonds. Changes to the allyl bisphenol structure will result in unexpected benefits, including high activity, low toxicity, and good bioavailability. Furthermore, alongside earlier experimental research in our laboratory, the structure-activity relationships of magnolol and honokiol were preliminarily summarized, providing experimental evidence for improving their development and utilization.


Subject(s)
Lignans , Magnolia , Lignans/pharmacology , Lignans/chemistry , Biphenyl Compounds/chemistry , Structure-Activity Relationship , Magnolia/chemistry
18.
Zhongguo Zhong Yao Za Zhi ; 48(12): 3215-3223, 2023 Jun.
Article in Chinese | MEDLINE | ID: mdl-37382005

ABSTRACT

This study aimed to investigate the relationship between coagulating cold and blood stasis syndrome and glycolysis, and observe the intervention effect of Liangfang Wenjing Decoction(LFWJD) on the expression of key glycolytic enzymes in the uterus and ovaries of rats with coagulating cold and blood stasis. The rat model of coagulating cold and blood stasis syndrome was established by ice-water bath. After modeling, the quantitative scoring of symptoms were performed, and according to the scoring results, the rats were randomly divided into a model group and LFWJD low-, medium-and high-dose groups(4.7, 9.4, 18.8 g·kg~(-1)·d~(-1)), with 10 in each group. Another 10 rats were selected as the blank group. After 4 weeks of continuous administration by gavage, the quantitative scoring of symptoms was repeated. Laser speckle flowgraphy was used to detect the changes of microcirculation in the ears and uterus of rats in each group. Hematoxylin-eosin(HE) staining was used to observe the pathological morphology of uterus and ovaries of rats in each group. The mRNA and protein expressions of pyruvate dehydrogenase kinase 1(PDK1), hexokinase 2(HK2) and lactate dehydrogenase A(LDHA) in the uterus and ovaries of rats were examined by real-time quantitative polymerase chain reaction(RT-qPCR) and Western blot, respectively. The rats in the model group showed signs of coagulating cold and blood stasis syndrome, such as curl-up, less movement, thickened veins under the tongue, and reduced blood perfusion in the microcirculation of the ears and uterus, and HE staining revealed a thinning of the endometrium with disorganized arrangement of epithelial cells and a decrease in the number of ovarian follicles. Compared with the model group, the treatment groups had alleviated coagulating cold and blood stasis, which was manifested as red tongue, reduced nail swelling, no blood stasis at the tail end as well as increased blood perfusion of the microcirculation in the ears and uterus(P<0.05 or P<0.01). Among the groups, the LFWJD medium-and high-dose groups had the most significant improvement in coagulating cold and blood stasis, with neatly arranged columnar epithelial cells in uterus, and the number of ovarian follicles was higher than that in the model group, especially mature follicles. The mRNA and protein expressions of PDK1, HK2, LDHA in uterus and ovaries were up-regulated in the model group(P<0.05 or P<0.01), while down-regulated in LFWJD medium-and high-dose groups(P<0.05 or P<0.01). The LFWJD low-dose group presented a decrease in the mRNA expressions of PDK1, HK2 and LDHA in uterus and ovaries as well as in the protein expressions of HK2 and LDHA in uterus and HK2 and PDK1 in ovaries(P<0.05 or P<0.01). The therapeutic mechanism of LFWJD against coagulating cold and blood stasis syndrome is related to the down-regulation of key glycolytic enzymes PDK1, HK2 and LDHA, and the inhibition of glycolytic activities in uterus and ovaries.


Subject(s)
Ovary , Uterus , Female , Animals , Rats , Ovarian Follicle , Lactate Dehydrogenase 5 , Glycolysis
19.
Brain Behav ; 13(8): e3131, 2023 08.
Article in English | MEDLINE | ID: mdl-37337730

ABSTRACT

BACKGROUND: Williams syndrome is an autosomal dominant multisystem disorder caused by a 1.5-1.8 Mb deletion on chromosome 7q11.23. It is characterized by facial deformations, cardiovascular abnormalities, developmental delays, gastrointestinal manifestations, and endocrine disorders. CASE DESCRIPTION: A 1-year-old child presenting with developmental delays, special facial features, gastrointestinal bleeding, renal calcium deposition, and hypotonia was admitted to the hospital for "hypercalcemia and gastrointestinal bleeding." Genetic testing showed a deletion mutation in the 7q11.23 region. Currently, the child receiving treatment to promote calcium excretion and rehabilitation training, but hypercalcemia has recurred. CONCLUSION: The clinical phenotype of Williams syndrome is complex, and different severities, characterized by developmental delays, facial deformities, cardiovascular abnormalities, gastrointestinal symptoms and endocrine disorders, should be considered in children. The syndrome may require thorough genetic testing for diagnosis and early intervention treatment to improve patient quality of life.


Subject(s)
Hypercalcemia , Williams Syndrome , Humans , Williams Syndrome/complications , Williams Syndrome/diagnosis , Williams Syndrome/genetics , Hypercalcemia/complications , Hypercalcemia/diagnosis , Calcium , Quality of Life , Gastrointestinal Hemorrhage/etiology
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