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1.
Cell Signal ; 124: 111376, 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39236836

RESUMO

While certain members of ubiquitin-coupled enzymes (E2s) have garnered attention as potential therapeutic targets across diverse diseases, research progress on Ubiquitin-Conjugating Enzyme 5 (UBC5)-a pivotal member of the E2s family involved in crucial cellular processes such as apoptosis, DNA repair, and signal transduction-has been relatively sluggish. Previous findings suggest that UBC5 plays a vital role in the ubiquitination of various target proteins implicated in diseases and homeostasis, particularly in various cancer types. This review comprehensively introduces the structure and biological functions of UBC5, with a specific focus on its contributions to the onset and advancement of diverse diseases. It suggests that targeting UBC5 holds promise as a therapeutic approach for disease therapy. Recent discoveries highlighting the high homology between UBC5, UBC1, and UBC4 have provided insight into the mechanism of UBC5 in protein degradation and the regulation of cellular functions. As our comprehension of the structural distinctions among UBC5 and its homologues, namely UBC1 and UBC4, advances, our understanding of UBC5's functional significance also expands.

2.
EBioMedicine ; 108: 105340, 2024 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-39303669

RESUMO

BACKGROUND: The continuous emergence of multidrug-resistant (MDR) Acinetobacter baumannii (Ab) strains poses further challenges in its control and clinical management. It is necessary to decipher the mechanisms underlying the high mortality of Ab infections to explore unconventional strategies for controlling outbreaks of drug-resistant infections. METHODS: The immune responses of Ab sepsis infection were investigated using flow cytometry, RNA-seq, qRT-PCR, and ELISA and scRNA-seq. The detailed pathways mediating Ab immune responses were also depicted and a specific therapy was developed based on the understanding of the mechanisms underlying Ab-induced cytokine storms. FINDINGS: The results highlighted the critical role of alveolar and interstitial macrophages as targets of Ab during the infection process. These cells were found to undergo polarization towards the M1 phenotype, triggering a cytokine storm that eventually caused the death of the host. The polarization and excessive inflammatory response mediated by macrophages were mainly regulated by the TLR2/Myd88/NF-κB signaling pathway. Suppression of Ab-triggered inflammatory responses and M1 polarization by the drug naproxen (NPXS) was shown to confer full protection of mice from lethal infections. INTERPRETATION: The findings in this work depict the major mechanisms underlying the high mortality rate of Ab infections and highlight the clinical potential application of anti-inflammatory drugs or immunosuppressants in reducing the mortality of such infections, including those caused by MDR strains. FUNDING: Funding sources are described in the acknowledgments section.

3.
J Pharm Anal ; 14(9): 100978, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39315124

RESUMO

Jumonji domain-containing protein D3 (JMJD3) is a 2-oxoglutarate-dependent dioxygenase that specifically removes transcriptional repression marks di- and tri-methylated groups from lysine 27 on histone 3 (H3K27me2/3). The erasure of these marks leads to the activation of some associated genes, thereby influencing various biological processes, such as development, differentiation, and immune response. However, comprehensive descriptions regarding the relationship between JMJD3 and inflammation are lacking. Here, we provide a comprehensive overview of JMJD3, including its structure, functions, and involvement in inflammatory pathways. In addition, we summarize the evidence supporting JMJD3's role in several inflammatory diseases, as well as the potential therapeutic applications of JMJD3 inhibitors. Additionally, we also discuss the challenges and opportunities associated with investigating the functions of JMJD3 and developing targeted inhibitors and propose feasible solutions to provide valuable insights into the functional exploration and discovery of potential drugs targeting JMJD3 for inflammatory diseases.

4.
BMC Gastroenterol ; 24(1): 308, 2024 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-39261771

RESUMO

BACKGROUND: The netrin-1/CD146 pathway regulates colorectal cancer (CRC) liver metastasis, angiogenesis, and vascular development. However, few investigations have yet examined the biological function of netrin-1/CD146 complex in CRC. In this work, we investigated the relationship between the netrin-1/CD146 axis and S100 proteins in sentinel lymph node, and revealed a possible new clue for vascular metastasis of CRC. METHODS: The expression levels of netrin-1 and CD146 proteins in CRC, as well as S100A8 and S100A9 proteins in the sentinel lymph nodes were determined by immunohistochemistry. Using GEPIA and UALCAN, we analyzed netrin-1 and CD146 gene expression in CRC, their association with CRC stage, and their expression levels and prognosis in CRC patients. RESULTS: The expression level of netrin-1 in N1a+1b (CRC lymphatic metastasis groups, exculded N1c) was positively increased with N0 (p = 0.012). The level of netrin-1 protein was positively correlated with CD146 protein (p < 0.05). The level of S100A9 protein was positively correlated with CD146 protein (r = 0.492, p = 0.007). Moreover, netrin-1 expression was obviously correlated with S100A9 expression in the N1 stage (r = 0.867, p = 0.000). CD146 level was correlated with S100A9 level in the N2 stage (r = 0.731, p = 0.039). CD146 mRNA expression was higher in normal colorectal tissues than in CRC (p < 0.05). Netrin-1 and CD146 expression were not significantly associated with the tumor stages and prognosis of patients with CRC (p > 0.05). CONCLUSIONS: The netrin-1/CD146 and netrin-1/S100A9 axis in CRC tissues might related with early stage of lymph node metastasis, thus providing potential novel channels for blocking lymphatic metastasis and guiding biomarker discovery in CRC patients.


Assuntos
Antígeno CD146 , Calgranulina B , Neoplasias Colorretais , Metástase Linfática , Netrina-1 , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Calgranulina A/genética , Calgranulina A/metabolismo , Calgranulina B/genética , Calgranulina B/metabolismo , Antígeno CD146/genética , Antígeno CD146/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Linfonodos/patologia , Linfonodos/metabolismo , Metástase Linfática/genética , Metástase Linfática/patologia , Estadiamento de Neoplasias , Netrina-1/metabolismo , Netrina-1/genética , Prognóstico
5.
Front Neurol ; 15: 1434433, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39224884

RESUMO

Background: Previous studies have shown a connection between physical activity and migraines, but they don't prove a cause-and-effect relationship due to potential biases in observational methods. Methods: Utilizing accelerometer-measured physical activity data from a cohort of 377,234 participants in the UK Biobank and information from 599,356 European migraine patients (including 48,975 cases and 550,381 controls) obtained from 24 cohorts, we performed a bidirectional Mendelian randomization analysis to investigate the genetic bidirectional causal relationship between accelerometer-measured physical activity and migraines. Results: Research findings indicated a slight negative genetic correlation between "average acceleration" physical activity (rg = -0.091, p = 0.011), overall physical activity (rg = -0.081, p = 0.017), and migraine. Nevertheless, no shared genetic components were observed between migraine and "fraction of accelerations > 425 mg" of physical activity (rg = -0.124, p = 0.076). The study results also demonstrated a lack of genetic bidirectional causality between accelerometer-measured physical activity and migraine ("average acceleration", OR = 1.002, 95% CI 0.975-1.031, p = 0.855, "fraction of accelerations > 425 mg", OR = 1.127, 95% CI 0.802-1.583, p = 0.488, overall physical activity, OR = 0.961, 95% CI 0.713-1.296, p = 0.799), and vice versa. Additionally, this lack of causal association persists even after adjusting for obesity (OR = 1.005, p = 0.578), education (OR = 1.019, p = 0.143), and depression (OR = 1.005, p = 0.847), either separately or simultaneously. Conclusion: The Mendelian randomization results based on genetic data do not provide support for a causal association between physical activity and migraine.

6.
Chem Sci ; 15(33): 13191-13200, 2024 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-39183934

RESUMO

The accurate construction of mono-, bi- and multi-layer networks has been an important challenge, especially for bi- and multi-layer networks. Monolayer, bilayer, sandwich bilayer, four-layer, and multi-layer two-dimensional pillararene-type metal-organic coordination networks have been constructed from functionalized pillar[5]arene and pillar[6]arene by utilizing the coordination interaction of cobalt and copper ions and combining with temperature control and guest induction. These two-dimensional coordination networks exhibit the excellent plasticity of pillararenes and structural variety, which are characterized by X-ray single crystal diffraction and PXRD, confirming that pillararenes units can function as excellent tunable scaffolds for structural regulation. Two-dimensional chiral double-layer structure products are also constructed from R- and S-pillar[6]arene, which are obtained by high-performance liquid chromatography. Atomic force microscopic imaging confirms the thicknesses of these networks. Moreover, these networks also exhibit high iodine adsorption capacity in aqueous environments at ambient temperature. The monolayer, bilayer, sandwich bilayer, four-layer and multi-layer structures of the pillararene-type networks represent a new facile supramolecular self-assembly strategy and platform for designing more mono-, bi- and multi-layer two-dimensional nanomaterials and chiral two-dimensional double-layer structures provide a new method for the construction of more two-dimensional chiral polymers.

7.
PeerJ ; 12: e17615, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38948228

RESUMO

Background: Fibroblast growth factor 21 (FGF21) is a key hormone factor that regulates glucose and lipid homeostasis. Exercise may regulate its effects and affect disease states. Therefore, we sought to determine how exercise affects FGF21 concentrations in adults. Methods: The review was registered in the International Prospective Systematic Review (PROSPERO, CRD42023471163). The Cochrane Library, PubMed, and Web of Science databases were searched for studies through July 2023. Studies that assessed the effects of exercise training on FGF21 concentration in adults were included. The random effect model, data with standardized mean difference (SMD), and 95% confidence intervals (CI) were used to evaluate the pooled effect size of exercise training on FGF21. The risk of heterogeneity and bias were evaluated. A total of 12 studies involving 401 participants were included. Results: The total effect size was 0.3 (95% CI [-0.3-0.89], p = 0.33) when comparing participants who exercised to those who were sedentary. However, subgroup analysis indicated that concurrent exercise and a duration ≥10 weeks significantly decreased FGF21 concentrations with an effect size of -0.38 (95% CI [-0.74--0.01], p < 0.05) and -0.38 (95% CI [-0.63--0.13], p < 0.01), respectively. Conclusion: Concurrent exercise and longer duration may be more efficient way to decrease FGF21 concentrations in adults with metabolic disorder.


Assuntos
Exercício Físico , Fatores de Crescimento de Fibroblastos , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Exercício Físico/fisiologia , Adulto
8.
Chem Asian J ; : e202400554, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38956446

RESUMO

A six-cyclic crown ether-type pillar[5]arene was synthesized, and the five ethylene oxide loops were located outside the cavity and not affected by temperature changes which was confirmed by variable-temperature NMR experiment in DMSO-d6 and CDCl3 and 2D 1H-1H NOESY experiment in CDCl3. The six-cyclic pillar[5]-crown also showed greater binding ability of host-guest with bis(pyridinium) derivatives than conventional alkoxy pillar[5]arenes that illustrated through 1H NMR titration spectroscopic experiment in acetone-d6/CDCl3 (1 : 1) and UV-vis titration experiments in CHCl3 at room temperature. The five benzocrown ethers at the periphery were able to bind metal cations by 1H NMR titration spectroscopic experiment in CD2Cl2/methanol-d4(9 : 1).

9.
Pharmacol Res ; 206: 107294, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38992851

RESUMO

Liver fibrosis is a determinant-stage process of many chronic liver diseases and affected over 7.9 billion populations worldwide with increasing demands of ideal therapeutic agents. Discovery of active molecules with anti-hepatic fibrosis efficacies presents the most attacking filed. Here, we revealed that hepatic L-aspartate levels were decreased in CCl4-induced fibrotic mice. Instead, supplementation of L-aspartate orally alleviated typical manifestations of liver injury and fibrosis. These therapeutic efficacies were alongside improvements of mitochondrial adaptive oxidation. Notably, treatment with L-aspartate rebalanced hepatic cholesterol-steroid metabolism and reduced the levels of liver-impairing metabolites, including corticosterone (CORT). Mechanistically, L-aspartate treatment efficiently reversed CORT-mediated glucocorticoid receptor ß (GRß) signaling activation and subsequent transcriptional suppression of the mitochondrial genome by directly binding to the mitochondrial genome. Knockout of GRß ameliorated corticosterone-mediated mitochondrial dysfunction and hepatocyte damage which also weakened the improvements of L-aspartate in suppressing GRß signaling. These data suggest that L-aspartate ameliorates hepatic fibrosis by suppressing GRß signaling via rebalancing cholesterol-steroid metabolism, would be an ideal candidate for clinical liver fibrosis treatment.


Assuntos
Ácido Aspártico , Tetracloreto de Carbono , Cirrose Hepática , Fígado , Camundongos Endogâmicos C57BL , Receptores de Glucocorticoides , Animais , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/genética , Masculino , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Ácido Aspártico/metabolismo , Camundongos , Corticosterona , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Colesterol/metabolismo , Transdução de Sinais/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/patologia , Camundongos Knockout
10.
Psychol Res Behav Manag ; 17: 2135-2147, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38826679

RESUMO

Purpose: During the period of COVID-19 pandemic, the social restrictions and isolation exerted a significant impact on the sleep quality of Chinese college students. This study aims to delve into the influence of physical activity on the sleep quality of college students as well as the mediating roles of stress and smartphone addiction. Materials and Methods: A cohort of 274 eligible college students (146 males and 128 females) were selected for the investigation. The International Physical Activity Questionnaire Short Form, Stress Perception Scale, Smartphone Addiction Scale, and Pittsburgh Sleep Quality Index were employed to assess the levels of physical activity, stress, smartphone addiction, and sleep quality among college students. For data analysis, descriptive statistics, correlation analysis, and chained mediation effect tests were performed sequentially. Results: The findings revealed: (1) a significant negative correlation between physical activity and stress, smartphone addiction, and sleep quality among college students (r = -0.216, p < 0.001; r = -0.224, p < 0.001; r = -0.259, p < 0.001); (2) independent mediating roles of stress and smartphone addiction in the relationship between physical activity and sleep quality; and (3) chained mediating effects of stress and smartphone addiction in the association between physical activity and sleep quality. Conclusion: This study deepens our comprehension of how physical activity augments the quality of slumber, concurrently emphasizing that mitigating stress levels and alleviating smartphone addiction constitute effective strategies for preventing sleep issues among college students.

11.
Imeta ; 3(1): e171, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38868505

RESUMO

In this study, we have successfully constructed a comprehensive database of metagenome-assembled genomes (MAGs) pertaining to the gut microbiota of the giant panda. Through our analysis, we have identified significant reservoirs of antibiotic resistance genes (ARGs), namely Escherichia coli, Citrobacter portucalensis, and Klebsiella pneumoniae. Furthermore, we have elucidated the primary contributors to ARGs, including Streptococcus alactolyticus and Clostridium SGBP116, in both captive and wild pandas. Additionally, our findings have demonstrated a higher prevalence of ARGs in the metagenome, with notable expression of the RPOB2 gene in S. alactolyticus. Crucially, 1217 ARGs shared homology with human gut ARGs, underscoring the interaction relationship between pandas and human microbiomes. These findings are instrumental in understanding the antibiotic resistance landscape in the giant panda's gut, providing a framework for developing strategies to combat antibiotic resistance and safeguard the health of this endangered species.

12.
Microorganisms ; 12(6)2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38930536

RESUMO

Licorice (Glycyrrhiza glabra) is a plant of the genus Glycyrrhiza in the family Fabaceae/Leguminosae and is a renowned natural herb with a long history of medicinal use dating back to ancient times. Glycyrrhizin (GLY), the main active component of licorice, serves as a widely utilized therapeutic agent in clinical practice. GLY exhibits diverse medicinal properties, including anti-inflammatory, antibacterial, antiviral, antitumor, immunomodulatory, intestinal environment maintenance, and liver protection effects. However, current research primarily emphasizes GLY's antiviral activity, while providing limited insight into its antibacterial properties. GLY demonstrates a broad spectrum of antibacterial activity via inhibiting the growth of bacteria by targeting bacterial enzymes, impacting cell membrane formation, and altering membrane permeability. Moreover, GLY can also bolster host immunity by activating pertinent immune pathways, thereby enhancing pathogen clearance. This paper reviews GLY's inhibitory mechanisms against various pathogenic bacteria-induced pathological changes, its role as a high-mobility group box 1 inhibitor in immune regulation, and its efficacy in combating diseases caused by pathogenic bacteria. Furthermore, combining GLY with other antibiotics reduces the minimum inhibitory concentration, potentially aiding in the clinical development of combination therapies against drug-resistant bacteria. Sources of information were searched using PubMed, Web of Science, Science Direct, and GreenMedical for the keywords "licorice", "Glycyrrhizin", "antibacterial", "anti-inflammatory", "HMGB1", and combinations thereof, mainly from articles published from 1979 to 2024, with no language restrictions. Screening was carried out by one author and supplemented by others. Papers with experimental flaws in their experimental design and papers that did not meet expectations (antifungal papers, etc.) were excluded.

14.
Front Endocrinol (Lausanne) ; 15: 1369676, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38745947

RESUMO

Background: Depression and coronary heart disease (CHD) have common risk mechanisms. Common single nucleotide polymorphisms (SNPs) may be associated with the risk of depression combined with coronary heart disease. Methods: This study was designed according to the PRISMA-P guidelines. We will include case-control studies and cohort studies investigating the relationship between gene SNPs and depression and coronary heart disease comorbidities. The Newcastle-Ottawa Scale (NOS) will be used to assess the risk of bias. When measuring dichotomous outcomes, we will use the odds ratio (OR) and 95% confidence interval (95%CIs) in a case-control study. Five genetic models (allele model, homozygous model, co-dominant model, dominant model, and recessive model) will be evaluated for each included study. Subgroup analysis by ethnicity will be performed. If necessary, post hoc analysis will be made according to different types. Results: A total of 13 studies were included in this study, and the types of genes included are FKBP5 and SGK1 genes that act on glucocorticoid; miR-146a, IL-4-589, IL-6-174, TNF-α-308, CRP-717 genes that act on inflammatory mechanisms; eNOS genes from endothelial cells; HSP70 genes that act on the autoimmune response; ACE2 and MAS1 genes that act to mediate Ang(1-7) in the RAS system; 5-HTTLPR gene responsible for the transport of serotonin 5-HT and neurotrophic factor BDNF gene. There were three studies on 5-HTTLPR and BDNF genes, respectively, while there was only one study targeting FKBP5, SGK1, miR-146a, IL-4-589, IL-6-174, TNF-alpha-308, CRP-717, eNOS, HSP70, ACE2, and MAS1 genes. We did not perform a meta-analysis for genes reported in a single study, and meta-analysis was performed separately for studies exploring the 5-HTTLPR and BDNF genes. The results showed that for the 5-HTTLPR gene, there was a statistically significant association between 5-HTTLPR gene polymorphisms and depression in combination with coronary diseases (CHD-D) under the co-dominant model (LS vs LL: OR 1.76, 95%CI 1.20-2.59; SS vs LL: OR 2.80, 95%CI 1.45 to 5.41), the dominant model (LS+SS vs LL: OR 2.06, 95%CI 1.44 to 2.96), and the homozygous model (SS vs LL: OR 2.80 95%CI 1.45 to 5.5.41) were statistically significant for CHD-D, demonstrating that polymorphisms in the 5-HTTLPR gene are associated with the development of CHD-D and that the S allele in the 5-HTTLPR gene is likely to be a risk factor for CHD-D. For the BDNF gene, there were no significant differences between one of the co-dominant gene models (AA vs GG: OR 6.63, 95%CI 1.44 to 30.64), the homozygous gene model (AA vs GG: OR 6.63,95% CI 1.44 to 30.64), the dominant gene model (GA+AA vs GG: OR4.29, 95%CI 1.05 to 17.45), recessive gene model (AA vs GG+GA: OR 2.71, 95%CI 1.16 to 6.31), and allele model (A vs G: OR 2.59, 95%CI 1.18 to 5.67) were statistically significant for CHD-D, demonstrating that BDNFrs6265 gene polymorphisms are associated with the CHD-D development and that the A allele in the BDNFrs6265 gene is likely to be a risk factor for CHD-D. We analyzed the allele frequencies of SNPs reported in a single study and found that the SNPs in the microRNA146a gene rs2910164, the SNPs in the ACE2 gene rs2285666 and the SNPs in the SGK1 gene rs1743963 and rs1763509 were risk factors for the development of CHD-D. We performed a subgroup analysis of three studies involving the BDNFrs6265 gene. The results showed that European populations were more at risk of developing CHD-D than Asian populations in both dominant model (GA+AA vs GG: OR 10.47, 95%CI 3.53 to 31.08) and co-dominant model (GA vs GG: OR 6.40, 95%CI 1.98 to 20.73), with statistically significant differences. In contrast, the studies involving the 5-HTTLPR gene were all Asian populations, so subgroup analyses were not performed. We performed sensitivity analyses of studies exploring the 5-HTTLPR and BDNF rs6265 genes. The results showed that the results of the allele model, the dominant model, the recessive model, the homozygous model and the co-dominant model for both 5-HTTLPR and BDNF rs6265 genes were stable. Due to the limited number of studies of the 5-HTTLPR and BDNF genes, it was not possible to determine the symmetry of the funnel plot using Begg's funnel plot and Egger's test. Therefore, we did not assess publication bias. Discussion: SNPs of the microRNA146a gene at rs2910164, the ACE2 gene at the rs2285666 and the SGK1 gene at rs1743963 and rs1763509, and the SNPs at the 5-HTTLPR and BDNF gene loci are associated with the onset of comorbid depression in coronary heart disease. We recommend that future research focus on studying SNPs' impact on comorbid depression in coronary heart disease, specifically targeting the 5-HTTLPR and BDNF gene at rs6265. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021229371.


Assuntos
Doença das Coronárias , Depressão , Polimorfismo de Nucleotídeo Único , Humanos , Depressão/genética , Depressão/epidemiologia , Doença das Coronárias/genética , Predisposição Genética para Doença
15.
Mol Cancer ; 23(1): 109, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38769556

RESUMO

Breast cancer (BC) is the most frequent malignant cancer diagnosis and is a primary factor for cancer deaths in women. The clinical subtypes of BC include estrogen receptor (ER) positive, progesterone receptor (PR) positive, human epidermal growth factor receptor 2 (HER2) positive, and triple-negative BC (TNBC). Based on the stages and subtypes of BC, various treatment methods are available with variations in the rates of progression-free disease and overall survival of patients. However, the treatment of BC still faces challenges, particularly in terms of drug resistance and recurrence. The study of epigenetics has provided new ideas for treating BC. Targeting aberrant epigenetic factors with inhibitors represents a promising anticancer strategy. The KDM5 family includes four members, KDM5A, KDM5B, KDM5C, and KDMD, all of which are Jumonji C domain-containing histone H3K4me2/3 demethylases. KDM5 proteins have been extensively studied in BC, where they are involved in suppressing or promoting BC depending on their specific upstream and downstream pathways. Several KDM5 inhibitors have shown potent BC inhibitory activity in vitro and in vivo, but challenges still exist in developing KDM5 inhibitors. In this review, we introduce the subtypes of BC and their current therapeutic options, summarize KDM5 family context-specific functions in the pathobiology of BC, and discuss the outlook and pitfalls of KDM5 inhibitors in this disease.


Assuntos
Neoplasias da Mama , Histona Desmetilases , Terapia de Alvo Molecular , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Histona Desmetilases/antagonistas & inibidores , Histona Desmetilases/metabolismo , Histona Desmetilases/genética , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Histona Desmetilases com o Domínio Jumonji/metabolismo , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Histona Desmetilases com o Domínio Jumonji/genética , Biomarcadores Tumorais
16.
Microbiol Res ; 285: 127769, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38797112

RESUMO

Carbapenem-resistant Klebsiella pneumoniae (CRKP) has emerged as a global threat due to its high mortality in clinical patients. However, the specific mechanisms underlying this increased mortality remain unclear. The objective of this study is to investigate how the development of a resistance phenotype contributes to the significantly higher mortality associated with this pathogen. To achieve this, a collection of isogeneic strains was generated. The clinical carbapenem-susceptible K. pneumoniae (CSKP) strain HKU3 served as the control isolate, while HKU3-KPC was created through conjugation with a blaKPC-2-bearing plasmid and served as clinical CRKP strain. Using a sepsis model, it was demonstrated that both HKU3 and HKU3-KPC exhibited similar levels of virulence. Flow cytometry, RNA-seq, and ELISA analysis were employed to assess immune cell response, M1 macrophage polarization, and cytokine storm induction, revealing that both strains elicited comparable types and levels of these immune responses. Subsequently, meropenem was utilized to treat K. pneumoniae infection, and it was found that meropenem effectively reduced bacterial load, inhibited M1 macrophage polarization, and suppressed serum cytokine production during HKU3 (CSKP) infection. However, these effects were not observed in the case of HKU3-KPC (CRKP) infection. These findings provide evidence that the high mortality associated with CRKP is attributed to its enhanced survival within the host during antibiotic treatment, resulting in a cytokine storm and subsequent host death. The development of an effective therapy for CRKP infections could significantly reduce the mortality caused by this pathogen.


Assuntos
Antibacterianos , Enterobacteriáceas Resistentes a Carbapenêmicos , Carbapenêmicos , Infecções por Klebsiella , Klebsiella pneumoniae , Meropeném , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/patogenicidade , Klebsiella pneumoniae/genética , Infecções por Klebsiella/microbiologia , Infecções por Klebsiella/mortalidade , Infecções por Klebsiella/tratamento farmacológico , Virulência , Antibacterianos/farmacologia , Meropeném/farmacologia , Carbapenêmicos/farmacologia , Animais , Camundongos , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Enterobacteriáceas Resistentes a Carbapenêmicos/genética , Humanos , Macrófagos/microbiologia , Macrófagos/imunologia , beta-Lactamases/genética , beta-Lactamases/metabolismo , Sepse/microbiologia , Sepse/mortalidade , Sepse/tratamento farmacológico , Citocinas/metabolismo , Testes de Sensibilidade Microbiana , Proteínas de Bactérias/genética , Modelos Animais de Doenças , Carga Bacteriana
17.
Biomolecules ; 14(5)2024 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-38785979

RESUMO

The balance between ubiquitination and deubiquitination is instrumental in the regulation of protein stability and maintenance of cellular homeostasis. The deubiquitinating enzyme, ubiquitin-specific protease 36 (USP36), a member of the USP family, plays a crucial role in this dynamic equilibrium by hydrolyzing and removing ubiquitin chains from target proteins and facilitating their proteasome-dependent degradation. The multifaceted functions of USP36 have been implicated in various disease processes, including cancer, infections, and inflammation, via the modulation of numerous cellular events, including gene transcription regulation, cell cycle regulation, immune responses, signal transduction, tumor growth, and inflammatory processes. The objective of this review is to provide a comprehensive summary of the current state of research on the roles of USP36 in different pathological conditions. By synthesizing the findings from previous studies, we have aimed to increase our understanding of the mechanisms underlying these diseases and identify potential therapeutic targets for their treatment.


Assuntos
Neoplasias , Ubiquitina Tiolesterase , Humanos , Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/enzimologia , Neoplasias/patologia , Ubiquitina Tiolesterase/metabolismo , Ubiquitina Tiolesterase/genética , Animais , Ubiquitinação , Inflamação/metabolismo , Transdução de Sinais , Ubiquitina/metabolismo
18.
Angew Chem Int Ed Engl ; 63(32): e202401850, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-38706222

RESUMO

Seeking high-performance photoresists is an important item for semiconductor industry due to the continuous miniaturization and intelligentization of integrated circuits. Polymer resin containing carbonate group has many desirable properties, such as high transmittance, acid sensitivity and chemical formulation, thus serving as promising photoresist material. In this work, a series of aqueous developable CO2-sourced polycarbonates (CO2-PCs) were produced via alternating copolymerization of CO2 and epoxides bearing acid-cleavable cyclic acetal groups in the presence of tetranuclear organoborane catalyst. The produced CO2-PCs were investigated as chemical amplification resists in deep ultraviolet (DUV) lithography. Under the catalysis of photogenerated acid, the acetal (ketal) groups in CO2-PC were hydrolysed into two equivalents of hydroxyl groups, which change the exposed area from hydrophobicity to hydrophilicity, thus enabling the exposed area to be developed with water. Through normalized remaining thickness analysis, the optimal CO2-derived resist achieved a remarkable sensitivity of 1.9 mJ/cm2, a contrast of 7.9, a favorable resolution (750 nm, half pitch), and a good etch resistance (38 % higher than poly(tert-butyl acrylate)). Such performances outperform commercial KrF and ArF chemical amplification resists (i.e., polyhydroxystyrene-derived and polymethacrylate-based resists), which endows broad application prospects in the field of DUV (KrF and ArF) and extreme ultraviolet (EUV) lithography for nanomanufacturing.

20.
Front Public Health ; 12: 1368199, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38645442

RESUMO

Background: Internet addiction poses a significant threat to the health of college students worldwide, but physical activity, as a highly safe and effective rehabilitative measure, has shown promise for alleviating this issue nowadays. However, during the COVID-19 pandemic, the mediating processes in this association remained unclear. This study aims to explore the impact of physical activity on internet addiction among college students and the mediating role of subjective well-being. Methods: A survey was conducted on 216 eligible college students using the physical activity level scale, the internet addiction test, and the subjective well-being scale. For data analysis, independent sample t-tests, correlation analysis, hierarchical regression analysis, and mediating effect tests were in turn carried out in this work. Results: The study revealed noteworthy gender disparities in physical activity and internet addiction among college students (ß = -0.356, p < 0.01; ß = 0.140, p < 0.05). Compared to females, male students manifest elevated levels of physical activity and lower scores in internet addiction. Physical activity and subjective well-being exerted a significantly negative predictive influence on internet addiction (ß = -0.162, p < 0.05; ß = -0.508, p < 0.001). What's more, subjective well-being assumed a crucial mediating role in the relationship between physical activity and internet addiction, with the mediating effect accounting for 72.81% of the total effect. Conclusion: This study deepens the understanding of how physical activity reduces internet addiction risk while emphasizing that enhancing subjective well-being is an effective strategy for college students to cope with Internet addiction.


Assuntos
COVID-19 , Exercício Físico , Transtorno de Adição à Internet , Estudantes , Humanos , Masculino , Feminino , COVID-19/epidemiologia , COVID-19/psicologia , Exercício Físico/psicologia , Estudantes/psicologia , Estudantes/estatística & dados numéricos , Estudos Transversais , China/epidemiologia , Transtorno de Adição à Internet/epidemiologia , Transtorno de Adição à Internet/psicologia , Adulto Jovem , Universidades , Inquéritos e Questionários , Adulto , Fatores Sexuais , Adolescente , Comportamento Aditivo/psicologia
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