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1.
Cell ; 187(16): 4176-4192.e17, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-38959890

RESUMO

Hypothalamic neural circuits regulate instinctive behaviors such as food seeking, the fight/flight response, socialization, and maternal care. Here, we identified microdeletions on chromosome Xq23 disrupting the brain-expressed transient receptor potential (TRP) channel 5 (TRPC5). This family of channels detects sensory stimuli and converts them into electrical signals interpretable by the brain. Male TRPC5 deletion carriers exhibited food seeking, obesity, anxiety, and autism, which were recapitulated in knockin male mice harboring a human loss-of-function TRPC5 mutation. Women carrying TRPC5 deletions had severe postpartum depression. As mothers, female knockin mice exhibited anhedonia and depression-like behavior with impaired care of offspring. Deletion of Trpc5 from oxytocin neurons in the hypothalamic paraventricular nucleus caused obesity in both sexes and postpartum depressive behavior in females, while Trpc5 overexpression in oxytocin neurons in knock-in mice reversed these phenotypes. We demonstrate that TRPC5 plays a pivotal role in mediating innate human behaviors fundamental to survival, including food seeking and maternal care.


Assuntos
Depressão Pós-Parto , Neurônios , Obesidade , Canais de Cátion TRPC , Animais , Feminino , Camundongos , Obesidade/metabolismo , Obesidade/genética , Masculino , Humanos , Canais de Cátion TRPC/metabolismo , Canais de Cátion TRPC/genética , Depressão Pós-Parto/metabolismo , Neurônios/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Camundongos Endogâmicos C57BL , Ocitocina/metabolismo , Comportamento Materno
2.
Cell ; 187(18): 4905-4925.e24, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-38971151

RESUMO

Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (PARP) inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor (PARPi) niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTregs) as key responders to HRD and neoadjuvant therapies, co-occurring with other tumor-reactive T cells, particularly terminally exhausted CD8+ T cells (Tex). TME-wide interferon signaling correlates with cancer cells upregulating MHC class II and co-inhibitory ligands, potentially driving Treg and Tex fates. Depleting eTregs in HRD mouse models, with or without PARP inhibition, significantly suppresses tumor growth without observable toxicities, underscoring the potential of eTreg-focused therapeutics for HGSOC and other HRD-related tumors.


Assuntos
Terapia Neoadjuvante , Neoplasias Ovarianas , Piperidinas , Inibidores de Poli(ADP-Ribose) Polimerases , Linfócitos T Reguladores , Microambiente Tumoral , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/imunologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Humanos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Camundongos , Terapia Neoadjuvante/métodos , Microambiente Tumoral/efeitos dos fármacos , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Indazóis/uso terapêutico , Indazóis/farmacologia , Recombinação Homóloga , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral
3.
J Neurosci ; 44(30)2024 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-38897723

RESUMO

Light plays an essential role in a variety of physiological processes, including vision, mood, and glucose homeostasis. However, the intricate relationship between light and an animal's feeding behavior has remained elusive. Here, we found that light exposure suppresses food intake, whereas darkness amplifies it in male mice. Interestingly, this phenomenon extends its reach to diurnal male Nile grass rats and healthy humans. We further show that lateral habenula (LHb) neurons in mice respond to light exposure, which in turn activates 5-HT neurons in the dorsal Raphe nucleus (DRN). Activation of the LHb→5-HTDRN circuit in mice blunts darkness-induced hyperphagia, while inhibition of the circuit prevents light-induced anorexia. Together, we discovered a light-responsive neural circuit that relays the environmental light signals to regulate feeding behavior in mice.


Assuntos
Comportamento Alimentar , Habenula , Luz , Animais , Masculino , Camundongos , Habenula/fisiologia , Comportamento Alimentar/fisiologia , Núcleo Dorsal da Rafe/fisiologia , Humanos , Camundongos Endogâmicos C57BL , Ingestão de Alimentos/fisiologia , Vias Neurais/fisiologia , Ratos , Neurônios Serotoninérgicos/fisiologia , Rede Nervosa/fisiologia , Escuridão
4.
J Cell Physiol ; 239(1): 79-96, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37942585

RESUMO

Radiation-induced heart damage caused by low-dose X-rays has a significant impact on tumour patients' prognosis, with cardiac hypertrophy being the most severe noncarcinogenic adverse effect. Our previous study demonstrated that mitophagy activation promoted cardiac hypertrophy, but the underlying mechanisms remained unclear. In the present study, PARL-IN-1 enhanced excessive hypertrophy of cardiomyocytes and exacerbated mitochondrial damage. Isobaric tags for relative and absolute quantification-based quantitative proteomics identified NDP52 as a crucial target mediating cardiac hypertrophy induced by low-dose X-rays. SUMOylation proteomics revealed that the SUMO E3 ligase MUL1 facilitated NDP52 SUMOylation through SUMO2. Co-IP coupled with LC-MS/MS identified a critical lysine residue at position 262 of NDP52 as the key site for SUMO2-mediated SUMOylation of NDP52. The point mutation plasmid NDP52K262R inhibited mitophagy under MUL1 overexpression, as evidenced by inhibition of LC3 interaction with NDP52, PINK1 and LAMP2A. A mitochondrial dissociation study revealed that NDP52K262R inhibited PINK1 targeting to endosomes early endosomal marker (EEA1), late/lysosome endosomal marker (LAMP2A) and recycling endosomal marker (RAB11), and laser confocal microscopy confirmed that NDP52K262R impaired the recruitment of mitochondria to the autophagic pathway through EEA1/RAB11 and ATG3, ATG5, ATG16L1 and STX17, but did not affect mitochondrial delivery to lysosomes via LAMP2A for degradation. In conclusion, our findings suggest that MUL1-mediated SUMOylation of NDP52 plays a crucial role in regulating mitophagy in the context of low-dose X-ray-induced cardiac hypertrophy. Two hundred sixty-second lysine of NDP52 is identified as a key SUMOylation site for low-dose X-ray promoting mitophagy activation and cardiac hypertrophy. Collectively, this study provides novel implications for the development of therapeutic strategies aimed at preventing the progression of cardiac hypertrophy induced by low-dose X-rays.


Assuntos
Mitofagia , Proteínas Nucleares , Proteínas Quinases , Humanos , Cardiomegalia/genética , Cromatografia Líquida , Lisina/metabolismo , Mitofagia/genética , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/genética , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Sumoilação , Espectrometria de Massas em Tandem , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Raios X , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo
5.
J Am Chem Soc ; 146(29): 19874-19885, 2024 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-39007743

RESUMO

Detection of serum protein biomarkers is extremely challenging owing to the superior complexity of serum. Here, we report a method of proteome fishing from the serum. It uses a magnetic nanoparticle-protein corona and a multiplexed aptamer panel, which we incubated with the nanoparticle-protein corona for biomarker recognition. To transfer protein biomarker detection to aptamer detection, we established a CRISPR/Cas12a-based orthogonal multiplex aptamer sensing (COMPASS) platform by profiling the aptamers of protein corona with clinical nonsmall cell lung cancer (NSCLC) serum samples. Furthermore, we determined the four out of nine (FOON) panel (including HE4, NSE, AFP, and VEGF165) to be the most cost-effective and accurate panel for COMPASS in NSCLC diagnosis. The diagnostic accuracy of NSCLC by the FOON panel with internal and external cohorts was 95.56% (ROC-AUC = 99.40%) and 89.58% (ROC-AUC = 95.41%), respectively. Our developed COMPASS technology circumvents the otherwise challenging multiplexed serum protein amplification problem and avoids aptamer degradation in serum. Therefore, this novel COMPASS could lead to the development of a facile, cost-effective, intelligent, and high-throughput diagnostic platform for large-cohort cancer screening.


Assuntos
Aptâmeros de Nucleotídeos , Sistemas CRISPR-Cas , Carcinoma Pulmonar de Células não Pequenas , Aptâmeros de Nucleotídeos/química , Humanos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/sangue , Proteoma/análise , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/diagnóstico , Biomarcadores Tumorais/sangue , Nanopartículas de Magnetita/química , Coroa de Proteína/química
6.
Anal Chem ; 96(36): 14363-14371, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39192740

RESUMO

Highly abundant proteins present in biological fluids and tissues significantly interfere with low-abundance protein identification by mass spectrometry (MS), limiting proteomic depth and hindering protein biomarker discovery. Herein, to enhance the coverage of tissue proteomics, we developed a nanoparticle-protein corona (NP-PC)-based method for the aging mouse proteome atlas. Based on this method, we investigated the complexity of life process of 5 major organs, including the heart, liver, spleen, lungs, and kidneys, from 4 groups of mice at different ages. Compared with the conventional strategy, NP-PC-based proteomics significantly increased the number of identified protein groups in the heart (from 3007 to 3927; increase of 30.6%), liver (from 2982 to 4610; increase of 54.6%), spleen (from 5047 to 7351; increase of 45.7%), lungs (from 4984 to 6903; increase of 38.5%), and kidneys (from 3550 to 5739; increase of 61.7%), and we identified a total of 10 104 protein groups. The overall data indicated that 3-week-old mice showed more differences compared with the other three age groups. The proteins of amino acid-related metabolism were increased in aged mice compared with those in the 3-week-old mice. Protein-related infections were increased in the spleen of the aged mice. Interestingly, the spliceosome-related pathway significantly changed from youth to elders in the liver, spleen, and lungs, indicating the vital role of the spliceosome during the aging process. Our established aging mouse organ proteome atlas provides comprehensive insights into understanding the aging process, and it may help in prevention and treatment of age-related diseases.


Assuntos
Envelhecimento , Nanopartículas , Coroa de Proteína , Proteoma , Proteômica , Animais , Camundongos , Envelhecimento/metabolismo , Proteoma/análise , Proteoma/metabolismo , Nanopartículas/química , Coroa de Proteína/química , Coroa de Proteína/metabolismo , Camundongos Endogâmicos C57BL , Rim/metabolismo , Rim/química , Masculino , Fígado/metabolismo , Fígado/química
7.
BMC Cancer ; 24(1): 401, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38561685

RESUMO

BACKGROUND: To investigate related factors for postoperative pathological upgrading of cervical biopsy to cervical cancer (CC) in patients with cervical intraepithelial neoplasia (CIN)3 after conical resection. METHODS: This retrospective study collected data from patients diagnosed with CIN3 by cervical biopsies at the author's Hospital between January 2012 and December 2022. The primary outcome was the pathological results of patients after conical resection. The pathological findings were categorized into the pathological upgrading group if postoperative pathology indicated CC, while those with normal, inflammatory, or cervical precancerous lesions were classified into the pathological non-upgrading group. The factors associated with upgrading were identified using multivariable logistic regression analysis. RESULTS: Among 511 patients, there were 125 patients in the pathological upgrading group (24.46%). The patients in the upgrading group were younger (47.68 ± 9.46 vs. 52.11 ± 7.02, P < 0.001), showed a lower proportion of menopausal women (38.40% vs. 53.02%, P = 0.0111), a lower proportion of HSIL (40.00% vs. 57.77%, P = 0.001), a higher rate of HPV-16/18 positive (25.60% vs. 17.36%, P = 0.011), a higher rate of contact bleeding (54.40% vs. 21.50%, P < 0.001), lower HDL levels (1.31 ± 0.29 vs. 1.37 ± 0.34 mmol/L, P = 0.002), higher neutrophil counts (median, 3.50 vs. 3.10 × 109/L, P = 0.001), higher red blood cell counts (4.01 ± 0.43 vs. 3.97 ± 0.47 × 1012/L, P = 0.002), higher platelet counts (204.84 ± 61.24 vs. 187.06 ± 73.66 × 109/L, P = 0.012), and a smaller platelet volume (median, 11.50 vs. 11.90 fL, P = 0.002).The multivariable logistic regression analysis showed that age (OR = 0.90, 95% CI: 0.86-0.94, P < 0.001), menopausal (OR = 2.68, 95% CI: 1.38-5.22, P = 0.004), contact bleeding (OR = 4.80, 95% CI: 2.91-7.91, P < 0.001), and mean platelet volume (OR = 0.83, 95% CI: 0.69-0.99, P = 0.038) were independently associated with pathological upgrading from CIN3 to CC after conical resection. CONCLUSION: Age, menopausal, contact bleeding, and mean platelet volume are risk factors of pathological upgrading from CIN3 to CC after conical resection, which could help identify high risk and susceptible patients of pathological upgrading to CC.


Assuntos
Infecções por Papillomavirus , Displasia do Colo do Útero , Neoplasias do Colo do Útero , Humanos , Feminino , Estudos Retrospectivos , Papillomavirus Humano 16 , Papillomavirus Humano 18 , Displasia do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/diagnóstico , Biópsia , Infecções por Papillomavirus/complicações
8.
Pharmacol Res ; 208: 107383, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39214266

RESUMO

Mitochondria exhibit heterogeneous shapes and networks within and among cell types and tissues, also in normal or osteoporotic bone tissues with complex cell types. This dynamic characteristic is determined by the high plasticity provided by mitochondrial dynamics and is stemmed from responding to the survival and functional requirements of various bone cells in a specific microenvironments. In contrast, mitochondrial dysfunction, induced by dysregulation of mitochondrial dynamics, may act as a trigger of cell death signals, including common apoptosis and other forms of programmed cell death (PCD). These PCD processes consisting of tightly structured cascade gene expression events, can further influence the bone remodeling by facilitating the death of various bone cells. Mitochondrial dynamics, therefore, drive the bone cells to stand at the crossroads of life and death by integrating external signals and altering metabolism, shape, and signal-response properties of mitochondria. This implies that targeting mitochondrial dynamics displays significant potential in treatment of osteoporosis. Considerable effort has been made in osteoporosis to emphasize the parallel roles of mitochondria in regulating energy metabolism, calcium signal transduction, oxidative stress, inflammation, and cell death. However, the emerging field of mitochondrial dynamics-related PCD is not well understood. Herein, to bridge the gap, we outline the latest knowledge on mitochondrial dynamics regulating bone cell life or death during normal bone remodeling and osteoporosis.


Assuntos
Mitocôndrias , Dinâmica Mitocondrial , Osteoporose , Osteoporose/metabolismo , Osteoporose/patologia , Humanos , Animais , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Remodelação Óssea , Morte Celular , Apoptose , Osso e Ossos/metabolismo , Osso e Ossos/patologia
9.
Artigo em Inglês | MEDLINE | ID: mdl-39279255

RESUMO

Psoriasis is a common immune-related polygenic inflammatory skin disease. Salidroside (SAL) exerts anti-inflammatory and antioxidant effects and is used to treat skin diseases. However, the specific effects of SAL on psoriasis remain unclear. In this study, we aimed to investigate the efficacy of SAL for psoriasis treatment. Mice were treated with imiquimod (IMQ) to establish an in vivo psoriasis model. Histological analysis was conducted via hematoxylin and eosin staining. Cytokine release was determined via enzyme-linked immunosorbent assay. Additionally, mRNA levels were determined via reverse transcription-quantitative polymerase chain reaction. Protein expression was assessed via Western blotting. Gasdermin D (GSDMD) and Ki-67 expression levels were determined via immunohistochemistry. Caspase 1 and GSDMD expression levels were determined via immunofluorescence assay. Furthermore, macrophage function and keratinocyte pyroptosis were also analyzed via flow cytometry. Cell proliferation was determined using 5-ethynyl-2'deoxyuridine assay. SAL alleviated IMQ-induced psoriasis. IMQ-mediated GSDMD-driven pyroptosis and keratinocyte hyperproliferation promoted M1 macrophage polarization. However, SAL treatment suppressed GSDMD expression, thereby inhibiting keratinocyte proliferation and pyroptosis and promoting M2 macrophage polarization. GSDMD deficiency further promoted the effects of SAL and suppressed psoriasis progression. Overall, our findings suggest that SAL exerts protective effects against psoriasis. Specifically, it exerts anti-inflammatory effects by regulating M2 macrophage polarization and inhibiting keratinocyte pyroptosis-driven proliferation induced by the immune microenvironment in psoriasis.

10.
Lipids Health Dis ; 23(1): 51, 2024 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-38368320

RESUMO

BACKGROUND: Myocardial ischemia-reperfusion injury (MIRI) is widespread in the treatment of ischemic heart disease, and its treatment options are currently limited. Adiponectin (APN) is an adipocytokine with cardioprotective properties; however, the mechanisms of APN in MIRI are unclear. Therefore, based on preclinical (animal model) evidence, the cardioprotective effects of APN and the underlying mechanisms were explored. METHODS: The literature was searched for the protective effect of APN on MIRI in six databases until 16 November 2023, and data were extracted according to selection criteria. The outcomes were the size of the myocardial necrosis area and hemodynamics. Markers of oxidation, apoptosis, and inflammation were secondary outcome indicators. The quality evaluation was performed using the animal study evaluation scale recommended by the Systematic Review Center for Laboratory animal Experimentation statement. Stata/MP 14.0 software was used for the summary analysis. RESULTS: In total, 20 papers with 426 animals were included in this study. The pooled analysis revealed that APN significantly reduced myocardial infarct size [weighted mean difference (WMD) = 16.67 (95% confidence interval (CI) = 13.18 to 20.16, P < 0.001)] and improved hemodynamics compared to the MIRI group [Left ventricular end-diastolic pressure: WMD = 5.96 (95% CI = 4.23 to 7.70, P < 0.001); + dP/dtmax: WMD = 1393.59 (95% CI = 972.57 to 1814.60, P < 0.001); -dP/dtmax: WMD = 850.06 (95% CI = 541.22 to 1158.90, P < 0.001); Left ventricular ejection fraction: WMD = 9.96 (95% CI = 7.29 to 12.63, P < 0.001)]. Apoptosis indicators [caspase-3: standardized mean difference (SMD) = 3.86 (95% CI = 2.97 to 4.76, P < 0.001); TUNEL-positive cells: WMD = 13.10 (95% CI = 8.15 to 18.05, P < 0.001)], inflammatory factor levels [TNF-α: SMD = 4.23 (95% CI = 2.48 to 5.98, P < 0.001)], oxidative stress indicators [Superoxide production: SMD = 4.53 (95% CI = 2.39 to 6.67, P < 0.001)], and lactate dehydrogenase levels [SMD = 2.82 (95% CI = 1.60 to 4.04, P < 0.001)] were significantly reduced. However, the superoxide dismutase content was significantly increased [SMD = 1.91 (95% CI = 1.17 to 2.65, P < 0.001)]. CONCLUSION: APN protects against MIRI via anti-inflammatory, antiapoptotic, and antioxidant effects, and this effect is achieved by activating different signaling pathways.


Assuntos
Infarto do Miocárdio , Traumatismo por Reperfusão Miocárdica , Ratos , Animais , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/metabolismo , Ratos Sprague-Dawley , Adiponectina/genética , Transdução de Sinais , Apoptose
11.
BMC Palliat Care ; 23(1): 155, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38902684

RESUMO

OBJECTIVE: Explore the feasibility of a mobile health(mHealth) and virtual reality (VR) based nutrition-exercise-psychology integrated rehabilitation model in Chinese cancer patients. METHODS: We recruited cancer patients in the Oncology department of the Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University from October 2022 to April 2023. The rehabilitation program was provided by a team of medical oncologists, dietitians, psychotherapists, and oncology specialist nurses. Participants received standard anti-cancer therapy and integrated intervention including hospitalized group-based exercise classes, at-home physical activity prescription, behavior change education, oral nutrition supplements, and psychological counseling. An effective intervention course includes two consecutive hospitalization and two periods of home-based rehabilitation (8 weeks). Access the feasibility as well as changes in aspects of physical, nutritional, and psychological status. RESULTS: At the cutoff date of April 2023, the recruitment rate was 75% (123/165). 11.4%patients were lost to follow-up, and 3.25% withdrew halfway. Respectively, the completion rate of nutrition, exercise, and psychology were 85%,55%, and 63%. Nutrition interventions show the highest compliance. The parameters in nutrition, psychology, muscle mass, and quality of life after the rehabilitation showed significant improvements (P < .05). There was no significant statistical difference (P > .05) in handgrip strength and 6-minute walking speed. CONCLUSION: It is feasible to conduct mHealth and VR-based nutrition-exercise-psychology integrated rehabilitation model in Chinese cancer patients. A larger multi-center trial is warranted in the future. TRIAL REGISTRATION: ChiCTR2200065748 Registered 14 November 2022.


Assuntos
Estudos de Viabilidade , Neoplasias , Telemedicina , Realidade Virtual , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Neoplasias/psicologia , Neoplasias/reabilitação , Neoplasias/complicações , Estudos Prospectivos , Adulto , Idoso , Exercício Físico/psicologia , Terapia por Exercício/métodos , Terapia por Exercício/normas , Terapia por Exercício/psicologia , China
12.
Phytother Res ; 2024 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-38706097

RESUMO

Inflammatory bowel disease (IBD) is an autoimmune disorder primarily characterized by intestinal inflammation and recurrent ulceration, leading to a compromised intestinal barrier and inflammatory infiltration. This disorder's pathogenesis is mainly attributed to extensive damage or death of intestinal epithelial cells, along with abnormal activation or impaired death regulation of immune cells and the release of various inflammatory factors, which contribute to the inflammatory environment in the intestines. Thus, maintaining intestinal homeostasis hinges on balancing the survival and functionality of various cell types. Programmed cell death (PCD) pathways, including apoptosis, pyroptosis, autophagy, ferroptosis, necroptosis, and neutrophil extracellular traps, are integral in the pathogenesis of IBD by mediating the death of intestinal epithelial and immune cells. Natural products derived from plants, fruits, and vegetables have shown potential in regulating PCD, offering preventive and therapeutic avenues for IBD. This article reviews the role of natural products in IBD treatment by focusing on targeting PCD pathways, opening new avenues for clinical IBD management.

13.
J Environ Manage ; 365: 121531, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38909582

RESUMO

Exploring the ecological utility of cultivated land's carbon metabolism offers policy insights for ensuring its healthy operation and promote the dual carbon goals (carbon peak and carbon neutrality). We employed ecological network analysis (ENA) and kernel density estimation to conduct an empirical study, taking Hubei Province from 2000 to 2020 as an example. The results revealed apparent negative effects of carbon metabolic flow on regional carbon balance. Specifically, cultivated land conversion into transportation and industrial land contributed significantly to the harmful carbon flow. Ecological relationships showed fierce competition for carbon storage, leading to overall adverse ecological effects. The ecological utility indicated detrimental impacts on the orderly functioning of land-use carbon metabolism. Cultivated land's carbon metabolism will be essential in achieving land-use carbon neutrality. Therefore, territorial spatial low-carbon optimization should be implemented to realize its green and sustainable development.


Assuntos
Carbono , China , Carbono/metabolismo , Ecossistema , Ecologia , Conservação dos Recursos Naturais , Agricultura
14.
J Biol Chem ; 298(8): 102179, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35752365

RESUMO

Lipid droplets (LDs) are intracellular organelles that dynamically regulate lipids and energy homeostasis in the cell. LDs can grow through either local lipid synthesis or LD fusion. However, how lipids involving in LD fusion for LD growth is largely unknown. Here, we show that genetic mutation of acox-3 (acyl-CoA oxidase), maoc-1 (enoyl-CoA hydratase), dhs-28 (3-hydroxylacyl-CoA dehydrogenase), and daf-22 (3-ketoacyl-CoA thiolase), all involved in the peroxisomal ß-oxidation pathway in Caenorhabditis elegans, led to rapid fusion of adjacent LDs to form giant LDs (gLDs). Mechanistically, we show that dysfunction of peroxisomal ß-oxidation results in the accumulation of long-chain fatty acid-CoA and phosphocholine, which may activate the sterol-binding protein 1/sterol regulatory element-binding protein to promote gLD formation. Furthermore, we found that inactivation of either FAT-2 (delta-12 desaturase) or FAT-3 and FAT-1 (delta-15 desaturase and delta-6 desaturase, respectively) to block the biosynthesis of polyunsaturated fatty acids (PUFAs) with three or more double bonds (n≥3-PUFAs) fully repressed the formation of gLDs; in contrast, dietary supplementation of n≥3-PUFAs or phosphocholine bearing these PUFAs led to recovery of the formation of gLDs in peroxisomal ß-oxidation-defective worms lacking PUFA biosynthesis. Thus, we conclude that n≥3-PUFAs, distinct from other well-known lipids and proteins, promote rapid LD fusion leading to LD growth.


Assuntos
Caenorhabditis elegans , Ácidos Graxos Ômega-3 , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Coenzima A/metabolismo , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/metabolismo , Ácidos Graxos/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Insaturados/metabolismo , Gotículas Lipídicas/metabolismo , Fosforilcolina/metabolismo , Esteróis/metabolismo
15.
Plant Mol Biol ; 113(4-5): 193-204, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37878187

RESUMO

Cymbidium ensifolium is one of the national orchids in China, which has high ornamental value with changeable flower colors. To understand the formation mechanism of different flower colors of C. ensifolium, this research conducted transcriptome and metabolome analyses on four different colored sepals of C. ensifolium. Metabolome analysis detected 204 flavonoid metabolites, including 17 polyphenols, 27 anthocyanins, 75 flavones, 34 flavonols, 25 flavonoids, 18 flavanones, and 8 isoflavones. Among them, purple-red and red sepals contain a lot of anthocyanins, including cyanidin, pelargonin, and paeoniflorin, while yellow-green and white sepals have less anthocyanins detected, and their metabolites are mainly flavonols, flavanones and flavonoids. Transcriptome sequencing analysis showed that the expression levels of the anthocyanin biosynthetic enzyme genes in red and purple-red sepals were significantly higher than those in white and yellow-green sepals of C. ensifolium. The experimental results showed that CeF3'H2, CeDFR, CeANS, CeF3H and CeUFGT1 may be the key genes involved in anthocyanin production in C. ensifolium sepals, and CeMYB104 has been proved to play an important role in the flower color formation of C. ensifolium. The results of transformation showed that the CeMYB104 is involved in the synthesis of anthocyanins and can form a purple-red color in the white perianth of Phalaenopsis. These findings provide a theoretical reference to understand the formation mechanism of flower color in C. ensifolium.


Assuntos
Flavanonas , Orchidaceae , Antocianinas , Transcriptoma , Flavonoides/metabolismo , Flores/genética , Flores/metabolismo , Flavonóis , Orchidaceae/genética , Orchidaceae/metabolismo , Flavanonas/metabolismo , Cor , Regulação da Expressão Gênica de Plantas
16.
J Am Chem Soc ; 145(23): 12861-12869, 2023 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-37276358

RESUMO

Targeted protein degradation (TPD) is an emerging technique for protein regulation. Currently, all TPD developed in eukaryotic cells relies on either ubiquitin-proteasome or lysosomal systems, thus are powerless against target proteins in membrane organelles lacking proteasomes and lysosomes, such as mitochondria. Here, we developed a mitochondrial protease targeting chimera (MtPTAC) to address this issue. MtPTAC is a bifunctional small molecule that can bind to mitochondrial caseinolytic protease P (ClpP) at one end and target protein at the other. Mechanistically, MtPTAC activates the hydrolase activity of ClpP while simultaneously bringing target proteins into proximity with ClpP. Taking mitochondrial RNA polymerase (POLRMT) as a model protein, we have demonstrated the powerful proteolytic ability and antitumor application prospects of MtPTAC, both in vivo and in vitro. This is the first modularly designed TPD that can specifically hydrolyze target proteins inside mitochondria.


Assuntos
Mitocôndrias , Proteínas , Proteólise , Mitocôndrias/metabolismo , Proteínas/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismo , Endopeptidases/metabolismo
17.
Biochem Biophys Res Commun ; 656: 104-114, 2023 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-36963347

RESUMO

Podocyte injury is a crucial factor in the pathogenesis of diabetic kidney disease (DKD), and finding potential therapeutic interventions that can mitigate podocyte injury holds significant clinical relevance. This study was to elucidate the role of growth associated protein-43(Gap43) in podocyte injury of high glucose (HG). We confirmed the expression of Gap43 in human glomerulus and found that Gap43 expression was downregulated in podocytes of patients with DKD and HG-treated podocytes in vitro. Gap43 knockdown in podocytes promoted podocyte apoptosis, increased migration ability and decreased nephrin expression, while overexpression of Gap43 markedly suppressed HG-induced injury. Moreover, the increased expression and activity of calcineurin (CaN) were also abrogated by overexpression Gap43 in HG. Pretreatment with a typical CaN inhibitor FK506 in Gap43 knockdown podocytes restored the injury. Mechanistically, co-immunoprecipitation experiments suggested that Gap43 could bind to calmodulin (CaM). Pull-down assay further demonstrated that Gap43 and CaM directly interacts with each other via amino acids 30-52 of Gap43 and amino acids 133-197 of CaM. In addition, we also identified Pax5 as potential transcription inhibitor factor mediating Gap43 expression. In conclusion, the study indicated that the Gap43/CaM-CaN pathway may be exploited as a promising therapeutic target for protecting against podocyte injury in high glucose.


Assuntos
Nefropatias Diabéticas , Proteína GAP-43 , Podócitos , Humanos , Apoptose , Calcineurina/metabolismo , Calmodulina/metabolismo , Nefropatias Diabéticas/metabolismo , Proteína GAP-43/metabolismo , Glucose/metabolismo , Hiperglicemia/metabolismo , Podócitos/metabolismo
18.
BMC Med ; 21(1): 495, 2023 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-38093264

RESUMO

BACKGROUND: Multimorbidity is better prevented in younger ages than in older ages. This study aims to identify the differences in comorbidity patterns in middle-aged inpatients from China and the United Kingdom (UK). METHODS: We utilized 184,133 and 180,497 baseline hospitalization records in middle-aged populations (40-59 years) from Shaanxi, China, and UK Biobank. Logistic regression was used to calculate odds ratios and P values for 43,110 unique comorbidity patterns in Chinese inpatients and 21,026 unique comorbidity patterns in UK inpatients. We included the statistically significant (P values adjusted by Bonferroni correction) and common comorbidity patterns (the pattern with prevalence > 1/10,000 in each dataset) and employed network analysis to construct multimorbidity networks and compare feature differences in multimorbidity networks for Chinese and UK inpatients, respectively. We defined hub diseases as diseases having the top 10 highest number of unique comorbidity patterns in the multimorbidity network. RESULTS: We reported that 57.12% of Chinese inpatients had multimorbidity, substantially higher than 30.39% of UK inpatients. The complete multimorbidity network for Chinese inpatients consisted of 1367 comorbidities of 341 diseases and was 2.93 × more complex than that of 467 comorbidities of 215 diseases in the UK. In males, the complexity of the multimorbidity network in China was 2.69 × more than their UK counterparts, while the ratio was 2.63 × in females. Comorbidities associated with hub diseases represented 68.26% of comorbidity frequencies in the complete multimorbidity network in Chinese inpatients and 55.61% in UK inpatients. Essential hypertension, dyslipidemia, type 2 diabetes mellitus, and gastritis and duodenitis were the hub diseases in both populations. The Chinese inpatients consistently demonstrated a higher frequency of comorbidities related to circulatory and endocrine/nutritional/metabolic diseases. In the UK, aside from these comorbidities, comorbidities related to digestive and genitourinary diseases were also prevalent, particularly the latter among female inpatients. CONCLUSIONS: Chinese inpatients exhibit higher multimorbidity prevalence and more complex networks compared to their UK counterparts. Multimorbidity with circulatory and endocrine/nutritional/metabolic diseases among both Chinese and UK inpatients necessitates tailored surveillance, prevention, and intervention approaches. Targeted interventions for digestive and genitourinary diseases are warranted for the UK.


Assuntos
Diabetes Mellitus Tipo 2 , Doenças Metabólicas , Doenças Urogenitais , Masculino , Pessoa de Meia-Idade , Humanos , Feminino , Multimorbidade , Diabetes Mellitus Tipo 2/epidemiologia , Pacientes Internados , Comorbidade , Doenças Metabólicas/epidemiologia , Prevalência , China/epidemiologia , Reino Unido/epidemiologia
19.
Environ Sci Technol ; 57(33): 12270-12279, 2023 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-37561606

RESUMO

Aquaculture ponds are an important artificial aquatic system for global food fish production but also are a hot spot of greenhouse gas (GHG) emissions. The GHG mitigation strategy and the underlying mechanism for aquaculture ponds are still poorly understood. In this study, we conducted a 2 year field experiment to determine the effects of planting high-stalk rice (an artificially bred emergent plant for ponds) on GHG emissions from aquaculture ponds. Our results showed that planting high-stalk rice reduced CH4 emission by 64.4% and N2O emission by 76.2% over 2 years. Planting high-stalk rice significantly increased the content of O2 and the abundance of pmoA in the sediment, thus prompting CH4 oxidation in the ponds. The reduction of N2O emission from ponds was attributed to the decreased inorganic nitrogen, amoA-B and nirS in the sediment induced by rice. Furthermore, high-stalk rice culture in the pond increased shrimp yields and gained rice yields, resulting in a significant reduction of yield-scaled global warming potential. Our findings suggest that breeding appropriate emergent aquatic plants is a potential pathway to mitigate GHG emission from aquaculture ponds with more food yields and economic benefits.


Assuntos
Gases de Efeito Estufa , Oryza , Animais , Gases de Efeito Estufa/análise , Lagoas , Metano/análise , Aquicultura/métodos , Óxido Nitroso/análise , Agricultura/métodos , Solo , China
20.
J Asian Nat Prod Res ; 25(4): 324-329, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35763403

RESUMO

Two new iridoid glycosides, named 3'-O-benzoyl-dolichocymboside D (1) and dolichocymboside E (2), along with ten known glycosides (3-12), were isolated from the ethanol extract of the whole plants of Odontites vulgaris Moench. The structures of the isolated compounds were elucidated by 1D and 2D NMR and HR-ESI-MS spectra and by comparison with those reported in the literature. This is the first report on compounds 11 and 12 isolated from the family Scrophulariaceae, and compounds 8-10 were isolated from the genus Odontites.


Assuntos
Glicosídeos Iridoides , Extratos Vegetais , Glicosídeos Iridoides/química , Extratos Vegetais/química , Glicosídeos/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular
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