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1.
Cell ; 187(9): 2194-2208.e22, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38552625

RESUMO

Effective treatments for complex central nervous system (CNS) disorders require drugs with polypharmacology and multifunctionality, yet designing such drugs remains a challenge. Here, we present a flexible scaffold-based cheminformatics approach (FSCA) for the rational design of polypharmacological drugs. FSCA involves fitting a flexible scaffold to different receptors using different binding poses, as exemplified by IHCH-7179, which adopted a "bending-down" binding pose at 5-HT2AR to act as an antagonist and a "stretching-up" binding pose at 5-HT1AR to function as an agonist. IHCH-7179 demonstrated promising results in alleviating cognitive deficits and psychoactive symptoms in mice by blocking 5-HT2AR for psychoactive symptoms and activating 5-HT1AR to alleviate cognitive deficits. By analyzing aminergic receptor structures, we identified two featured motifs, the "agonist filter" and "conformation shaper," which determine ligand binding pose and predict activity at aminergic receptors. With these motifs, FSCA can be applied to the design of polypharmacological ligands at other receptors.


Assuntos
Quimioinformática , Desenho de Fármacos , Polifarmacologia , Animais , Camundongos , Humanos , Quimioinformática/métodos , Ligantes , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/química , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT1A de Serotonina/química , Masculino , Sítios de Ligação
2.
PLoS Pathog ; 20(9): e1012471, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39236038

RESUMO

Bats are natural reservoirs for zoonotic pathogens, yet the determinants of microbial persistence as well as the specific functionality of their immune system remain largely enigmatic. Their propensity to harbor viruses lethal to humans and/or livestock, mostly in absence of clinical disease, makes bats stand out among mammals. Defending against pathogens relies on avoidance, resistance, and/or tolerance strategies. In bats, disease tolerance has recently gained increasing attention as a prevailing host defense paradigm. We here summarize the current knowledge on immune responses in bats in the context of infection with zoonotic agents and discuss concepts related to disease tolerance. Acknowledging the wide diversity of bats, the broad spectrum of bat-associated microbial species, and immune-related knowledge gaps, we identify research priorities necessary to provide evidence-based proofs for disease tolerance in bats. Since disease tolerance relies on networks of biological processes, we emphasize that investigations beyond the immune system, using novel technologies and computational biology, could jointly advance our knowledge about mechanisms conferring bats reservoir abilities. Although disease tolerance may not be the "one fit all" defense strategy, deciphering disease tolerance in bats could translate into novel therapies and inform prevention of spillover infections to humans and livestock.


Assuntos
Quirópteros , Tolerância Imunológica , Animais , Quirópteros/imunologia , Quirópteros/virologia , Tolerância Imunológica/imunologia , Reservatórios de Doenças/virologia , Zoonoses/imunologia , Humanos
3.
EMBO J ; 40(13): e106272, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33942347

RESUMO

Cellular stress has been associated with inflammation, yet precise underlying mechanisms remain elusive. In this study, various unrelated stress inducers were employed to screen for sensors linking altered cellular homeostasis and inflammation. We identified the intracellular pattern recognition receptors NOD1/2, which sense bacterial peptidoglycans, as general stress sensors detecting perturbations of cellular homeostasis. NOD1/2 activation upon such perturbations required generation of the endogenous metabolite sphingosine-1-phosphate (S1P). Unlike peptidoglycan sensing via the leucine-rich repeats domain, cytosolic S1P directly bound to the nucleotide binding domains of NOD1/2, triggering NF-κB activation and inflammatory responses. In sum, we unveiled a hitherto unknown role of NOD1/2 in surveillance of cellular homeostasis through sensing of the cytosolic metabolite S1P. We propose S1P, an endogenous metabolite, as a novel NOD1/2 activator and NOD1/2 as molecular hubs integrating bacterial and metabolic cues.


Assuntos
Inflamação/metabolismo , Lisofosfolipídeos/metabolismo , Proteína Adaptadora de Sinalização NOD1/metabolismo , Proteína Adaptadora de Sinalização NOD2/metabolismo , Esfingosina/análogos & derivados , Animais , Linhagem Celular , Linhagem Celular Tumoral , Feminino , Células HEK293 , Células HeLa , Humanos , Camundongos , NF-kappa B/metabolismo , Peptidoglicano/metabolismo , Transdução de Sinais/fisiologia , Esfingosina/metabolismo , Células THP-1
4.
Nat Rev Mol Cell Biol ; 14(9): 600-6, 2013 09.
Artigo em Inglês | MEDLINE | ID: mdl-23921333

RESUMO

An interactive, intellectual environment with good funding opportunities is essential for the development and success of basic research. The fast-growing economy and investment in science, together with a visionary plan, have attracted foreign scholars to work in China, motivated world-class Chinese scientists to return and strengthened the country's international collaborations. As a result, molecular and cell biology research in China has evolved rapidly over the past decade.


Assuntos
Biologia Celular , Biologia Molecular , Pesquisa/economia , Pesquisa/tendências , China , Humanos , Cooperação Internacional , Pesquisa/organização & administração , Pesquisadores/tendências , Apoio à Pesquisa como Assunto/organização & administração , Apoio à Pesquisa como Assunto/tendências
5.
Proc Natl Acad Sci U S A ; 119(17): e2120557119, 2022 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-35439052

RESUMO

The sun (∼6,000 K) and outer space (∼3 K) are two significant renewable thermodynamic resources for human beings on Earth. The solar thermal conversion by photothermal (PT) and harvesting the coldness of outer space by radiative cooling (RC) have already attracted tremendous interest. However, most of the PT and RC approaches are static and monofunctional, which can only provide heating or cooling respectively under sunlight or darkness. Herein, a spectrally self-adaptive absorber/emitter (SSA/E) with strong solar absorption and switchable emissivity within the atmospheric window (i.e., 8 to 13 µm) was developed for the dynamic combination of PT and RC, corresponding to continuously efficient energy harvesting from the sun and rejecting energy to the universe. The as-fabricated SSA/E not only can be heated to ∼170 °C above ambient temperature under sunshine but also be cooled to 20 °C below ambient temperature, and thermal modeling captures the high energy harvesting efficiency of the SSA/E, enabling new technological capabilities.

6.
Nano Lett ; 24(8): 2488-2495, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38198618

RESUMO

Electromagnetic chirality transfer represents an effective means of the nanoscale manipulation of optical chirality. While most of the previous reports have exclusively focused on the circular dichroism (CD) transfer from UV-responsive chiral molecules toward visible-resonant achiral colloidal nanoparticles, here we demonstrate a reverse process in which plasmonic chirality can be transferred to achiral molecules, either upward from visible to UV or downward from visible to near infrared (NIR). By hybridizing achiral UV- or NIR-responsive dye molecules with chiral metal nanoparticles in solution, we observe a chiral-plasmon-induced CD (CPICD) signal at the intrinsically achiral molecular absorption bands. Full-wave electromagnetic modeling reveals that both near-field Coulomb interaction and far-field radiative coupling contribute to the observed CPICD, indicating that the mechanism considered here is universal for different material systems and types of optical resonances. Our study provides a set of design guidelines for broadband nanophotonic chiral sensing from the UV to NIR spectral regime.

7.
Small ; 20(35): e2403020, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38804864

RESUMO

Energy conversion from the environment into electricity is the most direct and effective electricity source to sustainably power off-grid electronics, once the electricity requirement exceeds the capability of traditional centralized power supply systems. Normally photovoltaic cells have enabled distributed power generation during the day, but do not work at night. Thus, efficient electricity generation technologies for a sustainable all-day power supply with no necessity for energy storage remain a challenge. Herein, an innovative all-day power generation strategy is reported, which self-adaptively integrates the diurnal photothermal and nocturnal radiative cooling processes into the thermoelectric generator (TEG) via the spectrally dynamic modulated coating, to continuously harvest the energy from the hot sun and the cold universe for power generation. Synergistic with the optimized latent heat phase change material, the electricity generation performance of the TEG is dramatically enhanced, with a maximum power density exceeding 1000 mW m-2 during the daytime and up to 25 mW m-2 during the nighttime, corresponding to an improvement of 123.1% and 249.1%, compared with the conventional strategy. This work maximizes the utilization of ambient energy resources to provide an environmentally friendly and uninterrupted power generation strategy. This opens up new possibilities for sustained power generation both daytime and nighttime.

8.
J Virol ; 97(10): e0100623, 2023 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-37732785

RESUMO

IMPORTANCE: Zika virus (ZIKV) infection in pregnant women during the third trimester can cause neurodevelopmental delays and cryptorchidism in children without microcephaly. However, the consequences of congenital ZIKV infection on fertility in these children remain unclear. Here, using an immunocompetent mouse model, we reveal that congenital ZIKV infection can cause hormonal disorders of the hypothalamic-pituitary-gonadal axis, leading to reduced fertility and decreased sexual preference. Our study has for the first time linked the hypothalamus to the reproductive system and social behaviors after ZIKV infection. Although the extent to which these observations in mice translate to humans remains unclear, these findings did suggest that the reproductive health and hormone levels of ZIKV-exposed children should receive more attention to improve their living quality.


Assuntos
Complicações Infecciosas na Gravidez , Infecção por Zika virus , Zika virus , Animais , Criança , Feminino , Humanos , Masculino , Camundongos , Gravidez , Fertilidade , Hormônios , Eixo Hipotalâmico-Hipofisário-Gonadal , Microcefalia , Complicações Infecciosas na Gravidez/virologia , Zika virus/fisiologia , Infecção por Zika virus/patologia
9.
Cell ; 139(3): 535-46, 2009 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-19879840

RESUMO

Beta-arrestin1 is a multifunctional protein critically involved in signal transduction. Recently, it is also identified as a nuclear transcriptional regulator, but the underlying mechanisms and physiological significance remain to be explored. Here, we identified beta-arrestin1 as an evolutionarily conserved protein essential for zebrafish development. Zebrafish embryos depleted of beta-arrestin1 displayed severe posterior defects and especially failed to undergo hematopoiesis. In addition, the expression of cdx4, a critical regulator of embryonic blood formation, and its downstream hox genes were downregulated by depletion of beta-arrestin1, while injection of cdx4, hoxa9a or hoxb4a mRNA rescued the hematopoietic defects. Further mechanistic studies revealed that beta-arrestin1 bound to and sequestered the polycomb group (PcG) recruiter YY1, and relieved PcG-mediated repression of cdx4-hox pathway, thus regulating hematopoietic lineage specification. Taken together, this study demonstrated a critical role of beta-arrestin1 during zebrafish primitive hematopoiesis, as well as an important regulator of PcG proteins and cdx4-hox pathway.


Assuntos
Arrestinas/metabolismo , Hematopoese , Proteínas Repressoras/metabolismo , Transdução de Sinais , Fator de Transcrição YY1/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/metabolismo , Animais , Genes Homeobox , Proteínas de Homeodomínio/metabolismo , Proteínas do Grupo Polycomb , Fatores de Transcrição , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , beta-Arrestinas
10.
Nature ; 563(7729): 131-136, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30356214

RESUMO

Accurate repair of DNA double-stranded breaks by homologous recombination preserves genome integrity and inhibits tumorigenesis. Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that activates innate immunity by initiating the STING-IRF3-type I IFN signalling cascade1,2. Recognition of ruptured micronuclei by cGAS links genome instability to the innate immune response3,4, but the potential involvement of cGAS in DNA repair remains unknown. Here we demonstrate that cGAS inhibits homologous recombination in mouse and human models. DNA damage induces nuclear translocation of cGAS in a manner that is dependent on importin-α, and the phosphorylation of cGAS at tyrosine 215-mediated by B-lymphoid tyrosine kinase-facilitates the cytosolic retention of cGAS. In the nucleus, cGAS is recruited to double-stranded breaks and interacts with PARP1 via poly(ADP-ribose). The cGAS-PARP1 interaction impedes the formation of the PARP1-Timeless complex, and thereby suppresses homologous recombination. We show that knockdown of cGAS suppresses DNA damage and inhibits tumour growth both in vitro and in vivo. We conclude that nuclear cGAS suppresses homologous-recombination-mediated repair and promotes tumour growth, and that cGAS therefore represents a potential target for cancer prevention and therapy.


Assuntos
Núcleo Celular/metabolismo , Transformação Celular Neoplásica/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Nucleotidiltransferases/metabolismo , Reparo de DNA por Recombinação , Transporte Ativo do Núcleo Celular , Adulto , Animais , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/enzimologia , Quebras de DNA de Cadeia Dupla , Dano ao DNA , Feminino , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Nucleotidiltransferases/deficiência , Fosforilação , Ftalazinas/farmacologia , Piperazinas/farmacologia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/metabolismo , Ligação Proteica/efeitos dos fármacos , Reparo de DNA por Recombinação/genética , Quinases da Família src/metabolismo
11.
Molecules ; 29(1)2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38202819

RESUMO

Salvianolic acid B (Sal B) is the primary water-soluble bioactive constituent derived from the roots of Salvia miltiorrhiza Bunge. This research was designed to reveal the potential mechanism of Sal B anti-liver injury from the perspective of macrophages. In our lipopolysaccharide-induced M1 macrophage model, Sal B showed a clear dose-dependent gradient of inhibition of the macrophage trend of the M1 type. Moreover, Sal B downregulated the expression of lactate dehydrogenase A (LDHA), while the overexpression of LDHA impaired Sal B's effect of inhibiting the trend of macrophage M1 polarization. Additionally, this study revealed that Sal B exhibited inhibitory effects on the lactylation process of histone H3 lysine 18 (H3K18la). In a ChIP-qPCR analysis, Sal B was observed to drive a reduction in H3K18la levels in the promoter region of the LDHA, NLRP3, and IL-1ß genes. Furthermore, our in vivo experiments showed that Sal B has a good effect on alleviating CCl4-induced liver injury. An examination of liver tissues and the Kupffer cells isolated from those tissues proved that Sal B affects the M1 polarization of macrophages and the level of histone lactylation. Together, our data reveal that Sal B has a potential mechanism of inhibiting the histone lactylation of macrophages by downregulating the level of LDHA in the treatment of liver injury.


Assuntos
Benzofuranos , Depsídeos , Histonas , Ácido Láctico , Fígado , Macrófagos , Lactato Desidrogenase 5
12.
Molecules ; 29(8)2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38675536

RESUMO

Traditional Chinese medicine (TCM) possesses the potential of providing good curative effects with no side effects for the effective management of slow transit constipation (STC), an intestinal disease characterized by colonic dyskinesia. Mulberry leaves (Morus alba L.) and black sesame (Sesamum indicum L.), referred to as SH, are processed and conditioned as per standardized protocols. SH has applications as food and medicine. Accordingly, we investigated the therapeutic potential of SH in alleviating STC. The analysis of SH composition identified a total of 504 compounds. The intervention with SH significantly improved intestinal motility, reduced the time for the first black stool, increased antioxidant activity, and enhanced water content, thereby effectively alleviating colon damage caused by STC. Transcriptome analysis revealed the SH in the treatment of STC related to SOD1, MUC2, and AQP1. The analysis of 16S rRNA gene sequences indicated notable differences in the abundance of 10 bacteria between the SH and model. Metabolomic analysis further revealed that SH supplementation increased the levels of nine metabolites associated with STC. Integrative analysis revealed that SH modulated amino acid metabolism, balanced intestinal flora, and targeted key genes (i.e., SOD1, MUC2, AQP1) to exert its effects. SH also inhibited the AQP1 expression and promoted SOD1 and MUC2 expression.


Assuntos
Constipação Intestinal , Morus , Folhas de Planta , Sesamum , Morus/química , Constipação Intestinal/tratamento farmacológico , Folhas de Planta/química , Sesamum/química , Animais , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Microbioma Gastrointestinal/efeitos dos fármacos , Metabolômica/métodos , Masculino , Motilidade Gastrointestinal/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Antioxidantes/farmacologia , Antioxidantes/química , Perfilação da Expressão Gênica , Modelos Animais de Doenças , Multiômica
13.
Angew Chem Int Ed Engl ; : e202417605, 2024 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-39468954

RESUMO

Designing solid polymer electrolytes (SPEs) with high ionic conductivity for room-temperature operation is essential for advancing flexible all-solid-state energy storage devices. Innovative strategies are urgently required to develop SPEs that are safe, stable, and high-performing. In this work, we introduce photoexcitation-modulated heterojunctions as catalytically active fillers within SPEs, guided by photocatalytic design principles, and employ natural bacterial cellulose to enhance the mechanical properties of the inorganic-filled SPEs. In-situ photothermal experiments and theoretical calculations reveal that the strong photogenerated electric field produced by trace heterojunctions within poly(ethylene oxide) electrolytes under photoexcitation significantly enhances lithium salt dissociation, increasing the concentration of mobile Li+. This results in a substantial increase in ionic conductivity, reaching 0.135 mS cm-1 at 25 °C, with a Li+ transference number as high as 0.46. The flexible all-solid-state lithium-metal pouch cells exhibit an impressive discharge capacity of 178.8 mAh g-1 even after repeated bending and folding, and demonstrate exceptional long-term cycling stability, retaining 86.7% of their initial capacity after 250 cycles at 1 C (25 °C). This research offers a novel approach to developing high-performance flexible lithium-metal batteries.

14.
Stem Cells ; 40(9): 857-869, 2022 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-35772103

RESUMO

G-protein-coupled receptors (GPCRs) reportedly relay specific signals, such as dopamine and serotonin, to regulate neurogenic processes although the underlying signaling pathways are not fully elucidated. Based on our previous work, which demonstrated dopamine receptor D1 (DRD1) effectively induces the proliferation of human neural stem cells, here we continued to show the knockout of ß-arrestin 2 by CRISPR/Cas9 technology significantly weakened the DRD1-induced proliferation and neurosphere growth. Furthermore, inhibition of the downstream p38 MAPK by its specific inhibitors or small hairpin RNA mimicked the weakening effect of ß-arrestin 2 knockout. In addition, blocking of Epac2, a PKA independent signal pathway, by its specific inhibitors or small hairpin RNA also significantly reduced DRD1-induced effects. Simultaneous inhibition of ß-arrestin 2/p38 MAPK and Epac2 pathways nearly abolished the DRD1-stimulated neurogenesis, indicating the cooperative contribution of both pathways. Consistently, the expansion and folding of human cerebral organoids as stimulated by DRD1 were also mediated cooperatively by both ß-arrestin 2/p38 MAPK and Epac2 pathways. Taken together, our results reveal that GPCRs apply at least 2 different signal pathways to regulate neurogenic processes in a delicate and balanced manners.


Assuntos
Dopamina , Células-Tronco Neurais , Proliferação de Células , Humanos , Células-Tronco Neurais/metabolismo , Organoides/metabolismo , RNA Interferente Pequeno , Receptores de Dopamina D1/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Serotonina , beta-Arrestina 2/genética , beta-Arrestina 2/metabolismo , beta-Arrestinas/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
BMC Cancer ; 23(1): 536, 2023 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-37308852

RESUMO

BACKGROUND: Lymph node size is considered as a criterion for possible lymph node metastasis in imageology. Micro lymph nodes are easily overlooked by surgeons and pathologists. This study investigated the influencing factors and prognosis of micro lymph node metastasis in gastric cancer. METHODS: 191 eligible gastric cancer patients who underwent D2 lymphadenectomy from June 2016 to June 2017 in the Third Surgery Department at the Fourth Hospital of Hebei Medical University were retrospectively analyzed. Specimens were resected en bloc and the postoperative retrieval of micro lymph nodes was carried out by the operating surgeon for each lymph node station. Micro lymph nodes were submitted for pathological examination separately. According to the results of pathological results, patients were divided into the "micro-LNM (micro lymph node metastasis)" group (N = 85) and the "non micro-LNM" group (N = 106). RESULTS: The total number of lymph nodes retrieved was 10,954, of which 2998 (27.37%) were micro lymph nodes. A total of 85 (44.50%) gastric cancer patients had been proven to have micro lymph node metastasis. The mean number of micro lymph nodes retrieved was 15.7. The rate of micro lymph node metastasis was 8.1% (242/2998). Undifferentiated carcinoma (90.6% vs. 56.6%, P = 0.034) and more advanced Pathological N category (P < 0.001) were significantly related to micro lymph node metastasis. The patients with micro lymph node metastasis had a poor prognosis (HR for OS of 2.199, 95% CI = 1.335-3.622, P = 0.002). For the stage III patients, micro lymph node metastasis was associated with shorter 5-year OS (15.6% vs. 43.6%, P = 0.0004). CONCLUSIONS: Micro lymph node metastasis is an independent risk factor for poor prognosis in gastric cancer patients. Micro lymph node metastasis appears to be a supplement to N category in order to obtain more accurate pathological staging.


Assuntos
Carcinoma , Neoplasias Gástricas , Humanos , Metástase Linfática , Estudos Retrospectivos , Suplementos Nutricionais
16.
EMBO Rep ; 22(7): e51678, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-33987949

RESUMO

Mycobacterial arabinogalactan (AG) is an essential cell wall component of mycobacteria and a frequent structural and bio-synthetical target for anti-tuberculosis (TB) drug development. Here, we report that mycobacterial AG is recognized by galectin-9 and exacerbates mycobacterial infection. Administration of AG-specific aptamers inhibits cellular infiltration caused by Mycobacterium tuberculosis (Mtb) or Mycobacterium bovis BCG, and moderately increases survival of Mtb-infected mice or Mycobacterium marinum-infected zebrafish. AG interacts with carbohydrate recognition domain (CRD) 2 of galectin-9 with high affinity, and galectin-9 associates with transforming growth factor ß-activated kinase 1 (TAK1) via CRD2 to trigger subsequent activation of extracellular signal-regulated kinase (ERK) as well as induction of the expression of matrix metalloproteinases (MMPs). Moreover, deletion of galectin-9 or inhibition of MMPs blocks AG-induced pathological impairments in the lung, and the AG-galectin-9 axis aggravates the process of Mtb infection in mice. These results demonstrate that AG is an important virulence factor of mycobacteria and galectin-9 is a novel receptor for Mtb and other mycobacteria, paving the way for the development of novel effective TB immune modulators.


Assuntos
Mycobacterium tuberculosis , Peixe-Zebra , Animais , Galactanos , Galectinas/genética , Camundongos
17.
J Appl Toxicol ; 43(6): 772-788, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36301730

RESUMO

Abnormal ovarian function is the main manifestation of female reproductive toxicity. Granulosa cells (GCs) play an important role in determining the fate of follicles and are the main effector cells of the female reproductive system. Excessive apoptosis of GCs leads to pathological folliculogenesis and further reproductive damage. However, drugs available for treatment of female reproductive toxicity are limited. Recent studies have confirmed that various natural products and bioactive ingredients of traditional Chinese medicine (TCM) can inhibit apoptosis of GCs and protect ovarian function. In this review, the mechanisms underlying the proapoptotic and antiapoptotic effects of natural products and bioactive ingredients of TCM on the proliferation, function, and apoptosis of GCs are summarized based on the findings of reports published over the past 10 years as reference for the treatment of female reproductive toxicity.


Assuntos
Medicina Tradicional Chinesa , Folículo Ovariano , Feminino , Humanos , Células da Granulosa , Apoptose
18.
Int J Mol Sci ; 24(4)2023 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-36834819

RESUMO

Dysfunctional mitochondria and mitophagy are hallmarks of Alzheimer's disease (AD). It is widely accepted that restoration of mitophagy helps to maintain cellular homeostasis and ameliorates the pathogenesis of AD. It is imperative to create appropriate preclinical models to study the role of mitophagy in AD and to assess potential mitophagy-targeting therapies. Here, by using a novel 3D human brain organoid culturing system, we found that amyloid-ß (Aß1-42,10 µM) decreased the growth level of organoids, indicating that the neurogenesis of organoids may be impaired. Moreover, Aß treatment inhibited neural progenitor cell (NPC) growth and induced mitochondrial dysfunction. Further analysis revealed that mitophagy levels were reduced in the brain organoids and NPCs. Notably, galangin (10 µM) treatment restored mitophagy and organoid growth, which was inhibited by Aß. The effect of galangin was blocked by the mitophagy inhibitor, suggesting that galangin possibly acted as a mitophagy enhancer to ameliorate Aß-induced pathology. Together, these results supported the important role of mitophagy in AD pathogenesis and suggested that galangin may be used as a novel mitophagy enhancer to treat AD.


Assuntos
Doença de Alzheimer , Mitofagia , Humanos , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Organoides/metabolismo
19.
Int J Mol Sci ; 24(11)2023 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-37298652

RESUMO

Mouse guanylate-binding proteins (mGBPs) are recruited to various invasive pathogens, thereby conferring cell-autonomous immunity against these pathogens. However, whether and how human GBPs (hGBPs) target M. tuberculosis (Mtb) and L. monocytogenes (Lm) remains unclear. Here, we describe hGBPs association with intracellular Mtb and Lm, which was dependent on the ability of bacteria to induce disruption of phagosomal membranes. hGBP1 formed puncta structures which were recruited to ruptured endolysosomes. Furthermore, both GTP-binding and isoprenylation of hGBP1 were required for its puncta formation. hGBP1 was required for the recovery of endolysosomal integrity. In vitro lipid-binding assays demonstrated direct binding of hGBP1 to PI4P. Upon endolysosomal damage, hGBP1 was targeted to PI4P and PI(3,4)P2-positive endolysosomes in cells. Finally, live-cell imaging demonstrated that hGBP1 was recruited to damaged endolysosomes, and consequently mediated endolysosomal repair. In summary, we uncover a novel interferon-inducible mechanism in which hGBP1 contributes to the repair of damaged phagosomes/endolysosomes.


Assuntos
Proteínas de Ligação ao GTP , Fagossomos , Humanos , Animais , Camundongos , Proteínas de Ligação ao GTP/metabolismo , Fagossomos/metabolismo , Interferons/metabolismo , Endossomos/metabolismo
20.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 40(5): 928-937, 2023 Oct 25.
Artigo em Zh | MEDLINE | ID: mdl-37879922

RESUMO

Accurate segmentation of pediatric echocardiograms is a challenging task, because significant heart-size changes with age and faster heart rate lead to more blurred boundaries on cardiac ultrasound images compared with adults. To address these problems, a dual decoder network model combining channel attention and scale attention is proposed in this paper. Firstly, an attention-guided decoder with deep supervision strategy is used to obtain attention maps for the ventricular regions. Then, the generated ventricular attention is fed back to multiple layers of the network through skip connections to adjust the feature weights generated by the encoder and highlight the left and right ventricular areas. Finally, a scale attention module and a channel attention module are utilized to enhance the edge features of the left and right ventricles. The experimental results demonstrate that the proposed method in this paper achieves an average Dice coefficient of 90.63% in acquired bilateral ventricular segmentation dataset, which is better than some conventional and state-of-the-art methods in the field of medical image segmentation. More importantly, the method has a more accurate effect in segmenting the edge of the ventricle. The results of this paper can provide a new solution for pediatric echocardiographic bilateral ventricular segmentation and subsequent auxiliary diagnosis of congenital heart disease.


Assuntos
Ecocardiografia , Ventrículos do Coração , Adulto , Humanos , Criança , Ventrículos do Coração/diagnóstico por imagem , Processamento de Imagem Assistida por Computador
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