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1.
bioRxiv ; 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-39314342

RESUMO

In Borrelia burgdorferi , the Lyme disease pathogen, differential gene expression is primarily controlled by the alternative sigma factor RpoS (σ S ). Understanding how RpoS levels are regulated is crucial for elucidating how B. burgdorferi is maintained throughout its enzootic cycle. Our recent studies have shown that a homolog of Fur/PerR repressor/activator, BosR, functions as an RNA-binding protein that controls the rpoS mRNA stability. However, the mechanisms of regulation of BosR, particularly in response to host signals and environmental cues, remain largely unclear. In this study, we revealed a positive feedback loop between RpoS and BosR, where RpoS post-transcriptionally regulates BosR levels. Specifically, mutation or deletion of rpoS significantly reduced BosR levels, while artificial induction of rpoS resulted in a dose-dependent increase in BosR levels. Notably, RpoS does not affect bosR mRNA levels but instead modulates the turnover rate of the BosR protein. Furthermore, we demonstrated that environmental cues do not directly influence bosR expression but instead induce rpoS transcription and RpoS production, thereby enhancing BosR protein levels. This discovery adds a new layer of complexity to the RpoN-RpoS pathway and suggests the need to re-evaluate the factors and signals previously believed to regulate RpoS levels through BosR. IMPORTANCE: Lyme disease is the most prevalent arthropod-borne infection in the United States. The etiological agent, Borreliella (or Borrelia ) burgdorferi , is maintained in nature through an enzootic cycle involving a tick vector and a mammalian host. RpoS, the master regulator of differential gene expression, plays a crucial role in tick transmission and mammalian infection of B. burgdorferi . This study reveals a positive feedback loop between RpoS and a Fur/PerR homolog. Elucidating this regulatory network is essential for identifying potential therapeutic targets to disrupt B. burgdorferi 's enzootic cycle. The findings also have broader implications for understanding the regulation of RpoS and Fur/PerR family in other bacteria.

2.
Zhonghua Er Ke Za Zhi ; 62(10): 941-948, 2024 Oct 02.
Artigo em Chinês | MEDLINE | ID: mdl-39327960

RESUMO

Objective: To analyze the factors affecting delayed chemotherapy in children with Burkitt lymphoma (BL) and their influence on prognosis. Methods: Retrospective cohort study. Clinical data of 591 children aged ≤18 years with BL from May 2017 to December 2022 in China Net Childhood Lymphoma (CNCL) was collected. The patients were treated according to the protocol CNCL-BL-2017. According to the clinical characteristics, therapeutic regimen was divided into group A, group B and group C .Based on whether the total chemotherapy time was delayed, patients were divided into two groups: the delayed chemotherapy group and the non-delayed chemotherapy group. Based on the total delayed time of chemotherapy, patients in group C were divided into non-delayed chemotherapy group, 1-7 days delayed group and more than 7 days delayed group. Relationships between delayed chemotherapy and gender, age, tumor lysis syndrome before chemotherapy, bone marrow involvement, disease group (B/C group), serum lactate dehydrogenase (LDH) > 4 times than normal, grade Ⅲ-Ⅳ myelosuppression after chemotherapy, minimal residual disease in the interim assessment, and severe infection (including severe pneumonia, sepsis, meningitis, chickenpox, etc.) were analyzed. Logistic analysis was used to identify the relevant factors. Kaplan-Meier method was used to analyze the patients' survival information. Log-Rank was used for comparison between groups. Results: Among 591 patients, 504 were males and 87 were females, the follow-up time was 34.8 (18.6,50.1) months. The 3-year overall survival (OS) rate was (92.5±1.1)%,and the 3-year event-free survival (EFS) rate was (90.5±1.2)%. Seventy-three (12.4%) patients were in delayed chemotherapy group and 518 (87.6%) patients were in non-delayed chemotherapy group. The reasons for chemotherapy delay included 72 cases (98.6%) of severe infection, 65 cases (89.0%) of bone marrow suppression, 35 cases (47.9%) of organ dysfunction, 22 cases (30.1%) of tumor lysis syndrome,etc. There were 7 cases of chemotherapy delay in group B, which were seen in COPADM (vincristine+cyclophosphamide+prednisone+daunorubicin+methotrexate+intrathecal injection,4 cases) and CYM (methotrexate+cytarabine+intrathecal injection,3 cases) stages. There were 66 cases of chemotherapy delay in group C, which were common in COPADM (28 cases) and CYVE 1 (low dose cytarabine+high dose cytarabine+etoposide+methotrexate, 12 cases) stages. Multinomial Logistic regression analysis showed that the age over 10 years old (OR=0.54,95%CI 0.30-0.93), tumor lysis syndrome before chemotherapy (OR=0.48,95%CI 0.27-0.84) and grade Ⅲ-Ⅳ myelosuppression after chemotherapy (OR=0.55,95%CI 0.33-0.91)were independent risk factors for chemotherapy delay.The 3-year OS rate and the 3-year EFS rate of children with Burkitt lymphoma in the delayed chemotherapy group were lower than those in the non-delayed chemotherapy group ((79.4±4.9)% vs. (94.2±1.1)%, (80.2±4.8)% vs. (92.0±1.2)%,both P<0.05). The 3-year OS rate of the group C with chemotherapy delay >7 days (42 cases) was lower than that of the group with chemotherapy delay of 1-7 days (22 cases) and the non-delay group (399 cases) ((76.7±6.9)% vs. (81.8±8.2)% vs. (92.7±1.3)%, P=0.002).The 3-year OS rate of the chemotherapy delay group (9 cases) in the COP (vincristine+cyclophosphamide+prednisone) phase was lower than that of the non-chemotherapy delay group (454 cases) ((66.7±15.7)% vs. (91.3±1.4)%, P=0.005). Similarly, the 3-year OS rate of the chemotherapy delay group (11 cases) in the COPADM1 phase was lower than that of the non-chemotherapy delay group (452 cases) ((63.6±14.5)% vs. (91.5±1.3)%, P=0.001). Conclusions: The delayed chemotherapy was related to the age over 10 years old, tumor lysis syndrome before chemotherapy and grade Ⅲ-Ⅳ myelosuppression after chemotherapy in pediatric BL. There is a significant relationship between delayed chemotherapy and prognosis of BL in children.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma de Burkitt , Humanos , Linfoma de Burkitt/tratamento farmacológico , Estudos Retrospectivos , Criança , Feminino , Masculino , Prognóstico , Pré-Escolar , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adolescente , Tempo para o Tratamento , China , Síndrome de Lise Tumoral/etiologia , Taxa de Sobrevida , Lactente
4.
Opt Lett ; 49(18): 5139-5142, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-39270249

RESUMO

We report an intra-cavity frequency doubled diamond Raman laser operating at 607 nm. A z-fold cavity design was configured to prevent back reflections into the fiber amplifier, which avoided the use of isolators in the pump beam path. A maximum output power of 60 W was generated in two output beams at an optical conversion efficiency of 28% from the 1045 nm pump. A maximum single-beam output power of 40 W was obtained using a highly reflecting end mirror for the visible. Output power and single frequency stability are negatively impacted by an increasing role of stimulated Brillouin scattering at output powers above 10 W.

6.
Proc Natl Acad Sci U S A ; 121(32): e2400153121, 2024 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-39088391

RESUMO

Although many cytokine pathways are important for dendritic cell (DC) development, it is less clear what cytokine signals promote the function of mature dendritic cells. The signal transducer and activator of transcription 4 (STAT4) promotes protective immunity and autoimmunity downstream of proinflammatory cytokines including IL-12 and IL-23. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), Stat4-/- mice are resistant to the development of inflammation and paralysis. To define whether STAT4 is required for intrinsic signaling in mature DC function, we used conditional mutant mice in the EAE model. Deficiency of STAT4 in CD11c-expressing cells resulted in decreased T cell priming and inflammation in the central nervous system. EAE susceptibility was recovered following adoptive transfer of wild-type bone marrow-derived DCs to mice with STAT4-deficient DCs, but not adoptive transfer of STAT4- or IL-23R-deficient DCs. Single-cell RNA-sequencing (RNA-seq) identified STAT4-dependent genes in DC subsets that paralleled a signature in MS patient DCs. Together, these data define an IL-23-STAT4 pathway in DCs that is key to DC function during inflammatory disease.


Assuntos
Células Dendríticas , Encefalomielite Autoimune Experimental , Interleucina-23 , Fator de Transcrição STAT4 , Transdução de Sinais , Animais , Fator de Transcrição STAT4/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Interleucina-23/metabolismo , Interleucina-23/imunologia , Camundongos , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Camundongos Knockout , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/imunologia , Inflamação/metabolismo , Inflamação/imunologia , Transferência Adotiva , Camundongos Endogâmicos C57BL , Humanos , Linfócitos T/imunologia , Linfócitos T/metabolismo
7.
Phys Rev Lett ; 133(4): 046701, 2024 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-39121432

RESUMO

Utilizing spin pumping, we present a comparative study of the spin-charge conversion in RuO_{2}(101) and RuO_{2}(110) films. RuO_{2}(101) shows a robust in-plane crystal-axis dependence, whereas RuO_{2}(110) exhibits an isotropic but stronger one. Symmetry-based analysis and first-principles calculations reveal that the spin-charge conversion in RuO_{2}(110) originates from the inverse spin Hall effect (ISHE) due to nodal lines splitting. In RuO_{2}(101), the ISHE also dominates although the inverse spin splitting effect (ISSE) may coexist. These findings, in sharp contrast to previously attributed ISSE, are further corroborated by the reciprocal relation between the spin pumping and the spin-torque ferromagnetic resonance measurements.

8.
Zhonghua Yi Xue Za Zhi ; 104(34): 3171-3174, 2024 Sep 03.
Artigo em Chinês | MEDLINE | ID: mdl-39193604

RESUMO

Gallbladder polyp is a common disease of gallbladder, the incidence of gallbladder polyp in China is about 5%~10%, and the trend is increasing year by year. The patients with gallbladder polyps had no obvious clinical symptoms, which was more than that found by ultrasonography during physical examination. At present, the diameter of gallbladder polyps>10 mm is still used by clinicians as the main surgical indication for cholecystectomy. According to the data, about 80% to 90% of gallbladder polyps are cholesterol type polyps and benign gallbladder polyps. For these patients whose gallbladder is removed due to benign gallbladder polyps, we consider that we can continue to observe or retain the gallbladder, without having to bear the adverse consequences that may be caused by gallbladder removal. Based on the literature analysis at home and abroad, this paper discusses the surgical treatment of gallbladder polyps and the results of postoperative pathological diagnosis, and reminds the majority of clinicians to be careful when removing gallbladder polyps.


Assuntos
Colecistectomia , Doenças da Vesícula Biliar , Pólipos , Humanos , Pólipos/cirurgia , Doenças da Vesícula Biliar/cirurgia , Vesícula Biliar/cirurgia , Neoplasias da Vesícula Biliar/cirurgia
9.
J Texture Stud ; 55(4): e12859, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39086085

RESUMO

Texture and sensory studies at various temperatures are important in evaluating and improving the functionality of butter. While literature is scarce, we evaluated and compared the effect of temperature (5-25°C) on the texture, rheological and sensory properties of commercial butter samples (salted, unsalted, cultured, and spreadable) from the New Zealand market. In addition, the instrumental analyses were compared with the sensory evaluation, to understand the possibility of using instrumental analysis to evaluate consumer liking for different butters. Butter type, temperature, and their type-temperature interaction exhibited significant differences for all instrumental textural parameters. As expected, higher temperature produced softer butter that was more spreadable, liquid-like, less adhesive, less cohesive, had lower storage modulus (G') and lower loss modulus (G″) with the melting of milk fat crystals; however, the rate of change varied for the different butter samples. We have established meltability as the parameter for evaluating butter selection for different applications. The spreadable butter sample exhibited the lowest hardness and G', and highest spreadability (p < .05) at all temperatures, owing to its low solid fat content and the abundance of low-melting triglycerides. The cultured butter sample had the highest melting point, owing to compositional differences. The instrumental and sensory texture analyses were highly correlated, indicating the comparative effectiveness of both approaches for studying the effects of different temperatures on butter textural properties. Overall, our findings provide detailed reference to the dairy industry for butter manufacture, considering variation in fatty acid composition, texture analysis, rheology, and sensory analysis, over the range of storage/usage temperatures.


Assuntos
Manteiga , Reologia , Temperatura , Nova Zelândia , Humanos , Manteiga/análise , Comportamento do Consumidor , Paladar , Manipulação de Alimentos/métodos , Adulto , Dureza , Feminino , Animais
10.
Nat Commun ; 15(1): 7454, 2024 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-39198464

RESUMO

Fast radio bursts (FRBs) are immensely energetic millisecond-duration radio pulses. Observations indicate that nearby FRBs can be produced by old stellar populations, as suggested by the localization of the repeating source FRB 20200120E in a globular cluster of M81. Nevertheless, the burst energies of FRB 20200120E are significantly smaller than those of other cosmological FRBs. Here, we report the detection of a bright burst from FRB 20200120E in 1.1 - 1.7 GHz, with a fluence of approximately 30 Jy ms, which is more than 42 times larger than the previously detected bursts near 1.4 GHz frequency. It reaches one-third of the energy of the weakest burst from FRB 20121102A and is detectable at a distance exceeding 200 Mpc. Our finding bridges the gap between nearby and cosmological FRBs and indicates that FRBs hosted in globular clusters can be bright enough to be observable at cosmological distances.

11.
bioRxiv ; 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-39185169

RESUMO

Borrelia burgdorferi (B. burgdorferi), an extracellular spirochetal pathogen, elicits a type-I interferon (IFN-I) response that contributes to the pathology of Lyme disease, including the development and severity of Lyme arthritis. However, the specific Pathogen-Associated Molecular Patterns (PAMPs) of B. burgdorferi responsible for triggering the IFN-I response are not well understood. Previous studies have identified an unknown, nuclease-resistant component in B. burgdorferi culture supernatants that significantly stimulates the IFN-I response, but its identity remains unknown. In this study, we reveal that B. burgdorferi secretes cyclic-di-adenosine monophosphate (c-di-AMP) as a key extracellular PAMP, inducing the host IFN-I response in macrophages. Using genetically manipulated B. burgdorferi strains, we demonstrate a requirement of c-di-AMP for stimulating IFN-I response by macrophages ex vivo. Additionally, infecting mice with B. burgdorferi alongside exogenous c-di-AMP resulted in a markedly increased IFN-I response in mouse tissues. Furthermore, inactivation or inhibition of the host STING signaling pathway significantly reduced the IFN-I response, indicating that c-di-AMP-induced IFN-I production is STING-dependent. Our findings identify c-di-AMP as a crucial PAMP secreted by B. burgdorferi to elicit the host IFN-I response via activation of STING signaling pathway, suggesting that targeting c-di-AMP production could represent a novel therapeutic strategy against Lyme arthritis.

13.
Zhonghua Yu Fang Yi Xue Za Zhi ; 58(6): 756-762, 2024 Jun 06.
Artigo em Chinês | MEDLINE | ID: mdl-38955721

RESUMO

Allergic diseases are affected by both genetic background and environmental factors.In recent years, many studies have shown that allergic diseases are closely related to the gut microbiome.This article will elaborate on the composition of gut microbiome in early life and its relationship with allergies, the mechanism of action, and the influence of gut microbiome colonization on the atopic march, in order to improve the understanding of the relationship between allergy prevention or treatment and gut microbiome in children, and provide new ideas for the early prevention of allergic diseases and the early intervention of allergic processes.


Assuntos
Hipersensibilidade , Humanos , Hipersensibilidade/microbiologia , Microbiota , Criança , Microbioma Gastrointestinal , Trato Gastrointestinal/microbiologia
14.
Zhonghua Yu Fang Yi Xue Za Zhi ; 58(6): 799-805, 2024 Jun 06.
Artigo em Chinês | MEDLINE | ID: mdl-38955726

RESUMO

Objective: To explore the distribution of allergen-specific IgE (sIgE) for children with atopic dermatitis in Tianjin City and provide the evidences of clinical diagnosis and treatment. Methods: A retrospective cross-sectional study was conducted to analyze the children who were suspected of atopic dermatitis and tested for serum sIgE in the Tianjin Children's Hospital from March 2021 to February 2023. Using first detection results only, a total of 1 841 serum samples were tested for twenty common allergens. The method was the enzyme-linked immune capture assay. The allergen epidemiological characteristics were statistically analyzed by Chi square test based on the children's characteristics and factors such as different sexes, ages and seasons by the mass data. Results: Among the 1 841 cases, the results showed that 1 247 (67.73%) were sensitized to at least 1 allergen-sIgE, comprising to 49.86% (918/1 841) to food allergen-sIgE and 47.96% (883/1 841) to aeroallergen-sIgE. The top three food allergens-sIgE were egg 32.10% (591/1 841), milk 25.91% (477/1 841) and wheat flour 14.61% (269/1 841); the top three positive rates of aeroallergens-sIgE were house dust 24.33% (448/1 841), alternaria 20.59% (379/1 841) and dermatophagoides farinae 14.83% (273/1 841). The positive rates of food allergens-sIgE were the highest in the 1-3 years old group (64.11%, 434/677) (χ2=122.854, P<0.001), while the positive rates of aeroallergens-sIgE were higher in the 11-14 years old group (71.26%, 62/87) (χ2=134.968, P<0.001). No seasonal difference was revealed in the overall positive rate of food allergen-sIgE and aeroallergen-sIgE (χ2=4.047, P=0.256; χ2=7.549, P=0.056). The positive rates of soybean-sIgE and milk-sIgE were the highest in summer (χ2=11.329, P=0.010; χ2=28.720, P<0.001), whereas alternaria-sIgE and mugwort-sIgE were the highest in summer and autumn, respectively (χ2=8.462, P=0.037; χ2=10.641, P=0.014). Among the 1 841 cases, 32.21% were sensitized to three or more allergens-sIgE. The sIgE concentration levels of egg, milk and house dust were mainly level 1 to 2, and the proportions of level 3 and above were all under 15%; although the positive rates of crab, shrimp, and peanut were low, the proportions of grade 3 and above were all beyond 30%. Children sensitized to alternaria, dermatophagoides farinae, mugwort, and cat dander had higher sIgE concentration levels, which were 68.07%, 49.45%, 56.57% and 47.83% respectively. Conclusions: This study can reflect the epidemic characteristics of allergen-sIgE in children with atopic dermatitis in Tianjin region to a certain extent. Allergen-sIgE positivity in patients differed by age, and there were seasonal differences and grade distribution differences in the positive rates of some allergens-sIgE. It is necessary to reasonably avoid the high-risk allergens according to the epidemiological characteristics and clinical symptoms, which provide valuable information for the prevention, diagnosis and treatment of atopic dermatitis.


Assuntos
Alérgenos , Dermatite Atópica , Imunoglobulina E , Humanos , Dermatite Atópica/imunologia , Estudos Transversais , Alérgenos/imunologia , Criança , Estudos Retrospectivos , Imunoglobulina E/imunologia , Imunoglobulina E/sangue , Pré-Escolar , Masculino , Feminino , China , Adolescente , Lactente , Hipersensibilidade Alimentar/imunologia
15.
Zhonghua Yu Fang Yi Xue Za Zhi ; 58(6): 917-923, 2024 Jun 06.
Artigo em Chinês | MEDLINE | ID: mdl-38955742

RESUMO

Persistent Organic Pollutants (POPs) have the characteristics of resistance to environmental degradation, bioaccumulation and long-distance migration potential. Maternal exposure to POPs during pregnancy can enter the fetal blood circulation through the placental barrier, and have a potential impact on the functional development of the nervous system of the offspring. This in turn leads to the occurrence and development of neurological defects and diseases in adulthood. The purpose of this paper is to elucidate the effects of exposure to three major POPs (organochlorine compounds, perfluoroalkyl and polyfluoroalkyl substances, and polybrominated diphenyl ethers) during pregnancy on the functional development of the nervous system (social emotions, cognition, language, exercise, and adaptability) in children, and to provide reference for subsequent studies.


Assuntos
Sistema Nervoso , Poluentes Orgânicos Persistentes , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Humanos , Feminino , Criança , Sistema Nervoso/efeitos dos fármacos , Sistema Nervoso/crescimento & desenvolvimento , Exposição Materna/efeitos adversos , Éteres Difenil Halogenados/toxicidade , Hidrocarbonetos Clorados , Desenvolvimento Infantil/efeitos dos fármacos , Poluentes Ambientais/toxicidade
16.
Zhonghua Wei Chang Wai Ke Za Zhi ; 27(7): 672-677, 2024 Jul 25.
Artigo em Chinês | MEDLINE | ID: mdl-39004982

RESUMO

Radical gastrectomy is the core of comprehensive treatment for patients with locally advanced gastric cancer,while reasonable and standardized lymphadenectomy is the key to radical gastrectomy.With the continuous development of treatment methods and therapeutic drugs for advanced gastric cancer, it is worth exploring whether the scope of lymphadenectomy needs to be changed. Neoadjuvant immunotherapy has brought a new breakthrough for locally advanced gastric cancer, increased pathological complete response rate, reduced clinical stage of tumors, and increased radical surgical resection rate, but it has not brought long-term benefits to patients. Lymph nodes play an important role in human anti-tumor immune response, and some basic studies suggest that preserving some normal lymph nodes may be more helpful to enhance the efficacy of immunotherapy. Thus, in the era of immunotherapy, the extent of lymph node dissection for locally advanced gastric cancer needs to balance continuous drug benefits, patient quality of life, and survival benefits, awaiting further high-quality clinical research for determination. Questions such as how to differentiate between normal and metastatic lymph nodes, how to rationally preserve normal lymph nodes, and whether preserving partial lymph node function can lead to greater benefits for patients from immunotherapy warrant further exploration.


Assuntos
Gastrectomia , Imunoterapia , Excisão de Linfonodo , Terapia Neoadjuvante , Neoplasias Gástricas , Neoplasias Gástricas/terapia , Neoplasias Gástricas/patologia , Humanos , Excisão de Linfonodo/métodos , Imunoterapia/métodos , Gastrectomia/métodos , Linfonodos/patologia , Metástase Linfática , Qualidade de Vida
17.
Nan Fang Yi Ke Da Xue Xue Bao ; 44(6): 1126-1134, 2024 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-38977342

RESUMO

OBJECTIVE: To investigate the protective effect of recombinant Schistosoma japonicum cystatin (rSj-Cys) against acute liver injury induced by lipopolysaccharide (LPS) and D-GalN in mice. METHODS: Adult male C57BL/6J mice with or without LPS/D-GaIN-induced acute liver injury were given intraperitoneal injections of rSj-Cys or PBS 30 min after modeling (n=18), and serum and liver tissues samples were collected from 8 mice in each group 6 h after modeling. The survival of the remaining 10 mice in each group within 24 h was observed. Serum levels of ALT, AST, TNF-α and IL-6 of the mice were measured, and liver pathologies was observed with HE staining. The hepatic expressions of macrophage marker CD68, Bax, Bcl-2 and endoplasmic reticulum stress (ERS)-related proteins were detected using immunohistochemistry or immunoblotting, and TUNEL staining was used to detect hepatocyte apoptosis. RESULTS: The survival rates of PBS- and rSj-Cys-treated mouse models of acute liver injury were 30% and 80% at 12 h and were 10% and 60% at 24 h after modeling, respectively; no death occurred in the two control groups within 24 h. The mouse models showed significantly increased serum levels of AST, ALT, IL-6 and TNF-α and serious liver pathologies with increased hepatic expressions of CD68 and Bax, lowered expression of Bcl-2, increased hepatocyte apoptosis, and up-regulated expressions of ERS-related signaling pathway proteins GRP78, CHOP and NF-κB p-p65. Treatment of the mouse models significantly lowered the levels of AST, ALT, IL-6 and TNF-α, alleviated liver pathologies, reduced hepatic expressions of CD68, Bax, GRP78, CHOP and NF-κB p-p65, and enhanced the expression of Bcl-2. In the normal control mice, rSj-Cys injection did not produce any significant changes in these parameters compared with PBS. CONCLUSION: rSj-Cys alleviates LPS/D-GalN-induced acute liver injury in mice by suppressing ERS, attenuating inflammation and inhibiting hepatocyte apoptosis.


Assuntos
Apoptose , Cistatinas , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático , Hepatócitos , Inflamação , Camundongos Endogâmicos C57BL , Schistosoma japonicum , Animais , Camundongos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Masculino , Hepatócitos/metabolismo , Hepatócitos/efeitos dos fármacos , Cistatinas/farmacologia , Fígado/patologia , Fígado/metabolismo , Lipopolissacarídeos , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Proteínas Recombinantes/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Galactosamina , Antígenos CD/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Molécula CD68
18.
bioRxiv ; 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39026894

RESUMO

Modifiers of Huntington's disease (HD) include mismatch repair (MMR) genes; however, their underlying disease-altering mechanisms remain unresolved. Knockout (KO) alleles for 9 HD GWAS modifiers/MMR genes were crossed to the Q140 Huntingtin (mHtt) knock-in mice to probe such mechanisms. Four KO mice strongly ( Msh3 and Pms1 ) or moderately ( Msh2 and Mlh1 ) rescue a triad of adult-onset, striatal medium-spiny-neuron (MSN)-selective phenotypes: somatic Htt DNA CAG-repeat expansion, transcriptionopathy, and mHtt protein aggregation. Comparatively, Q140 cortex also exhibits an analogous, but later-onset, pathogenic triad that is Msh3 -dependent. Remarkably, Q140/homozygous Msh3-KO lacks visible mHtt aggregates in the brain, even at advanced ages (20-months). Moreover, Msh3 -deficiency prevents striatal synaptic marker loss, astrogliosis, and locomotor impairment in HD mice. Purified Q140 MSN nuclei exhibit highly linear age-dependent mHtt DNA repeat expansion (i.e. repeat migration), with modal-CAG increasing at +8.8 repeats/month (R 2 =0.98). This linear rate is reduced to 2.3 and 0.3 repeats/month in Q140 with Msh3 heterozygous and homozygous alleles, respectively. Our study defines somatic Htt CAG-repeat thresholds below which there are no detectable mHtt nuclear or neuropil aggregates. Mild transcriptionopathy can still occur in Q140 mice with stabilized Htt 140-CAG repeats, but the majority of transcriptomic changes are due to somatic repeat expansion. Our analysis reveals 479 genes with expression levels highly correlated with modal-CAG length in MSNs. Thus, our study mechanistically connects HD GWAS genes to selective neuronal vulnerability in HD, in which Msh3 and Pms1 set the linear rate of neuronal mHtt CAG-repeat migration to drive repeat-length dependent pathogenesis; and provides a preclinical platform for targeting these genes for HD suppression across brain regions. One Sentence Summary: Msh3 and Pms1 are genetic drivers of sequential striatal and cortical pathogenesis in Q140 mice by mediating selective CAG-repeat migration in HD vulnerable neurons.

20.
Zhonghua Xue Ye Xue Za Zhi ; 45(5): 488-494, 2024 May 14.
Artigo em Chinês | MEDLINE | ID: mdl-38964924

RESUMO

Objective: To explore the efficacy and safety of cryopreservation-free integrated autologous hematopoietic stem cell transplantation (HSCT) model for patients with multiple myeloma. Methods: A total of 96 patients with newly diagnosed multiple myeloma (NDMM) between July 31, 2020, and December 31, 2022, were retrospectively analyzed, of which 41 patients in the observation group received integrated non-cryopreserved transplantation mode. After hematopoietic stem cells were mobilized and collected, melphalan was started immediately for pre-transplant conditioning, and non-cryopreserved grafts from the medical blood transfusion refrigerator were directly injected intravenously into the patient within 24-48 h after the melphalan conditioning. The control group consisted of 55 patients who received traditional transplantation mode. After hematopoietic stem cells were collected, stem cell cryopreservation was performed in liquid nitrogen, and then the transplant plans were started at the right time. All patients received mobilization of autologous hematopoietic stem cells using the G-CSF combined with the plerixafor. Results: ① A total of 34 patients (82.9% ) with VGPR plus CR in the observation group were significantly higher than 33 patients (60.0% ) in the control group (P=0.016). ②Compared with the control group, the incidence of grade 1 oral mucosal inflammation was higher in the observation group (P<0.001) ; however, the incidence of grades 2 and 3 oral mucosal inflammation was lower (P=0.004, P=0.048), and neither group experienced grade 4 or above oral mucosal inflammation. The incidence of grade 1 diarrhea was higher in the observation group (P=0.002), whereas the incidence of grade 3 diarrhea was lower (P=0.007). No statistically significant difference was observed in the incidence of grade 4 diarrhea (P=0.506), and neither group experienced grade 5 diarrhea. ③ The incidence of bacterial infection in the observation group was lower than that in the control group (34.1% vs 65.5%, P=0.002), whereas no statistically significant difference was observed in the incidence of fungal infection (29.3% vs 31.4%, P=0.863) and viral infection (4.88% vs 3.64%, P=0.831). ④No statistically significant difference was observed in the implantation time of granulocytes and platelets between the observation and control groups [10 (8-20) days vs 11 (8-17) days, P=0.501; 13 (10-21) days vs 15 (10-20) days, P=0.245]. ⑤ All patients did not receive lenalidomide treatment 100 days post-transplantation. At 30 days post-transplantation, the CTL, NK, and Th cell counts in the observation group were lower than those in the control group (P<0.001, P=0.002, P=0.049), and the NKT cell counts were higher than those in the control group (P=0.024). At 100 days post-transplantation, the CTL, NKT, and Th cell counts in the observation group were higher than those in the control group (P=0.025, P=0.011, P=0.007), and no statistically significant difference in NK cell counts was observed between the two groups (P=0.396). ⑥ The median follow-up was 18 (4-33) months. The overall 2-year survival rates of the observation and control groups post-transplantation were 91.5% and 78.2%, respectively (P=0.337). The recurrence-free survival rates were 85.3% and 77.6%, respectively (P=0.386), and the cumulative recurrence rates were 9.8% and 16.9%, respectively (P=0.373) . Conclusion: In NDMM, the cryopreservation-free integrated autologous HSCT model can achieve similar therapeutic effects as traditional transplantation models, with lower rates of severe mucosal inflammation and infection compared with traditional transplantation models.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Transplante Autólogo , Humanos , Mieloma Múltiplo/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Estudos Retrospectivos , Criopreservação , Mobilização de Células-Tronco Hematopoéticas/métodos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade
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