RESUMO
Insulin resistance and ß-cell dysfunction are two main molecular bases yet to be further elucidated for type 2 diabetes (T2D). Accumulating evidence indicates that stimulator of interferon genes (STING) plays an important role in regulating insulin sensitivity. However, its function in ß-cells remains unknown. Herein, using global STING knockout (STING-/-) and ß-cell-specific STING knockout (STING-ßKO) mouse models, we revealed a distinct role of STING in the regulation of glucose homeostasis through peripheral tissues and ß-cells. Specially, although STING-/- beneficially alleviated insulin resistance and glucose intolerance induced by high-fat diet, it surprisingly impaired islet glucose-stimulated insulin secretion (GSIS). Importantly, STING is decreased in islets of db/db mice and patients with T2D, suggesting a possible role of STING in ß-cell dysfunction. Indeed, STING-ßKO caused glucose intolerance due to impaired GSIS, indicating that STING is required for normal ß-cell function. Islet transcriptome analysis showed that STING deficiency decreased expression of ß-cell function-related genes, including Glut2, Kcnj11, and Abcc8, contributing to impaired GSIS. Mechanistically, the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and cleavage under targets and tagmentation (CUT&Tag) analyses suggested that Pax6 was the transcription factor that might be associated with defective GSIS in STING-ßKO mice. Indeed, Pax6 messenger RNA and protein levels were down-regulated and its nuclear localization was lost in STING-ßKO ß-cells. Together, these data revealed a function of STING in the regulation of insulin secretion and established pathophysiological significance of fine-tuned STING within ß-cells and insulin target tissues for maintaining glucose homeostasis.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Intolerância à Glucose/induzido quimicamente , Glucose/metabolismo , Insulina/metabolismo , Proteínas de Membrana/metabolismo , Animais , Diabetes Mellitus Experimental , Dieta Hiperlipídica/efeitos adversos , Regulação para Baixo , Regulação da Expressão Gênica , Homeostase , Humanos , Insulina/sangue , Resistência à Insulina , Células Secretoras de Insulina , Proteínas de Membrana/genética , Camundongos , Camundongos KnockoutRESUMO
Recessive mutations in IER3IP1 (immediate early response 3 interacting protein 1) cause a syndrome of microcephaly, epilepsy, and permanent neonatal diabetes (MEDS). IER3IP1 encodes an endoplasmic reticulum (ER) membrane protein, which is crucial for brain development; however, the role of IER3IP1 in ß cells remains unknown. We have generated two mouse models with either constitutive or inducible IER3IP1 deletion in ß cells, named IER3IP1-ßKO and IER3IP1-ißKO, respectively. We found that IER3IP1-ßKO causes severe early-onset, insulin-deficient diabetes. Functional studies revealed a markedly dilated ß-cell ER along with increased proinsulin misfolding and elevated expression of the ER chaperones, including PDI, ERO1, BiP, and P58IPK. Islet transcriptome analysis confirmed by qRT-PCR revealed decreased expression of genes associated with ß-cell maturation, cell cycle, and antiapoptotic genes, accompanied by increased expression of antiproliferation genes. Indeed, multiple independent approaches further demonstrated that IER3IP1-ßKO impaired ß-cell maturation and proliferation, along with increased condensation of ß-cell nuclear chromatin. Inducible ß-cell IER3IP1 deletion in adult (8-wk-old) mice induced a similar diabetic phenotype, suggesting that IER3IP1 is also critical for function and survival even after ß-cell early development. Importantly, IER3IP1 was decreased in ß cells of patients with type 2 diabetes (T2D), suggesting an association of IER3IP1 deficiency with ß-cell dysfunction in the more-common form of diabetes. These data not only uncover a critical role of IER3IP1 in ß cells but also provide insight into molecular basis of diabetes caused by IER3IP1 mutations.
Assuntos
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Animais , Camundongos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Insulina/metabolismo , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Homeostase/genética , Glucose/metabolismoRESUMO
OBJECTIVES: Previous observational studies have indicated correlations between various inflammatory cytokines and functional outcomes following ischemic stroke (IS); however, the causality remains unclear. We aimed to further evaluate the causal association between 41 circulating inflammatory cytokines and functional outcomes following IS. METHODS: Two-sample bidirectional Mendelian randomization (MR) analysis was used in this study. The genetic variation of 41 circulating inflammatory cytokines were derived from genome-wide association study (GWAS) data of European ancestry (n = 8293). The corresponding genetic association of functional outcomes following IS were derived from European ancestry GWAS data (n = 6021). RESULTS: Inverse variance weighted (IVW) analysis showed that genetically predicted increased levels of regulation and activation in normal T-cell expression and secretion factor (RANTES/CCL5) and eosinophilic chemotactic factor (EOTAXIN/CCL11) were positively correlated with the increased adverse functional outcomes (modified Rankin Scale [mRS≥3] following IS (OR: 1.40, 95% CI: 1.002-1.96, p = 0.049; OR: 1.33, 95% CI: 1.15-1.54, p = 0.0001). Interleukin 18 (IL-18) level might be the downstream consequence of adverse functional outcomes following IS (ß: -0.09, p = 0.039). Other inflammatory cytokines and functional outcomes following IS did not appear to be causally related. CONCLUSIONS: This study suggests a causality between inflammation and adverse functional outcomes following IS. RANTES (CCL5) and EOTAXIN (CCL11) may be the upstream factors of adverse functional outcomes following IS, while IL-18 may be the downstream effect of adverse functional outcomes following IS. Whether these cytokines can be used to predict or improve adverse functional outcomes after IS requires further researches.
Assuntos
Citocinas , AVC Isquêmico , Humanos , Interleucina-18 , Estudo de Associação Genômica Ampla , Análise da Randomização MendelianaRESUMO
The iron and steel industry (ISI) is a significant source of sulfur dioxide and particulate matter pollution in China. Existing research on regional environmental regulation or ISI emission reduction strategies tends to overlook spillover effects and the enterprise perspective. During the heating season, production limitations in ISI are potential policy measures for achieving structural emission reductions in heavily polluted cities in China's Jing-Jin-Ji and surrounding regions. We adopt a bottom-up modeling approach, incorporating effective production time to describe enterprise behavior and establishing a quantitative trade model based on trade theory. By modeling three types of production restriction policies outlined in policy documents, we evaluate the emission reduction effects of structure-adjustment measures using the example of reduced effective production time for steel-producing enterprises in the air pollution transmission channel in the Beijing-Tianjin-Hebei area. The results indicate the following: (1) Reducing the effective production time of ISI enterprises can help decrease domestic production value and total factor productivity in pollution-intensive industries, including but not limited to ISI. It also leads to reduced emissions of various pollutants in the implementation regions. (2) Due to interprovincial trade and input-output linkages, structural reduction measures in certain regions have implications for almost all other provinces' industrial structures. Differences in initial industrial structures, factor endowments, and geographical locations contribute to varying directions and magnitudes of industrial structural changes. Pollution-intensive industries' share tends to increase higher in less developed regions. (3) Our estimated pollution reduction is smaller compared to the literature evaluating clean air policies in similar regions using top-down strategies. This discrepancy arises because we analyze a single policy tool rather than modeling industry-wide emission fluctuations from the top down. Additionally, our modeling approach allows us to examine dynamic changes in comparative advantages. The increase in production scale for certain industries in policy-affected regions partially offsets the decline in pollution emissions. These findings enhance our understanding of structure-adjustment reduction measures' role and highlight their potential advantages and limitations.
RESUMO
Rosa roxburghii Tratt pomace is rich in insoluble dietary fiber (IDF). This study aimed to investigate the influence of three modification methods on Rosa roxburghii Tratt pomace insoluble dietary fiber (RIDF). The three modified RIDFs, named U-RIDF, C-RIDF, and UC-RIDF, were prepared using ultrasound, cellulase, and a combination of ultrasound and cellulase methods, respectively. The structure, physicochemical characteristics, and functional properties of the raw RIDF and modified RIDF were comparatively analyzed. The results showed that all three modification methods, especially the ultrasound-cellulase combination treatment, increased the soluble dietary fiber (SDF) content of RIDF, while also causing a transition in surface morphology from smooth and dense to wrinkled and loose structures. Compared with the raw RIDF, the modified RIDF, particularly UC-RIDF, displayed significantly improved water-holding capacity (WHC), oil-binding capacity (OHC), and swelling capacity (SC), with increases of 12.0%, 84.7%, and 91.3%, respectively. Additionally, UC-RIDF demonstrated the highest nitrite ion adsorption capacity (NIAC), cholesterol adsorption capacity (CAC), and bile salt adsorption capacity (BSAC). In summary, the combination of ultrasound and cellulase treatment proved to be an efficient approach for modifying IDF from RRTP, with the potential for developing a functional food ingredient.
Assuntos
Fibras na Dieta , Rosa , Fibras na Dieta/análise , Rosa/química , Solubilidade , Celulase/metabolismo , Celulase/química , AdsorçãoRESUMO
BACKGROUND: Pectin extracted by high-speed shearing from passion fruit peel (HSSP) is a potentially excellent wall material for encapsulating curcumin, which has multiple advantages over pectin prepared by heated water extraction. HSSP was used to fabricate complex nanoparticles of zein-sodium caseinate-pectin for encapsulation of curcumin in this study. The influence of heating on the physicochemical properties of the composite nanoparticles was also investigated, as well as the effect of composite nanoparticles on the encapsulation efficiency, antioxidant activity and release characteristics of curcumin. RESULTS: The nanoparticles were formed through electrostatic interactions, hydrogen bonds and hydrophobic interactions between the proteins and HSSP. A temperature of 50 °C was more favorable for generating compact and small-sized nanoparticles, which could effectively improve the encapsulation efficiency and functional properties. Moreover, compared to other pectin used in the study, the nanoparticles prepared with HSSP showed the best functionality with a particle size of 234.28 ± 0.85 nm, encapsulation rate of 90.22 ± 0.54%, free radical scavenging rate of 78.97% and strongest protective capacity in simulated gastric fluid and intestinal release effect. CONCLUSION: Zein-sodium caseinate-HSSP is effective for encapsulating and delivering hydrophobic bioactive substances such as curcumin, which has potential applications in the functional food and pharmaceutical industries. © 2024 Society of Chemical Industry.
Assuntos
Caseínas , Curcumina , Composição de Medicamentos , Frutas , Nanopartículas , Tamanho da Partícula , Passiflora , Pectinas , Zeína , Pectinas/química , Passiflora/química , Zeína/química , Caseínas/química , Curcumina/química , Nanopartículas/química , Frutas/química , Extratos Vegetais/química , Interações Hidrofóbicas e Hidrofílicas , Portadores de Fármacos/química , Antioxidantes/químicaRESUMO
Wound healing is an extremely complex process involving multiple levels of cells and tissues. It is mainly completed through four stages: haemostasis, inflammation, proliferation, and remodelling. When any one of these stages is impaired, it may lead to delayed healing or even transformation into chronic refractory wounds. Diabetes is a kind of common metabolic disease that affects approximately 500 million people worldwide, 25% of whom develop skin ulcers that break down repeatedly and are difficult to heal, making it a growing public health problem. Neutrophils extracellular traps and ferroptosis are new types of programmed cell death identified in recent years and have been found to interact with diabetic wounds. In this paper, the normal wound healing and interfering factors of the diabetic refractory wound were outlined. The mechanism of two kinds of programmed cell death was also described, and the interaction mechanism between different types of programmed cell death and diabetic refractory wounds was discussed.
Assuntos
Diabetes Mellitus , Armadilhas Extracelulares , Ferroptose , Humanos , Armadilhas Extracelulares/metabolismo , Neutrófilos/metabolismo , Diabetes Mellitus/metabolismo , Cicatrização/fisiologiaRESUMO
The conserved endoplasmic reticulum (ER) membrane protein TRAPα (translocon-associated protein, also known as signal sequence receptor 1, SSR1) has been reported to play a critical but unclear role in insulin biosynthesis. TRAPα/SSR1 is one component of a four-protein complex including TRAPß/SSR2, TRAPγ/SSR3, and TRAPδ/SSR4. The TRAP complex topologically has a small exposure on the cytosolic side of the ER via its TRAPγ/SSR3 subunit, whereas TRAPß/SSR2 and TRAPδ/SSR4 function along with TRAPα/SSR1 largely on the luminal side of the ER membrane. Here, we have examined pancreatic ß-cells with deficient expression of either TRAPß/SSR2 or TRAPδ/SSR4, which does not perturb mRNA expression levels of other TRAP subunits, or insulin mRNA. However, deficient protein expression of TRAPß/SSR2 and, to a lesser degree, TRAPδ/SSR4, diminishes the protein levels of other TRAP subunits, concomitant with deficient steady-state levels of proinsulin and insulin. Deficient TRAPß/SSR2 or TRAPδ/SSR4 is not associated with any apparent defect of exocytotic mechanism but rather by a decreased abundance of the proinsulin and insulin that accompanies glucose-stimulated secretion. Amino acid pulse labeling directly establishes that much of the steady-state deficiency of intracellular proinsulin can be accounted for by diminished proinsulin biosynthesis, observed in a pulse-labeling as short as 5 minutes. The proinsulin and insulin levels in TRAPß/SSR2 or TRAPδ/SSR4 null mutant ß-cells are notably recovered upon re-expression of the missing TRAP subunit, accompanying a rebound of proinsulin biosynthesis. Remarkably, overexpression of TRAPα/SSR1 can also suppress defects in ß-cells with diminished expression of TRAPß/SSR2, strongly suggesting that TRAPß/SSR2 is needed to support TRAPα/SSR1 function.
Assuntos
Proteínas de Ligação ao Cálcio/deficiência , Retículo Endoplasmático/metabolismo , Glucose/metabolismo , Insulina/biossíntese , Insulinoma/patologia , Glicoproteínas de Membrana/deficiência , Proinsulina/biossíntese , Receptores Citoplasmáticos e Nucleares/deficiência , Receptores de Peptídeos/deficiência , Animais , Células Cultivadas , Células Secretoras de Insulina/citologia , Insulinoma/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , RatosRESUMO
BACKGROUND: Parkinson's disease (PD) and restless legs syndrome/Willis-Ekbom disease (RLS/WED) are both common movement disorders. Based on their clinical overlap, association studies of PD and RLS/WED have been conducted for many years. OBJECTIVE: To investigate whether or not the genetic risk factor of PD was also associated with RLS/WED. SUBJECTS AND METHODS: We included 102 idiopathic RLS/WED patients and 189 matched controls from southeast China. The clinical data included the International Restless Legs Syndrome Study Group Rating Scale, the subtypes of RLS/WED symptoms (painful or other discomfort), the comorbidities, the pregnancy history of female patients, the Hamilton Depression Scale (HAMD), and the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Risk gene analysis between RLS/WED and control groups including 21 SNPs (single nucleotide polymorphisms) was conducted. Genotyping was done by Sanger sequencing. RESULTS: We found that rs4273468 polymorphism of BST1 gene increased the risk of idiopathic RLS/WED patients in southeastern Chinese population (P = <0.001, OR = 2.85, p = 0.019 after Bonferroni correction). Moreover, the haplotype of G-G (rs4698412-rs4273468) was significantly associated with Chinese RLS/WED patients (p = <0.001). CONCLUSION: BST1 may contribute to the development of RLS/WED. Further studies on larger cohorts are needed to confirm these findings.
Assuntos
ADP-Ribosil Ciclase/genética , Antígenos CD/genética , Síndrome das Pernas Inquietas/genética , Adulto , China , Estudos de Coortes , Feminino , Proteínas Ligadas por GPI/genética , Humanos , Masculino , Polimorfismo GenéticoRESUMO
Increasing evidence indicates that many small secretory preproteins can undergo post-translational translocation across the membrane of the endoplasmic reticulum. Although the cellular machinery involved in post-translational translocation of small secretory preproteins has begun to be elucidated, the intrinsic signals contained within these small secretory preproteins that contribute to their efficient post-translational translocation remain unknown. Here, we analyzed the eukaryotic secretory proteome and discovered the small secretory preproteins tend to have a higher probability to harbor the positive charge in the n-region of the signal peptide (SP). Eliminating the positive charge of the n-region blocked post-translational translocation of newly synthesized preproteins and selectively impaired translocation efficiency of small secretory preproteins. The pathophysiological significance of the positive charge in the n-region of SP was underscored by recently identified preproinsulin SP mutations that impair translocation of preproinsulin and cause maturity onset diabetes of youth (MODY). Remarkably, we have found that slowing the polypeptide elongation rate of small secretory preproteins could alleviate the translocation defect caused by loss of the n-region positive charge of the signal peptide. Together, these data reveal not only a previously unrecognized role of the n-region's positive charge in ensuring efficient post-translational translocation of small secretory preproteins, but they also highlight the molecular contribution of defects in this process to the pathogenesis of genetic disorders such as MODY.
Assuntos
Insulina/química , Insulina/metabolismo , Precursores de Proteínas/química , Precursores de Proteínas/metabolismo , Sinais Direcionadores de Proteínas , Motivos de Aminoácidos , Sequência de Aminoácidos , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Humanos , Insulina/genética , Dados de Sequência Molecular , Precursores de Proteínas/genética , Processamento de Proteína Pós-Traducional , Transporte Proteico , Alinhamento de SequênciaRESUMO
BACKGROUND: POEMS syndrome, a rare systemic disease, is characterized by 5 components: Peripheral neuropathy, Organomegaly, Endocrinopathy, M protein elevation, and Skin changes. It usually presents with multiplex endocrine manifestations and is easily misdiagnosed and incorrectly treated. CASE PRESENTATION: We report herein a case of POEMS syndrome that initially presented as hyperpigmentation and severe pitting edema of the lower extremities. Throughout the patient's multiple hospitalizations for more than one year, he was treated erroneously for Addison's disease and primary hypothyroidism due to the presence of limb numbness and weight loss. In addition, he was misdiagnosed with diabetic peripheral neuropathy due to a history of type 2 diabetes mellitus. CONCLUSION: Endocrinopathy is a critical feature of POEMS syndrome but its mechanisms are still poorly understood. The most common endocrine abnormality is hypogonadism, and the second is adrenal insufficiency, followed by hypothyroidism and subclinical hypothyroidism, then diabetes or glucose intolerance. In cases of the coexistence of endocrinopathy and unexplained peripheral neuropathy, especially in multisystem disorders, POEMS syndrome should be considered. Endocrine evaluation including thyrotropin, free thyroxine, fasting glucose, gonadal hormones, prolactin, cortisol, ACTH, and calcium should be assessed. The purpose of the current report was to provide increased awareness of POEMS syndrome.
Assuntos
Erros de Diagnóstico , Doenças do Sistema Endócrino/diagnóstico , Síndrome POEMS/diagnóstico , Doenças do Sistema Endócrino/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome POEMS/complicações , PrognósticoRESUMO
BACKGROUNDS: Several recent case-control studies have suggested some candidate genes being responsible for causing the restless legs syndrome (RLS). However, the association between those genes and the risk for RLS among the Asian population has not been well investigated. OBJECTIVES: The aim of the study was to investigate the genetic risk factors of RLS among the Chinese Population. METHODS: A total of 158 RLS patients and 229 controls were recruited and the diagnosis of RLS was based on the criteria of International RLS Study Group. Polymer chain reaction and sequencing were used to detect 14 single nucleotide polymorphisms (SNPs) in 9 genetic loci (heme oxygenase 1 [HMOX1], HMOX2, vitamin D3 [1, 25-dihydroxyvitamin D3] receptor gene [VDR], interleukin 17A [IL17A], IL1B, NOS1, alcohol-dehydrogenase [ADH1B], gamma-aminobutyrate acid receptors[GABRR3] and GABRA4). RESULTS: Among 14 selected SNPs, the frequency of IL1B rs1143634C allelic variant was lower in RLS patients than that in controls. Moreover, after adjustment for age and sex, rs731236 of VDR were found associated with increased risk of RLS in the dominant model. However, none of those results survived Bonferroni correction. The effects of HMOX1 and HMOX2 gene on developing RLS were not seen after the inclusion of RLS patients with a low ferritin level. CONCLUSIONS: Our study failed to replicate the association between 9 candidate genetic loci (HMOX1, HMOX2, VDR, IL17A, IL1B, NOS1, ADH1B, GABRR3 and GABRA4) and RLS in the Chinese population.
Assuntos
Polimorfismo de Nucleotídeo Único/genética , Síndrome das Pernas Inquietas/genética , Adulto , Povo Asiático/genética , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The cryptic plasmid is essential for Chlamydia muridarum dissemination from the genital tract to the gastrointestinal (GI) tract. Following intravaginal inoculation, a C. muridarum strain deficient in plasmid-encoded pGP3 or pGP4 but not pGP5, pGP7, or pGP8 failed to spread to the mouse gastrointestinal tract, although mice infected with these strains developed productive genital tract infections. pGP3- or pGP4-deficient strains also failed to colonize the gastrointestinal tract when delivered intragastrically. pGP4 regulates pGP3, while pGP3 does not affect pGP4 expression, indicating that pGP3 is critical for C. muridarum colonization of the gastrointestinal tract. Mutants deficient in GlgA, a chromosome-encoded protein regulated by pGP4, also consistently colonized the mouse gastrointestinal tract. Interestingly, C. muridarum colonization of the gastrointestinal tract positively correlated with pathogenicity in the upper genital tract. pGP3-deficient C. muridarum strains did not induce hydrosalpinx or spread to the GI tract even when delivered to the oviduct by intrabursal inoculation. Thus, the current study not only has revealed that pGP3 is a novel chlamydial colonization factor in the gastrointestinal tract but also has laid a foundation for investigating the significance of gastrointestinal Chlamydia.
Assuntos
Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Infecções por Chlamydia/microbiologia , Chlamydia muridarum/genética , Chlamydia muridarum/patogenicidade , Trato Gastrointestinal/microbiologia , Infecções do Sistema Genital/microbiologia , Fatores de Virulência/genética , Animais , Linhagem Celular Tumoral , Feminino , Genitália/microbiologia , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Oviductos/microbiologia , Plasmídeos/genéticaRESUMO
Intravaginal infection with Chlamydia muridarum in mice can ascend to the upper genital tract, resulting in hydrosalpinx, a pathological hallmark for tubal infertility in women infected with C. trachomatis. Here, we utilized in vivo imaging of C. muridarum infection in mice following an intravaginal inoculation and confirmed the rapid ascent of the chlamydial organisms from the lower to upper genital tracts. Unexpectedly, the C. muridarum-derived signal was still detectable in the abdominal area 100 days after inoculation. Ex vivo imaging of the mouse organs revealed that the long-lasting presence of the chlamydial signal was restricted to the gastrointestinal (GI) tract, which was validated by directly measuring the chlamydial live organisms and genomes in the same organs. The C. muridarum organisms spreading from the genital to the GI tracts were detected in different mouse strains and appeared to be independent of oral or rectal routes. Mice prevented from orally taking up excretions also developed the long-lasting GI tract infection. Inoculation of C. muridarum directly into the upper genital tract, which resulted in a delayed vaginal shedding of live organisms, accelerated the chlamydial spreading to the GI tract. Thus, we have demonstrated that the genital tract chlamydial organisms may use a systemic route to spread to and establish a long-lasting infection in the GI tract. The significance of the chlamydial spreading from the genital to GI tracts is discussed.
Assuntos
Infecções por Chlamydia/patologia , Trato Gastrointestinal/microbiologia , Animais , Chlamydia muridarum , Feminino , Imunofluorescência , Camundongos , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Hydrosalpinx induction in mice by Chlamydia muridarum infection, a model that has been used to study C. trachomatis pathogenesis in women, is known to depend on the cryptic plasmid that encodes eight genes designated pgp1 to pgp8. To identify the plasmid-encoded pathogenic determinants, we evaluated C. muridarum transformants deficient in the plasmid-borne gene pgp3, -4, or -7 for induction of hydrosalpinx. C. muridarum transformants with an in-frame deletion of either pgp3 or -4 but not -7 failed to induce hydrosalpinx. The deletion mutant phenotype was reproduced by using transformants with premature termination codon insertions in the corresponding pgp genes (to minimize polar effects inherent in the deletion mutants). Pgp4 is known to regulate pgp3 expression, while lack of Pgp3 does not significantly affect Pgp4 function. Thus, we conclude that Pgp3 is an effector virulence factor and that lack of Pgp3 may be responsible for the attenuation in C. muridarum pathogenicity described above. This attenuated pathogenicity was further correlated with a rapid decrease in chlamydial survival in the lower genital tract and reduced ascension to the upper genital tract in mice infected with C. muridarum deficient in Pgp3 but not Pgp7. The Pgp3-deficient C. muridarum organisms were also less invasive when delivered directly to the oviduct on day 7 after inoculation. These observations demonstrate that plasmid-encoded Pgp3 is required for C. muridarum survival in the mouse genital tract and represents a major virulence factor in C. muridarum pathogenesis in mice.
Assuntos
Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Infecções por Chlamydia/patologia , Chlamydia muridarum/patogenicidade , Doenças das Tubas Uterinas/microbiologia , Doenças das Tubas Uterinas/patologia , Plasmídeos , Fatores de Virulência/metabolismo , Animais , Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Infecções por Chlamydia/microbiologia , Chlamydia muridarum/genética , Modelos Animais de Doenças , Feminino , Células HeLa , Humanos , Camundongos Endogâmicos C3H , Virulência , Fatores de Virulência/genéticaRESUMO
Acute liver failure is mainly caused by the overdose of acetaminophen (APAP) globally. The traditional Chinese medicinal (TCM) herb, Taraxacum, contains Taraxasterol (TAX) as one of the active components. It is a pentacyclic-triterpene compound isolated from this herb. Present work aimed to investigate the in vitro and in vivo protection effect of TAX in APAP-induced acute liver injury, and determine the potential regulatory mechamisms. The liver injury caused by APAP is attenuated by TAX, as shown by the alleviated pathological changes of mice liver and the reduced serological indexes. TAX evidently controlled the oxidative stress and liver inflammation in mice liver. In vitro studies found that TAX reversed the decrease in LO2 cell viability induced by APAP, and protected LO2 cells from APAP-induced injury. In addition, TAX reduced the secretion of inflammatory factors in RAW264.7 macrophages as induced via APAP. Besides, TAX inhibited oxidative stress in LO2 cells induced by APAP in vitro. Noteworthy, TAX enhanced protein and mRNA expressions of Nrf2 in vivo, and knockdown of Nrf2 by using adeno-associated virus (AAV)-Nrf2-KO attenuated inhibitory impact of TAX in acute liver injury induced by APAP. Also, AAV-NRF2-KO weakened the inhibitory impact of TAX against APAP-triggered liver inflammation and oxidative stress of mice liver. Moreover, TAX activated the Nrf2 signaling in APAP-induced LO2 cells, as shown by the increased nuclear Nrf2 expression together with downstream HO-1 expression in vitro. Inhibition of Nrf2 by using ML-385, anNrf2inhibitor, weakened the inhibitory effect of TAX against APAP-induced oxidative stress and cell injury in LO2 cells. Moreover, inhibition of Nrf2 attenuated anti-inflammatory effect of TAX for APAP-induced RAW264.7 cells. Collectively, TAX could protect against APAP-triggered hepatotoxicitythrough suppression of liver oxidative stress and inflammatory response in mice.
Assuntos
Acetaminofen , Doença Hepática Induzida por Substâncias e Drogas , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Animais , Estresse Oxidativo/efeitos dos fármacos , Camundongos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Masculino , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/metabolismo , Fígado/imunologia , Triterpenos/farmacologia , Triterpenos/uso terapêutico , Células RAW 264.7 , Camundongos Endogâmicos C57BL , Humanos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Linhagem Celular , EsteróisRESUMO
Head and neck cancer ranks as the sixth most prevalent malignancy, constituting 5 % of all cancer cases. Its inconspicuous onset often leads to advanced stage diagnoses, prompting the need for early detection to enhance patient prognosis. Currently, research into early diagnostic markers relies predominantly on genomics, proteomics, transcriptomics, and other methods, which, unfortunately, necessitate tumor tissue homogenization, resulting in the loss of temporal and spatial information. Emerging as a recent addition to the omics toolkit, spatial metabolomics stands out. This method conducts in situ mass spectrometry analyses on fresh tissue specimens while effectively preserving their spatiotemporal information. The utilization of spatial metabolomics in life science research offers distinct advantages. This article comprehensively reviews the progress of spatial metabolomics in head and neck cancer research, encompassing insights into cancer cell metabolic reprogramming. Various mass spectrometry imaging techniques, such as secondary ion mass spectrometry, stroma-assisted laser desorption/ionization, and desorption electrospray ionization, enable in situ metabolite analysis for head and neck cancer. Finally, significant emphasis is placed on the application of presently available techniques for early diagnosis, margin assessment, and prognosis of head and neck cancer.
Assuntos
Neoplasias de Cabeça e Pescoço , Metabolômica , Humanos , Espectrometria de Massas , Metabolômica/métodos , Proteômica , Genômica , Neoplasias de Cabeça e Pescoço/diagnóstico , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodosRESUMO
Molecular docking and activity evaluation screened the dipeptide module GP with low xanthine oxidase (XOD) inhibitory activity and modules KE and KN with high activity, and identified them as low- and high-contribution modules, respectively. We hypothesized the substitution of low-contribution modules in peptides with high contributions would boost their XOD inhibitory activity. In the XOD inhibitory peptide GPAGPR, substitution of GP with both KE and KN led to enhanced affinity between the peptides and XOD. They also increased XOD inhibitory activity (26.4% and 10.3%) and decreased cellular uric acid concentrations (28.0% and 10.4%). RNA sequencing indicated that these improvements were attributable to the inhibition of uric acid biosynthesis. In addition, module substitution increased the angiotensin-converting enzyme inhibitory activity of GILRP and GAAGGAF by 84.8% and 76.5%. This study revealed that module substitution is a feasible strategy to boost peptide activity, and provided information for the optimization of hydrolysate preparation conditions.
Assuntos
Peptidil Dipeptidase A , Xantina Oxidase , Simulação de Acoplamento Molecular , Ácido Úrico , Peptídeos/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/químicaRESUMO
BACKGROUND: Fulminant type 1 diabetes mellitus (FT1DM) that occurs during pregnancy or the perinatal period is known as pregnancy-related FT1DM (PF), always without history of abnormal glucose metabolism. Here, we present four patients who developed FT1DM during treatment but were first diagnosed with gestational diabetes mellitus (GDM). CASE SUMMARY: The clinical data of four patients with GDM combined with FT1DM admitted to our hospital between July 2018 and April 2021 were collected, and the patients and their infants were followed up. All patients were diagnosed with GDM during the second trimester and were treated. The blood glucose level elevated suddenly during the third trimester and then were diagnosed with FT1DM. Two patients had an insulin allergy, and two had symptoms of upper respiratory tract infection before onset. One patient developed ketoacidosis, and three developed ketosis. Two patients had cesarean section deliveries, and two had vaginal deliveries. The growth and development of the infants were normal. C-peptide levels were lower than those at onset, suggesting progressive impairment of islet function. The frequencies of the DRB1 09:01, DQB1 03: 03, DQA1 03:02, DPA1 01:03, DPA1 02:02, DPB1 05:01, DRB4 01:03, G 01:01, and G 01:04 human leukocyte antigen (HLA)-G alleles were high in the present study. CONCLUSION: In comparison with pregnancy-associated FT1DM (PF), patients with GDM combined with FT1DM had an older age of onset, higher body mass index, slower onset, fewer prodromal symptoms, and less acidosis. The pathogenesis may be due to various factors affecting the already fragile ß-cells of GDM patients with genetically susceptible class II HLA genotypes. We speculate that GDM combined with FT1DM during pregnancy, referred to as "double diabetes," is a subtype of PF with its own unique characteristics that should be investigated further.
RESUMO
The changing global climate has significantly impacted the spread of plant pests. The cassava mealybug (Phenacoccus manihoti) is among the most dangerous quarantine pests affecting cassavas worldwide, causing substantial losses in agricultural production and food security across several regions. Although China is currently free of the cassava mealybug, its proximity to affected countries and extensive trade with these regions necessitate a detailed understanding of the pest's distribution pattern and dynamic ecological niche changes. Using the Biomod2 model, we selected two historical climate scenarios and two future climate scenarios (SSP1-2.6 and SSP5-8.5) to investigate the distribution patterns, potential habitats, distribution centers, and dynamic ecological niches of cassava mealybugs in China. Key environmental variables influencing the distribution were identified, including bio4, bio8, bio12, bio18, and bio19. The potential habitat of cassava mealybugs is mainly located in several provinces in southern China. In the future, the suitable habitat is projected to expand slightly under the influence of climate change, maintaining the overall trend, but the distribution center of suitable areas will shift northward. Dynamic ecological niche prediction results indicate the potential for further expansion; however, the ecological niches may be unequal and dissimilar in the invaded areas. The predictions could serve as a valuable reference for early warning systems and management strategies to control the introduction of cassava mealybugs.