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1.
J Nat Prod ; 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36607819

RESUMO

Lasiodiplodiapyrones A and B (1 and 2), two new preussomerin derivatives, possessing an unexpected 6-methyl-4H-furo[3,2-c]pyran-4-one moiety and a highly functionalized conjoint and complicated polycyclic ring system, along with two known congeners (3 and 4), were isolated from the fungus Lasiodiplodia pseudotheobromae. Their structures including absolute configurations were determined by spectroscopic analyses, Mosher's method, and ECD calculations. A biosynthetic pathway was proposed to explain the origin of lasiodiplodiapyrones A and B as well as their relationship with preussomerins. Compounds 1-4 showed suppressive effects on the production of NO with IC50 values of 4.8 ± 0.3, 8.5 ± 1.1, 5.9 ± 0.8, and 12.8 ± 1.3 µM, respectively.

2.
Signal Transduct Target Ther ; 8(1): 20, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36596779

RESUMO

An ongoing randomized, double-blind, controlled phase 2 trial was conducted to evaluate the safety and immunogenicity of a mosaic-type recombinant vaccine candidate, named NVSI-06-09, as a booster dose in subjects aged 18 years and older from the United Arab Emirates (UAE), who had administered two or three doses of inactivated vaccine BBIBP-CorV at least 6 months prior to enrollment. The participants were randomly assigned with 1:1 to receive a booster dose of NVSI-06-09 or BBIBP-CorV. The primary outcomes were immunogenicity and safety against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant, and the exploratory outcome was cross-immunogenicity against other circulating strains. Between May 25 and 30, 2022, 516 adults received booster vaccination with 260 in NVSI-06-09 group and 256 in BBIBP-CorV group. Interim results showed a similar safety profile between two booster groups, with low incidence of adverse reactions of grade 1 or 2. For immunogenicity, by day 14 post-booster, the fold rises in neutralizing antibody geometric mean titers (GMTs) from baseline elicited by NVSI-06-09 were remarkably higher than those by BBIBP-CorV against the prototype strain (19.67 vs 4.47-fold), Omicron BA.1.1 (42.35 vs 3.78-fold), BA.2 (25.09 vs 2.91-fold), BA.4 (22.42 vs 2.69-fold), and BA.5 variants (27.06 vs 4.73-fold). Similarly, the neutralizing GMTs boosted by NVSI-06-09 against Beta and Delta variants were also 6.60-fold and 7.17-fold higher than those by BBIBP-CorV. Our findings indicated that a booster dose of NVSI-06-09 was well-tolerated and elicited broad-spectrum neutralizing responses against divergent SARS-CoV-2 variants, including Omicron and its sub-lineages.


Assuntos
COVID-19 , Vacinas , Adulto , Humanos , SARS-CoV-2 , COVID-19/prevenção & controle
3.
Nutrients ; 15(1)2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36615906

RESUMO

Eccentric contraction can easily cause muscle damage and an inflammatory response, which reduces the efficiency of muscle contraction. Resveratrol causes anti-inflammatory effects in muscles, accelerates muscle repair, and promotes exercise performance after contusion recovery. However, whether resveratrol provides the same benefits for sports injuries caused by eccentric contraction is unknown. Thus, we explored the effects of resveratrol on inflammation and energy metabolism. In this study, mice were divided into four groups: a control group, an exercise group (EX), an exercise with low-dose resveratrol group (EX + RES25), and an exercise with high-dose resveratrol group (EX + RES150). The results of an exhaustion test showed that the time before exhaustion of the EX + RES150 group was greater than that of the EX group. Tumour necrosis factor-α (Tnfα) mRNA expression was lower in the EX + RES150 group than in the EX group. The energy utilisation of the EX + RES150 group was greater than that of the EX + RES25 group in different muscles. High-dose resveratrol intervention decreased Tnfα mRNA expression and enhanced the mRNA expressions of sirtuin 1, glucose transporter 4, AMP-activated protein kinase α1, and AMP-activated protein kinase α2 in muscles. These results revealed that high-dose resveratrol supplementation can reduce inflammation and oxidation and improve energy utilisation during short-duration high-intensity exercise.


Assuntos
Músculo Esquelético , Miosite , Camundongos , Animais , Resveratrol/farmacologia , Resveratrol/metabolismo , Músculo Esquelético/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Miosite/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Contração Muscular/fisiologia , RNA Mensageiro/metabolismo
4.
Theranostics ; 13(1): 125-147, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36593971

RESUMO

Coronavirus disease 2019 (COVID-19), an infectious disease caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has high incidence rates, spreads rapidly, and has caused more than 6.5 million deaths globally to date. Currently, several drugs have been used in the clinical treatment of COVID-19, including antivirals (e.g., molnupiravir, baricitinib, and remdesivir), monoclonal antibodies (e.g., etesevimab and tocilizumab), protease inhibitors (e.g., paxlovid), and glucocorticoids (e.g., dexamethasone). Increasing evidence suggests that circulating microRNAs (miRNAs) are important regulators of viral infection and antiviral immune responses, including the biological processes involved in regulating COVID-19 infection and subsequent complications. During viral infection, both viral genes and host cytokines regulate transcriptional and posttranscriptional steps affecting viral replication. Virus-encoded miRNAs are a component of the immune evasion repertoire and function by directly targeting immune functions. Moreover, several host circulating miRNAs can contribute to viral immune escape and play an antiviral role by not only promoting nonstructural protein (nsp) 10 expression in SARS coronavirus, but among others inhibiting NOD-like receptor pyrin domain-containing (NLRP) 3 and IL-1ß transcription. Consequently, understanding the expression and mechanism of action of circulating miRNAs during SARS-CoV-2 infection will provide unexpected insights into circulating miRNA-based studies. In this review, we examined the recent progress of circulating miRNAs in the regulation of severe inflammatory response, immune dysfunction, and thrombosis caused by SARS-CoV-2 infection, discussed the mechanisms of action, and highlighted the therapeutic challenges involving miRNA and future research directions in the treatment of COVID-19.


Assuntos
COVID-19 , MicroRNA Circulante , MicroRNAs , Humanos , Antivirais/farmacologia , COVID-19/genética , MicroRNAs/genética , MicroRNAs/metabolismo , SARS-CoV-2
5.
Chin Med ; 18(1): 5, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36627656

RESUMO

BACKGROUND: Amorpha-4,11-diene synthase (ADS) is a key enzyme in the artemisinin biosynthetic pathway. ADS promotes the first step of artemisinin synthesis by cyclizing faresyl pyrophosphate to synthesize the sesquiterpene product amorpha-4,11-diene. Thanks to the continuous improvement of genomic information, its evolutionary trace can be analyzed in a genome view. METHODS: Phylogenetic analysis was used to identify ADS-like genes in other Asteraceae. Gene structure and motif analysis was used to analyze the structural similarity of these identified genes. Heterologous expression and GC-MS analysis were performed to determine whether the functions of ADS and Cna4666 are consistent. Validation of ADS genes evolutionary trajectories was achieved by selective pressure and synteny analysis. RESULT: In this study, we extracted 8 ADS genes from the Artemisia annua L. genome annotation and 121 ADS similar genes from the genomes of Artemisia annua L. and other plants in the Asteraceae, and further exploring their evolutionary relationship. Phylogenetic analysis showed that the genes most closely related to ADS genes were found in the genome of Chrysanthemum nankingense. Among them, the gene structure and motif composition of Cna4666 is very similar to ADS, we wondered whether it has the potential to synthesize amorpha-4,11-diene. Therefore, we extracted the products of recombinant p0_ADS.1 and Cna4666 proteins by HS-SPME combined with GC-MS analysis, the results indicate that Cna4666 is an α-bisabolol synthase, which cannot synthesize amorpha-4,11-diene. Through synteny analysis, we did not find collinear blocks of ADS genes in the Helianthus annuus and C. nankingense genomes. Furthermore, Ka/Ks ratios indicated that the evolution of ADS genes from their similar genes principally underwent purifying selection, and there was a strong positive selection between ADS genes. CONCLUSIONS: This study proved that ADS is a multi-copy gene in Artemisia annua L., and they are not widely distributed in Asteraceae. The data will increase our understanding of the evolutionary selection pressure on ADS genes. The results suggest that ADS genes are subject to strong positive selection internally, and it is possible that they are a recently evolved gene in the Artemisia.

6.
Neurol Res ; : 1-9, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36692889

RESUMO

BACKGROUND: Observational studies showed renal function had associations with Alzheimer's disease (AD), Parkinson's disease (PD), Lewy body dementia (LBD) and multiple sclerosis (MS). However, it is unknown whether these associations are causal. METHODS: We use a two-sample Mendelian randomization (MR) analysis to investigate causal relationships between renal function and 6 neurodegenerative diseases (NDDs): AD (including familial AD), PD, LBD, frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and MS. Blood urea nitrogen (BUN), chronic kidney disease (CKD) and estimated glomerular filtration rate (eGFR) were used to measure renal function. The inverse-variance weighted (IVW) was the predominant estimation method. The results were further validated using sensitivity analysis (i.e. MR Egger regression, Cochran Q statistic of IVW, and leave-one-out method). RESULTS: There was no indication of any causative relationship of BUN, CKD, or eGFR with AD, familial AD, PD, LBD, FTD and ALS (all P values >0.05). The IVW analysis demonstrated a causal relationship between eGFR and MS [odds ratio (OR), 4.89; 95% confidence interval (CI), 1.43 to 16.71; P = 0.01] that was not verified in the MR-Egger and weighted median (all P values >0.05). However, no causal association of MS with BUN (OR, 0.91; 95% CI, 0.40-2.07; P = 0.82) and CKD (OR,1.04; 95% CI, 0.88-1.23; P = 0.66) was found. There was no single SNP that affects the overall trend. CONCLUSIONS: Our study showed that reduced eGFR was related to MS. The value of this study is that it provides a direction for further research on the relationship between reduced eGFR and MS.

7.
J Dent Sci ; 18(1): 129-134, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36643254

RESUMO

Background/purpose: Different moisture condition may affect the adhesion between obturation materials and root canal walls, thus further affect the quality of root canal obturation. The aim of this study was to evaluate the influence of dentin moisture conditions after different root canal drying protocols on the push-out strength of bioceramic root canal sealer. Materials and methods: Twenty root canals from extracted human decoronated premolars were prepared in vitro to #30/0.09 taper and assigned to 4 moisture condition groups after using different root canal drying protocols: normal moisture (paper point) group: the canals were blot dried with paper points until the last one appeared dry. Ethanol dry group: the canals were dried with paper points followed by dehydration with 95% ethanol. Isopropanol dry group: the canals were dried with paper points followed by dehydration with 70% isopropanol. Complete dry group: the canals were dried in an air-blowing thermostatic oven for at least 6 h until there was no change in weight at an interval of 1 h. After drying, the canals were obturated with bioceramic sealer iRoot SP. Then, each root was sectioned into eight slices with 1-mm-thick using a diamond saw (40 slices each group). The push-out strength was tested for each slice between the sealer and dentin wall using a universal testing machine at a crosshead speed of 0.5 mm/min, and failure modes were recorded. Two-way analysis of variance and Tukey test were used to analyze the push-out strength. Logarithmic linear regression analysis was used to compare the failure modes. Results: Push-out strength was statistically different in different moisture groups (P < 0.05). After drying using paper point, iRoot SP specimens showed the highest push-out strength (2.04 ± 0.03 MPa), followed by 95% ethanol, 70% isopropanol. The lowest push-out strength (0.68 ± 0.04 MPa) was observed under complete dry. For the failure modes, the majority were cohesive failures in the coronal and middle thirds of the root; while in the apical third, mixed failure was common. Conclusion: Different drying protocols influenced the push-out strength between bioceramic sealer and canal wall.

8.
Water Res ; 230: 119534, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36628867

RESUMO

The surface reactivity of iron (hydr)oxides plays a crucial role in controlling their interfacial reactions, for which various surface complexation models have been developed. The diversity of mineralogical properties of iron (hydr)oxides has resulted in a redundancy of model parameters, which hampers the modeling of iron (hydr)oxides in soils and sediments, where goethite, hematite and ferrihydrite dominate the iron (hydr)oxide mass fraction. To capture their combined surface reactivity, optimized generic protonation parameters of the Charge Distribution-Multisite Complexation (CD-MUSIC) extended-Stern-Gouy-Chapman (eSGC) model were derived by reanalyzing literature datasets and tested with some newly synthesized iron (hydr)oxides. It was observed that the proton and monovalent ion affinity constants of the different iron (hydr)oxides were located in a narrow range. For the singly- and triply-coordinated hydroxyl sites the obtained generic log(affinity constants) were 8.3 and 11.7 for the protonation reaction and -0.5 for the reaction with the monovalent background ions. Their combination with fixed site densities of singly-/triply-coordinated hydroxyl sites of 3.45/2.70, 5.00/2.50, and 5.80/1.40 sites/nm2 for goethite, hematite, and ferrihydrite, respectively, provided good results. The Stern layer capacitances of the inner and outer Stern layers were set equal and could be acquired by an empirical correlation with the sample specific surface area (SSA). The CD-MUSIC-eSGC model with the generic model parameters enables good quality predictions of the proton reactivity of iron (hydr)oxides in 1:1 electrolyte solutions regardless of the sample heterogeneity. The advantages of the generic CD-MUSIC-eSGC model are twofold: (1) protonation of iron (hydr)oxides can be described without making use of spectroscopic measurements and proton titrations, and (2) the model calculations are greatly simplified.


Assuntos
Ferro , Música , Óxidos , Prótons , Adsorção , Compostos Férricos/química , Minerais
9.
Respir Med ; 206: 107068, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36495788

RESUMO

BACKGROUND: Checklists are usually employed to assess the inhalation techniques in patients, but partial techniques are difficult to evaluate visually. This study aimed to assess the checklist validity and an agreement between checklists and an aerosol inhalation monitor (AIM) assessments. METHODS: This study used a checklist and an AIM to evaluate the participants' inhalation techniques with a pressurized metered-dose inhaler (MDI) and two dry powder inhalers (DPIs). The kappa (κ) coefficient, prevalence-adjusted and bias-adjusted κ (PABAK), sensitivity, specificity, positive predictive value, and negative predictive value were all calculated to determine the agreement between the checklist and AIM in an MDI and DPIs with different inhalation technique steps. RESULTS: The checklist and AIM exhibited poor agreement in the MDI for actuation and inhalation time, and a moderate agreement for inspiratory flow. The fair agreement was observed in DPIs for inspiratory flow between the checklist and AIM. The steps of holding breath in MDI and DPIs were highly correlated between both assessments. The lowest accuracy evaluated with an AIM was found in the step of actuation and inhalation time in the MDI and in the inspiratory flow step in DPIs. CONCLUSION: The checklist tended to overestimate the accuracy of critical techniques including the actuation and inhalation time in MDIs and the inspiratory flow in DPIs. Thus, the AIM device can be used as an objective auxiliary tool to assess and quantify the specific steps of inhalation technique for the users with MDI and DPIs.


Assuntos
Lista de Checagem , Nebulizadores e Vaporizadores , Humanos , Inaladores Dosimetrados , Administração por Inalação , Inaladores de Pó Seco , Aerossóis
10.
J Org Chem ; 88(1): 690-700, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36485009

RESUMO

A variety of tetrahydro-5H-indolo[2,3-b]quinolines were prepared in 40-97% yields through a copper(II)-catalyzed cascade reaction of aza-o-quinone methides generated in situ from 2-(chloromethyl)anilines and indoles. Experimental results showed that the reaction underwent double 1,4-additions and sequential intramolecular cyclization. The present method features broad substrate scope, good functional group tolerance, and easy gram scalable preparation of indolo[2,3-b]quinolines.


Assuntos
Indóis , Quinolinas , Indóis/química , Estrutura Molecular , Cobre/química , Quinolinas/química , Catálise
11.
Chem Commun (Camb) ; 59(3): 270-281, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36504223

RESUMO

Characterization of proteomes aims to comprehensively characterize proteins in cells or tissues via two main strategies: (1) bottom-up strategy based on the separation and identification of enzymatic peptides; (2) top-down strategy based on the separation and identification of intact proteins. However, it is challenged by the high complexity of proteomes. Consequently, the improvements in peptide and protein separation technologies for simplifying the sample should be critical. In this feature article, separation columns for peptide and protein separation were introduced, and peptide separation technologies for bottom-up proteomic analysis as well as protein separation technologies for top-down proteomic analysis were summarized. The achievement, recent development, limitation and future trends are discussed. Besides, the outlook on challenges and future directions of chromatographic separation in the field of proteomics was also presented.


Assuntos
Proteoma , Proteômica , Proteômica/métodos , Peptídeos/química
12.
J Gastroenterol Hepatol ; 37(2): 284-290, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34547818

RESUMO

BACKGROUND AND AIM: Immune checkpoint inhibitors (ICIs) have shown promise in treating a variety of cancers. Their increased use coincides with increased incidence of immunotherapy-mediated colitis (IMC), a common adverse effect. Optimal strategy for endoscopic evaluation of IMC (full colonoscopy or flexible sigmoidoscopy) is not well-defined. METHODS: Retrospective review of all patients at City of Hope referred to gastroenterology for evaluation of IMC due to gastrointestinal symptoms was performed. Patients with an existing histologic diagnosis of IMC established at an outside hospital or a diagnosis of infectious or chronic colitis were excluded. RESULTS: We identified 51 symptomatic patients on ICIs prompting evaluation for IMC with colonoscopy (47/51) or flexible sigmoidoscopy (4/51). All distal rectosigmoid biopsies during flexible sigmoidoscopy demonstrated histologic evidence of IMC. In full colonoscopy, IMC was either present in all segments of colon simultaneously (35/47) or absent from all segments (12/47). No isolated proximal colonic biopsies demonstrated IMC. Endoscopically normal mucosa demonstrated histologic evidence of IMC up to 68.6% of the time. Endoscopically abnormal right, transverse, and left colon had low sensitivity (35.3%, 34.3%, and 41.7%, respectively) and high specificity (100.0%, 100.0%, and 91.7%, respectively) for histological presence of IMC. CONCLUSIONS: Distal colon biopsies in patients on ICI therapy with diarrhea and suspected IMC were sufficient for diagnosing IMC in our cohort. Further, we found histologic evidence of IMC in biopsies taken from normal-appearing mucosa in a number of patients, suggesting that a normal endoscopic appearance does not preclude the presence of IMC and biopsies should be taken from both normal and abnormal-appearing mucosa.


Assuntos
Colite , Imunoterapia , Sigmoidoscopia , Colite/diagnóstico , Estudos Transversais , Humanos , Imunoterapia/efeitos adversos , Estudos Retrospectivos , Sensibilidade e Especificidade
13.
Arch Gerontol Geriatr ; 106: 104881, 2022 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-36470181

RESUMO

BACKGROUND: Acute cholecystitis (AC) is a life-threatening infectious/inflammatory disease in older patients. This study aimed to investigate the safety and optimal timing of surgery in patients aged ≥ 80 years with moderate to severe AC who received percutaneous transhepatic gallbladder drainage (PTGBD). METHODS: From January 2008 to February 2021, 152 patients were retrospectively enrolled. Clinical outcomes were compared among patients who received laparoscopic cholecystectomy (LC), open cholecystectomy (OC), and conversion surgery, and between those who received early (< 6 weeks after PTGBD) and delayed cholecystectomy (≥ 6 weeks after PTGBD). Logistic regression analysis was used to identify risk factors for recurrent AC, further biliary events, conversion, and perioperative complications. RESULTS: Sixty-seven patients underwent LC, 62 underwent OC, and 23 underwent conversion surgery. Operation-related complications and mortality rates did not differ among the types of surgery; however, LC group had shorter operative time than the other groups. Eighty-two patients underwent early cholecystectomy, while 70 underwent delayed cholecystectomy. There were no differences in operative time, operation-related complications, and mortality rates between the groups. However, higher rates of recurrent AC and biliary events were observed in the delayed cholecystectomy group (52.9% vs. 4.9% and 57.1% vs. 8.5%, p < 0.001). On multivariate analysis, delayed cholecystectomy was a significant risk factor for recurrent AC (odds ratio [OR] = 19.42, p < 0.001) and further biliary events (OR = 15.95, p < 0.001). CONCLUSIONS: Early cholecystectomy is recommended for patients aged ≥ 80 years with moderate to severe AC following PTGBD.

14.
Front Endocrinol (Lausanne) ; 13: 1001349, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36465658

RESUMO

Objective: Thyroid-associated ophthalmopathy (TAO) is a disfiguring autoimmune disease, which destroys the structure of orbital tissues and even threatens vision. Metabolic reprograming is critical in autoimmune diseases; however, the metabolic basis of TAO remains to be clarified. Our study aimed to reveal the metabolic profile of TAO. Methods: Orbital adipose/connective tissues from eleven TAO patients and twelve control subjects were collected during surgeries and analyzed with liquid chromatograph-mass spectrometer. Orthogonal partial least-squares discrimination analysis (OPLS-DA), variable importance in projection (VIP), heat map, and volcano plot were used to reveal metabolic profile in TAO. Pathway analysis and metabolites-gene analysis were utilized to explore potential metabolic metabolism in TAO. Results: 3038 metabolites were detected in samples from the TAO patients and the controls. OPLS-DA analysis of the metabolomics results showed two distinguished groups, demonstrating that TAO has a unique metabolome. Univariate tests identified 593 dysregulated metabolites (P < 0.05), including 367 increased metabolites and 226 decreased metabolites. Pathway analysis showed that changed metabolites were enriched in cholesterol metabolism, choline metabolism in cancer, fat digestion and absorption, regulation of lipolysis in adipocytes, and insulin resistance. In addition, metabolites-gene analysis illustrated that cholesterol metabolism was involved in the pathogenesis of TAO. Endoplasmic reticulum stress-related genes (ATF6, PERK, and IRE1α) expressions were higher in TAO orbital tissues than in control orbital tissues verified by western blot. Additionally, the expression level of diacylglycerol acyltransferase 1 (DGAT1), a key metabolic protein for triacylglycerol synthesis, was increased in orbital tissues of TAO detected by qRT-PCR, indicating disrupted cholesterol metabolism in TAO. Conclusion: The present study demonstrated different metabolite profiles and potential metabolic mechanisms in TAO.


Assuntos
Doenças Autoimunes , Oftalmopatia de Graves , Humanos , Oftalmopatia de Graves/genética , Endorribonucleases , Proteínas Serina-Treonina Quinases , Tecido Adiposo , Colesterol
15.
Comput Struct Biotechnol J ; 20: 6458-6466, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36467587

RESUMO

Various groups of antihypertensive drugs targeting different pathways have been developed; however, the pharmacometabolic responses to these drugs have rarely been compared to elucidate the common pathway of blood pressure regulation. Here, we performed a comparative multi-dimensional pharmacometabolic study on the four major lines of antihypertensive drugs, namely angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and diuretics (DIURs), through ultra-performance liquid chromatography coupled to quantum time-of-flight mass spectrometry. Two hundred fifty patients with young-onset hypertension, who were equally divided among five study groups: non-medicated, ACEi, ARB, CCB, and DIUR groups, were recruited. In a metabolome-wide association study conducted through analysis of covariance, 37 molecular features significantly associated with pharmacometabolic responses to antihypertensive drugs were identified. One-third of these features were shared by multiple medications. ACEis, ARBs, and DIURs shared more features than CCB, partially reflecting that ACEis, ARBs, and DIURs affect the renin-angiotensin-aldosterone system. Thirteen molecular features were consistently identified by all four models of the analysis of covariance. A tandem mass spectrometry (or MS/MS) experiment was performed to decipher the chemical structure of these 13 molecular features, including ARB-associated lysophosphatidylcholine (P4135), CCB-associated diacylglycerol(15:0/18:2) (P1175), and DIUR-associated oleamide (P1516). In addition, diacylglycerol(15:0/14:2) (P408) was significantly associated with the pharmacometabolic response to all four antihypertensive drugs. The identified metabolites provide insights into the mechanisms of blood pressure regulation and potential predictive markers of pharmacometabolic responses to antihypertensive drugs.

16.
Zool Stud ; 61: e39, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36568810

RESUMO

Pseudasphondylia species (Diptera: Cecidomyiidae) are known to induce fruit galls on Actinidia rufa (Siebold & Zucc.) Planch. ex Miq. and finger-like leaf galls on Elaeocarpus sylvestris (Lour.) Poir. in Taiwan, but their taxonomic positions remain undetermined. Based on gall morphology and host plants, they were supposed to be the same or allied species of known Japanese congeners, i.e., P. matatabi Yuasa & Kumazawa inducing flower-bud galls on Actinidia polygama (Sieb. et Zucc.) Maxim and P. elaeocarpi Tokuda & Yukawa inducing finger-like leaf galls on E. sylvestris. Species identifications of these Taiwanese species provide us an opportunity to study biogeographical aspects and transition of ecological features in these Pseudasphondylia species distributed in East Asian Arc. Morphological comparisons and species delimitation by molecular analysis indicated that the cecidomyiid on the fruit of A. rufa is distinct from P. matatabi and thus it is described as a species new to science, P. kiwiphila sp. nov. Lin, Tokuda, & Yang. The leaf galler on E. sylvestris was identical to P. elaeocarpi, whose southernmost distribution range extended to Taiwan, a new record of its distribution. COI-based phylogenetic tree (Bayesian inference and IQ tree) of Pseudasphondylia suggested that leaf galling habitat and univoltine life history are ancestral, whereas fruit or flower-bud galling and multivoltine life history are derived. In addition, the monophyletic Actinidia-associated species lineage is sistered to the clade including the remaining Japanese fruit and flower-bud gallers, suggesting that Pseudasphondylia has colonized on the host genus Actinidia once and later speciated on different plant species of the host genus. As a biogeographical aspect of P. elaeocarpi, 2.7% of the COI distance between Japanese and Taiwanese individuals indicates that they have diverged around 1.2 mya, which corresponds to the last but second separation of Taiwan and Japan in the Pleistocene. As for Actinidia-associated Pseudasphondylia species, the two valid species are allopatric and have distinct areas of origin, suggesting they may have speciated allopatrically. Nevertheless, there is still the possibility of ecological speciation due to the following reasons: (1) Host species (and varieties) and unidentified congener of Actinidia-associated Pseudasphondylia are occurring China, revealing potential occurrence of these gall midges. (2) The divergence time (2.2-2.9 mya) of the two known species corresponds to the late Pliocene to Pleistocene, when China, Taiwan, and Japan were part of the East Asian continent. During this period, their host species were sympatric in southeast China. (3) The host of two named Actinidia-associated Pseudasphondylia species each belong to different plant groups with distinct fruit features. These presume that the speciation might have been caused via sympatric host shift.

17.
Intern Emerg Med ; 2022 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-36577909

RESUMO

Acute kidney injury (AKI) is a common but fatal complication after cardiac surgery. In the absence of effective treatments, the identification and modification of risk factors has been a major component of disease management. However, the optimal blood pressure target for preventing cardiac surgery-associated acute kidney injury (CSA-AKI) remains unclear. We sought to determine the effect of postoperative mean arterial pressure (MAP) in CSA-AKI. It is hypothesized that longer periods of hypotension after cardiac surgery are associated with an increased risk of AKI. This prospective cohort study was conducted on adult patients who underwent cardiac surgery requiring cardiopulmonary bypass at a tertiary center between October 2018 and May 2020. The primary outcome is the occurrence of CSA-AKI. MAP and its duration in the ranges of less than 65, 65 to 74, and 75 to 84 mmHg within 24 h after surgery were recorded. The association between postoperative MAP and CSA-AKI was examined by using logistic regression. Among the 353 patients enrolled, 217 (61.5%) had a confirmed diagnosis of CSA-AKI. Each 1 h epoch of postoperative MAP less than 65 mmHg was associated with an adjusted odds ratio of 1.208 (95% CI, 1.007 to 1.449; P = 0.042), and each 1 h epoch of postoperative MAP between 65 and 74 mmHg was associated with an adjusted odds ratio of 1.144 (95% CI, 1.026 to 1.275; P = 0.016) for CSA-AKI. A potentially modifiable risk factor, postoperative MAP less than 75 mmHg for 1 h or more is associated with an increased risk of CSA-AKI.

18.
Medicina (Kaunas) ; 58(12)2022 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-36557066

RESUMO

Primary squamous cell carcinoma (SCC) of the liver is a rare disease that is difficult to diagnose until the pathology is confirmed. The age of the patients generally ranges from 18 to 83 years. The pathogenesis of primary SCC of the liver remains unclear and therapeutic guidelines have not yet been established. The overall survival rate may be less than 1 year. The prognosis for patients without surgery is worse than that for patients who undergo surgery. Herein, we report a case of primary SCC of the liver that responded well to intravenous carboplatin and 5-flurouracil (5-FU) with the aim of providing an alternative therapeutic option. A 61-year-old woman with no history of alcohol use disorder, cirrhosis, exposure to hepatotoxic chemicals, or a remarkable family history presented to our hospital with a complaint of epigastric pain, poor appetite, and fatigue, which had occurred 3 days before presentation. Blood tests revealed levels of alpha-fetoprotein of <2.0 ng/mL, carcinoembryonic antigen of 4.39 ng/mL, carbohydrate antigen (CA) 19-9 of 1306.15 U/mL, CA 125 of 66.3 U/mL, CA 153 of 19.7 U/mL, and SCC antigen of 8.5 ng/mL. Computed tomography scans of the abdomen showed a 5.8-cm lobulated soft-tissue mass with central necrosis in segment 6 of the liver, which caused compression of the common hepatic duct. Pathological examination of the masses revealed squamous cell carcinoma with focal glandular differentiation. The patient underwent palliative chemotherapy with intravenous carboplatin 150 mg (day 1) and 5-FU 1000 mg (days 1-4) instead of surgery. After two cycles of chemotherapy, jaundice and liver function improved. The patient was discharged in stable condition and was followed up in our outpatient department. Although the patient refused to undergo surgery, no tumor recurrence or distant metastasis was found during the 8-month follow-up period. This report highlights that neoadjuvant chemotherapy with carboplatin and 5-FU can be considered for primary SCC of the liver before a liver resection.


Assuntos
Carcinoma de Células Escamosas , Recidiva Local de Neoplasia , Feminino , Humanos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Carboplatina/uso terapêutico , Carcinoma de Células Escamosas/patologia , Fígado/patologia , Abdome , Fluoruracila/uso terapêutico
19.
BMC Med ; 20(1): 472, 2022 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-36482345

RESUMO

BACKGROUND: Anlotinib, a tyrosine kinase inhibitor, has shown encouraging anti-tumor activity in esophageal squamous cell carcinoma (ESCC). This study was designed to assess the efficacy and safety of anlotinib plus paclitaxel and cisplatin (TP) as first-line therapy for advanced ESCC. METHODS: In a multi-center, single-arm, phase II clinical trial, patients (aged > 18 years) with ESCC, which was judged to be locally advanced, recurrent, or metastatic, received 10 mg oral anlotinib once daily on days 1-14, 135 mg/m2 intravenous paclitaxel on day 1, and 60-75 mg/m2 intravenous cisplatin on days 1-3 every 3 weeks for a maximum of 4-6 cycles as the initial therapy in five centers in China. Subsequently, patients received anlotinib monotherapy (10 mg) as maintenance therapy until tumor progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). RESULTS: Forty-seven patients were enrolled in this study between October 2019 and March 2021. The median follow-up was 14.04 months (IQR, 9.30-19.38). Of 46 with assessable efficacy, the median PFS and median overall survival were 8.38 months (95% CI, 6.59-10.17) and 18.53 months (95% CI, 13.11-23.95), respectively. The objective response rate was 76.1% (95% CI, 61.2-87.4%), with 4 (8.7%) complete responses and 31 (67.4%) partial responses. The disease control rate was 91.3% (95% CI, 79.2-97.6%). The median duration of response was 6.80 months (95% CI, 4.52-9.08), and 1 patient had an ongoing response for 23 months. Subgroup analysis revealed no association between clinical factors and survival or response. Of the 47 patients with assessable safety, the main grade ≥ 3 treatment-emergent adverse events (TEAEs) were neutropenia (17.0%), bone marrow suppression (12.8%), and vomiting (10.6%). No treatment-related deaths or serious TEAEs were observed. Notably, higher c-Kit levels were an independent factor for superior PFS (HR = 0.032; 95% CI, 0.002-0.606; P = 0.022). CONCLUSIONS: The study demonstrated a manageable safety profile and durable clinical response of anlotinib plus TP as first-line therapy in advanced ESCC, which suggested a potential therapeutic option for this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT04063683. Registered 21 August 2019.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Paclitaxel/efeitos adversos , Cisplatino/efeitos adversos , Neoplasias Esofágicas/tratamento farmacológico , China
20.
Sci Adv ; 8(46): eabo2098, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36383661

RESUMO

Major depressive disorder (MDD) is a devastating mental disorder that affects up to 17% of the population worldwide. Although brain-wide network-level abnormalities in MDD patients via resting-state functional magnetic resonance imaging (rsfMRI) exist, the mechanisms underlying these network changes are unknown, despite their immense potential for depression diagnosis and management. Here, we show that the astrocytic calcium-deficient mice, inositol 1,4,5-trisphosphate-type-2 receptor knockout mice (Itpr2-/- mice), display abnormal rsfMRI functional connectivity (rsFC) in depression-related networks, especially decreased rsFC in medial prefrontal cortex (mPFC)-related pathways. We further uncover rsFC decreases in MDD patients highly consistent with those of Itpr2-/- mice, especially in mPFC-related pathways. Optogenetic activation of mPFC astrocytes partially enhances rsFC in depression-related networks in both Itpr2-/- and wild-type mice. Optogenetic activation of the mPFC neurons or mPFC-striatum pathway rescues disrupted rsFC and depressive-like behaviors in Itpr2-/- mice. Our results identify the previously unknown role of astrocyte dysfunction in driving rsFC abnormalities in depression.

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