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1.
Accid Anal Prev ; 204: 107648, 2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38833986

ABSTRACT

Illegal lane-transgressing is a typical aberrant riding behavior of riders of two-wheelers, i.e., motorcycles, bicycles, and e-bikes, which is highly frequent in accident reports. However, there is insufficient attention to this behavior at present. This study aims to explore the socio-psychologic factors that influence the illegal lane-transgressing behavior of two-wheeler riders when overtaking. For this purpose, a questionnaire was first composed. The questionnaire included the behavioral intention of two-wheeler riders towards illegal overtaking behavior and five influencing factors: safety knowledge, descriptive norms, injunctive norms, perceived behavior control, and risk perception. Second, a survey was conducted on different two-wheeler riders in Xi'an. Third, various types of two-wheelers were analyzed jointly and separately by structural equation models and analyses of variance. Results show that e-bike riders were more similar to motorcycle riders in behavioral intentions, with their risk perception weaker than other riders. Descriptive norms and perceived behavior control played the most significant roles in the structural equation model. It was also found that two-wheeler riders with a car license had better traffic safety performance. Based on the above results, it is recommended that attention be paid to illegal lane-transgression in the process of law enforcement and education, and a higher level of safety training should be provided for two-wheeler riders.

3.
J Pharm Pharmacol ; 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38836550

ABSTRACT

BACKGROUND: Tongue squamous cell carcinoma (TSCC) exhibits an aggressive biological behavior of lymph node and distant metastasis, which contributes to poorer prognosis and results in tongue function loss or death. In addition to known regulators and pathways of cell migration in TSCC, it is important to uncover pivotal switches governing tumor metastasis. METHODS: Cancer cell migration-associated transcriptional and epigenetic characteristics were profiled in TSCC, and the specific super-enhancers (SEs) were identified. Molecular function and mechanism studies were used to investigate the pivotal switches in TSCC metastasis. RESULTS: Ameboidal-type cell migration-related genes accompanied by transcriptional and epigenetic activity were enriched in TSCC. Meanwhile, the higher-ranked SE-related genes showed significant differences between 43 paired tumor and normal samples from the TCGA TSCC cohort. In addition, key motifs were detected in SE regions, and transcription factor-related expression levels were significantly associated with TSCC survival status. Notably, BATF and ATF3 regulated the expression of ameboidal-type cell migration-related MMP14 by switching the interaction with the SE region. CONCLUSION: SEs and related key motifs transcriptional regulate tumor metastasis-associated MMP14 and might be potential therapeutic targets for TSCC.

4.
Front Immunol ; 15: 1302909, 2024.
Article in English | MEDLINE | ID: mdl-38846934

ABSTRACT

Background: Membranous nephropathy (MN) is an autoimmune disease and represents the most prevalent type of renal pathology in adult patients afflicted with nephrotic syndrome. Despite substantial evidence suggesting a possible link between MN and cancer, the precise underlying mechanisms remain elusive. Methods: In this study, we acquired and integrated two MN datasets (comprising a single-cell dataset and a bulk RNA-seq dataset) from the Gene Expression Omnibus database for differential expression gene (DEG) analysis, hub genes were obtained by LASSO and random forest algorithms, the diagnostic ability of hub genes was assessed using ROC curves, and the degree of immune cell infiltration was evaluated using the ssGSEA function. Concurrently, we gathered pan-cancer-related genes from the TCGA and GTEx databases, to analyze the expression, mutation status, drug sensitivity and prognosis of hub genes in pan-cancer. Results: We conducted intersections between the set of 318 senescence-related genes and the 366 DEGs, resulting in the identification of 13 senescence-related DEGs. Afterwards, we meticulously analyzed these genes using the LASSO and random forest algorithms, which ultimately led to the discovery of six hub genes through intersection (PIK3R1, CCND1, TERF2IP, SLC25A4, CAPN2, and TXN). ROC curves suggest that these hub genes have good recognition of MN. After performing correlation analysis, examining immune infiltration, and conducting a comprehensive pan-cancer investigation, we validated these six hub genes through immunohistochemical analysis using human renal biopsy tissues. The pan-cancer analysis notably accentuates the robust association between these hub genes and the prognoses of individuals afflicted by diverse cancer types, further underscoring the importance of mutations within these hub genes across various cancers. Conclusion: This evidence indicates that these genes could potentially play a pivotal role as a critical link connecting MN and cancer. As a result, they may hold promise as valuable targets for intervention in cases of both MN and cancer.


Subject(s)
Glomerulonephritis, Membranous , Humans , Glomerulonephritis, Membranous/genetics , Glomerulonephritis, Membranous/immunology , Glomerulonephritis, Membranous/diagnosis , Glomerulonephritis, Membranous/metabolism , Gene Expression Profiling , Neoplasms/genetics , Neoplasms/immunology , Neoplasms/metabolism , Computational Biology/methods , Prognosis , Biomarkers, Tumor/genetics , Transcriptome , Gene Regulatory Networks , Biomarkers , Databases, Genetic
5.
Hellenic J Cardiol ; 2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38844023

ABSTRACT

BACKGROUND: We aimed to examine bi-ventricular remodeling and function following Ebstein's anomaly (EbA) surgical correction using echocardiographic techniques, particularly the relations between the bi-ventricular changes and the EbA types. METHODS: From April 2015 to August 2022, 110 patients with EbA were included in this retrospective study based on the Carpentier classification. Echocardiography assessments during the preoperative, early, and mid-term postoperative periods were performed. RESULTS: The 54 patients with types A and B EbA were included in group 1, whereas the 56 with types C and D were in group 2. Seventy-eight patients underwent surgical correction of EbA. The median age at operation was 8.8 years. During the mid-term follow-up, only 9.1% of the patients had moderate or severe tricuspid regurgitation. Right ventricular (RV) systolic function worsened in group 2 at discharge (fractional area change: 27.6±11.2 versus 35.4±11.5 [baseline], P<0.05; global longitudinal strain: -10.8±4.4 versus -17.9±4.7 [baseline], P=0.0001). RV function slowly recovered at a mean of 12-month follow-up. Regarding left ventricular (LV) and RV systolic function, no statistical difference was found between before and after surgery in group 1. CONCLUSIONS: A high success rate of surgical correction of EbA with an encouraging durability of the valve was noted. Bi-ventricular systolic function was maintained fairly in most patients with types A and B postoperatively. A late increase in RV systolic function after an initial reduction and unchanged LV systolic function were observed in the patients with types C and D postoperatively.

6.
Plant Commun ; : 100983, 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38845197

ABSTRACT

Whole-genome genotyping (WGG) stands as a pivotal element in genomic-assisted plant breeding. Nevertheless, sequencing-based approaches for WGG continue to be costly, primarily attributed to the high expenses associated with library preparation and the laborious protocol. During the prior development of Foreground and Background Integrated genotyping by sequencing (FBI-seq), we discovered that any sequence specific primer (SP) inherently possessed the capability to amplify a massive array of stable and reproducible non-specific PCR product across the genome. Here we further improved the FBI-seq by replacing the adapter ligated by Tn5 transposase with arbitrary degenerate (AD) primer. The protocol for the enhanced FBI-seq unexpectedly mirrors a simplified Thermal Asymmetric Interlaced (TAIL)-PCR, a technique widely employed for isolating flanking sequences. However, the improved TAIL-PCR maximizes the PTMA capabilities of both SP and AD primers. Additionally, leveraging next-generation sequencing enhances its ability to assay tens of thousands of genome-wide loci for any species. This cost-effective, user-friendly, and powerful WGG tool, TAIL-PCR by sequencing (TAIL-peq), holds great potential for widespread application in breeding programs, thereby facilitating genome-assisted crop improvement.

7.
Biomed Environ Sci ; 37(4): 399-405, 2024 Apr 20.
Article in English | MEDLINE | ID: mdl-38727162

ABSTRACT

Objective: This study aimed to determine the current epidemiological status of PLWHA aged ≥ 50 years in China from 2018 to 2021. It also aimed to recommend targeted interventions for the prevention and treatment of HIV/AIDS in elderly patients. Methods: Data on newly reported cases of PLWHA, aged ≥ 50 years in China from 2018 to 2021, were collected using the CRIMS. Trend tests and spatial analyses were also conducted. Results: Between 2018 and 2021, 237,724 HIV/AIDS cases were reported among patients aged ≥ 50 years in China. The main transmission route was heterosexual transmission (91.24%). Commercial heterosexual transmission (CHC) was the primary mode of transmission among males, while non-marital non-CHC ([NMNCHC]; 60.59%) was the prevalent route in women. The proportion of patients with CHC decreased over time ( Z = 67.716, P < 0.01), while that of patients with NMNCHC increased ( Z = 153.05, P < 0.01). The sex ratio varied among the different modes of infection, and it peaked at 17.65 for CHC. The spatial analysis indicated spatial clustering, and the high-high clustering areas were mainly distributed in the southwestern and central-southern provinces. Conclusion: In China, PLWHA, aged ≥ 50 years, were predominantly infected through heterosexual transmission. The primary modes of infection were CHC and NMNCHC. There were variations in the sex ratio among different age groups, infected through various sexual behaviors. HIV/AIDS cases exhibited spatial clustering. Based on these results, the expansion of HIV testing, treatment, and integrated behavioral interventions in high-risk populations is recommended to enhance disease detection in key regions.


Subject(s)
Acquired Immunodeficiency Syndrome , Epidemics , HIV Infections , Humans , China/epidemiology , Male , Female , Middle Aged , Aged , HIV Infections/epidemiology , HIV Infections/transmission , Acquired Immunodeficiency Syndrome/epidemiology , Acquired Immunodeficiency Syndrome/transmission , Aged, 80 and over , Prevalence
8.
World J Stem Cells ; 16(4): 459-461, 2024 Apr 26.
Article in English | MEDLINE | ID: mdl-38690518

ABSTRACT

Hypoxia can get more ability to inhibit inflammation. But how it impact on survival time of mesenchymal stem cells (MSCs) is confusing and how preconditioned MSCs inhibiting inflammation are partially known. Those issues decided the value of preconditioned MSCs by hypoxia.

9.
Hum Vaccin Immunother ; 20(1): 2338984, 2024 Dec 31.
Article in English | MEDLINE | ID: mdl-38698555

ABSTRACT

CAR-T cell therapy has emerged as a significant approach for the management of hematological malignancies. Over the past few years, the utilization of CAR-T cells in the investigation and treatment of solid tumors has gained momentum, thereby establishing itself as a prominent area of research. This descriptive study involved the retrieval of articles about CAR-T cell therapy for solid tumors from the Web of Science Core Collection (WoSCC) database. Subsequently, bibliometric analysis and knowledge map analysis were conducted on these articles. The field under consideration is currently experiencing a period of swift advancement, as evidenced by the escalating number of publications in this domain each year. The United States holds an indisputable position as the foremost leader in this particular field, with the University of Pennsylvania emerging as the most active institution. The authors with the highest citation frequency and co-citation frequency are Carl H. June and Shannon L. Maude, respectively. The research hotspots in this field mainly focus on five aspects. Additionally, 10 emerging themes were identified. This study undertakes a comprehensive, systematic, and objective analysis and exploration of the field of CAR-T cell treatment for solid tumors, utilizing bibliometric methods. The findings of this study are expected to serve as a valuable reference and enlightenment for future research endeavors in this particular domain.


Subject(s)
Bibliometrics , Immunotherapy, Adoptive , Neoplasms , Humans , Neoplasms/therapy , Immunotherapy, Adoptive/methods , Biomedical Research/trends , Receptors, Chimeric Antigen/immunology
10.
BMC Pulm Med ; 24(1): 220, 2024 May 03.
Article in English | MEDLINE | ID: mdl-38702679

ABSTRACT

BACKGROUND: Recent research suggests that periodontitis can increase the risk of chronic obstructive pulmonary disease (COPD). In this study, we performed two-sample Mendelian randomization (MR) and investigated the causal effect of periodontitis (PD) on the genetic prediction of COPD. The study aimed to estimate how exposures affected outcomes. METHODS: Published data from the Gene-Lifestyle Interaction in the Dental Endpoints (GLIDE) Consortium's genome-wide association studies (GWAS) for periodontitis (17,353 cases and 28,210 controls) and COPD (16,488 cases and 169,688 controls) from European ancestry were utilized. This study employed a two-sample MR analysis approach and applied several complementary methods, including weighted median, inverse variance weighted (IVW), and MR-Egger regression. Multivariable Mendelian randomization (MVMR) analysis was further conducted to mitigate the influence of smoking on COPD. RESULTS: We chose five single-nucleotide polymorphisms (SNPs) as instrumental variables for periodontitis. A strong genetically predicted causal link between periodontitis and COPD, that is, periodontitis as an independent risk factor for COPD was detected. PD (OR = 1.102951, 95% CI: 1.005-1.211, p = 0.039) MR-Egger regression and weighted median analysis results were coincident with those of the IVW method. According to the sensitivity analysis, horizontal pleiotropy's effect on causal estimations seemed unlikely. However, reverse MR analysis revealed no significant genetic causal association between COPD and periodontitis. IVW (OR = 1.048 > 1, 95%CI: 0.973-1.128, p = 0.2082) MR Egger (OR = 0.826, 95%CI:0.658-1.037, p = 0.1104) and weighted median (OR = 1.043, 95%CI: 0.941-1.156, p = 0.4239). The results of multivariable Mendelian randomization (MVMR) analysis, after adjusting for the confounding effect of smoking, suggest a potential causal relationship between periodontitis and COPD (P = 0.035). CONCLUSION: In this study, periodontitis was found to be independent of COPD and a significant risk factor, providing new insights into periodontitis-mediated mechanisms underlying COPD development.


Subject(s)
Genome-Wide Association Study , Mendelian Randomization Analysis , Polymorphism, Single Nucleotide , Pulmonary Disease, Chronic Obstructive , Smoking , Humans , Pulmonary Disease, Chronic Obstructive/genetics , Pulmonary Disease, Chronic Obstructive/epidemiology , Risk Factors , Smoking/epidemiology , Smoking/adverse effects , Periodontitis/genetics , Periodontitis/epidemiology , Severity of Illness Index , Genetic Predisposition to Disease , Periodontal Diseases/genetics , Periodontal Diseases/epidemiology
11.
Mol Cell Biochem ; 2024 May 15.
Article in English | MEDLINE | ID: mdl-38748384

ABSTRACT

Axis inhibitor protein 1 (AXIN1) is a protein recognized for inhibiting tumor growth and is commonly involved in cancer development. In this study, we explored the potential molecular mechanisms that connect alternative splicing of AXIN1 to the metastasis of hepatocellular carcinoma (HCC). Transcriptome sequencing, RT‒PCR, qPCR and Western blotting were utilized to determine the expression levels of AXIN1 in human HCC tissues and HCC cells. The effects of the AXIN1 exon 9 alternative splice isoform and SRSF9 on the migration and invasion of HCC cells were assessed through wound healing and Transwell assays, respectively. The interaction between SRSF9 and AXIN1 was investigated using UV crosslink RNA immunoprecipitation, RNA pulldown, and RNA immunoprecipitation assays. Furthermore, the involvement of the AXIN1 isoform and SRSF9 in HCC metastasis was validated in a nude mouse model. AXIN1-L (exon 9 including) expression was downregulated, while AXIN1-S (exon 9 skipping) was upregulated in HCC. SRSF9 promotes the production of AXIN1-S by interacting with the sequence of exons 8 and 10 of AXIN1. AXIN1-S significantly promoted HCC cells migration and invasion by activating the Wnt pathway, while the opposite effects were observed for AXIN1-L. In vivo experiments demonstrated that AXIN1-L inhibited HCC metastasis, whereas SRSF9 promoted HCC metastasis in part by regulating the level of AXIN1-S. AXIN1, a tumor suppressor protein that targets the AXIN1/Wnt/ß-catenin signaling axis, may be a promising prognostic factor and a valuable therapeutic target for HCC.

12.
Foods ; 13(9)2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38731757

ABSTRACT

The traditional fermentation process of soy sauce employs a hyperhaline model and has a long fermentation period. A hyperhaline model can improve fermentation speed, but easily leads to the contamination of miscellaneous bacteria and fermentation failure. In this study, after the conventional koji and moromi fermentation, the fermentation broth was pasteurized and diluted, and then inoculated with three selected microorganisms including Corynebacterium glutamicum, Corynebacterium ammoniagenes, and Lactiplantibacillus plantarum for secondary fermentation. During this ten-day fermentation, the pH, free amino acids, organic acids, nucleotide acids, fatty acids, and volatile compounds were analyzed. The fermentation group inoculated with C. glutamicum accumulated the high content of amino acid nitrogen of 0.92 g/100 mL and glutamic acid of 509.4 mg/100 mL. The C. ammoniagenes group and L. plantarum group were rich in nucleotide and organic acid, respectively. The fermentation group inoculated with three microorganisms exhibited the best sensory attributes, showing the potential to develop a suitable fermentation method. The brewing speed of the proposed process in this study was faster than that of the traditional method, and the umami substances could be significantly accumulated in this low-salt fermented model (7% w/v NaCl). This study provides a reference for the low-salt and rapid fermentation of seasoning.

13.
Adv Sci (Weinh) ; : e2400790, 2024 May 13.
Article in English | MEDLINE | ID: mdl-38741381

ABSTRACT

Heterotopic ossification (HO), the pathological formation of bone within soft tissues such as tendon and muscle, is a notable complication resulting from severe injury. While soft tissue injury is necessary for HO development, the specific molecular pathology responsible for trauma-induced HO remains a mystery. The previous study detected abnormal autophagy function in the early stages of tendon HO. Nevertheless, it remains to be determined whether autophagy governs the process of HO generation. Here, trauma-induced tendon HO model is used to investigate the relationship between autophagy and tendon calcification. In the early stages of tenotomy, it is observed that autophagic flux is significantly impaired and that blocking autophagic flux promoted the development of more rampant calcification. Moreover, Gt(ROSA)26sor transgenic mouse model experiments disclosed lysosomal acid dysfunction as chief reason behind impaired autophagic flux. Stimulating V-ATPase activity reinstated both lysosomal acid functioning and autophagic flux, thereby reversing tendon HO. This present study demonstrates that autophagy-lysosomal dysfunction triggers HO in the stages of tendon injury, with potential therapeutic targeting implications for HO.

14.
Virulence ; 15(1): 2350775, 2024 12.
Article in English | MEDLINE | ID: mdl-38736041

ABSTRACT

OBJECTIVES: The translocation of intestinal flora has been linked to the colonization of diverse and heavy lower respiratory flora in patients with septic ARDS, and is considered a critical prognostic factor for patients. METHODS: On the first and third days of ICU admission, BALF, throat swab, and anal swab were collected, resulting in a total of 288 samples. These samples were analyzed using 16S rRNA analysis and the traceability analysis of new generation technology. RESULTS: On the first day, among the top five microbiota species in abundance, four species were found to be identical in BALF and throat samples. Similarly, on the third day, three microbiota species were found to be identical in abundance in both BALF and throat samples. On the first day, 85.16% of microorganisms originated from the throat, 5.79% from the intestines, and 9.05% were unknown. On the third day, 83.52% of microorganisms came from the throat, 4.67% from the intestines, and 11.81% were unknown. Additionally, when regrouping the 46 patients, the results revealed a significant predominance of throat microorganisms in BALF on both the first and third day. Furthermore, as the disease progressed, the proportion of intestinal flora in BALF increased in patients with enterogenic ARDS. CONCLUSIONS: In patients with septic ARDS, the main source of lung microbiota is primarily from the throat. Furthermore, the dynamic trend of the microbiota on the first and third day is essentially consistent.It is important to note that the origin of the intestinal flora does not exclude the possibility of its origin from the throat.


Subject(s)
Bacteria , Bronchoalveolar Lavage Fluid , Microbiota , Pharynx , RNA, Ribosomal, 16S , Respiratory Distress Syndrome , Sepsis , Humans , Male , Female , Respiratory Distress Syndrome/microbiology , Middle Aged , Pharynx/microbiology , RNA, Ribosomal, 16S/genetics , Bronchoalveolar Lavage Fluid/microbiology , Aged , Sepsis/microbiology , Bacteria/classification , Bacteria/isolation & purification , Bacteria/genetics , Pulmonary Alveoli/microbiology , Adult , Intensive Care Units , Gastrointestinal Microbiome
15.
Hum Brain Mapp ; 45(7): e26709, 2024 May.
Article in English | MEDLINE | ID: mdl-38746977

ABSTRACT

The high prevalence of conversion from amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD) makes early prevention of AD extremely critical. Neuroticism, a heritable personality trait associated with mental health, has been considered a risk factor for conversion from aMCI to AD. However, whether the neuroticism genetic risk could predict the conversion of aMCI and its underlying neural mechanisms is unclear. Neuroticism polygenic risk score (N-PRS) was calculated in 278 aMCI patients with qualified genomic and neuroimaging data from ADNI. After 1-year follow-up, N-PRS in patients of aMCI-converted group was significantly greater than those in aMCI-stable group. Logistic and Cox survival regression revealed that N-PRS could significantly predict the early-stage conversion risk from aMCI to AD. These results were well replicated in an internal dataset and an independent external dataset of 933 aMCI patients from the UK Biobank. One sample Mendelian randomization analyses confirmed a potentially causal association from higher N-PRS to lower inferior parietal surface area to higher conversion risk of aMCI patients. These analyses indicated that neuroticism genetic risk may increase the conversion risk from aMCI to AD by impairing the inferior parietal structure.


Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Disease Progression , Magnetic Resonance Imaging , Multifactorial Inheritance , Neuroticism , Parietal Lobe , Humans , Alzheimer Disease/genetics , Alzheimer Disease/diagnostic imaging , Cognitive Dysfunction/diagnostic imaging , Cognitive Dysfunction/genetics , Cognitive Dysfunction/etiology , Cognitive Dysfunction/physiopathology , Male , Female , Aged , Parietal Lobe/diagnostic imaging , Parietal Lobe/pathology , Aged, 80 and over , Mendelian Randomization Analysis , Middle Aged , Genetic Predisposition to Disease
16.
Small ; : e2401308, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38773889

ABSTRACT

Incorporating ultralow loading of nanoparticles into polymers has realized increases in dielectric constant and breakdown strength for excellent energy storage. However, there are still a series of tough issues to be dealt with, such as organic solvent uses, which face enormous challenges in scalable preparation. Here, a new strategy of dual in situ synthesis is proposed, namely polymerization of polyethylene terephthalate (PET) synchronizes with growth of calcium borate nanoparticles, making polyester nanocomposites from monomers directly. Importantly, this route is free of organic solvents and surface modification of nanoparticles, which is readily accessible to scalable synthesis of polyester nanocomposites. Meanwhile, uniform dispersion of as ultralow as 0.1 wt% nanoparticles and intense bonding at interfaces have been observed. Furthermore, the PET-based nanocomposite displays obvious increases in both dielectric constant and breakdown strength as compared to the neat PET. Its maximum discharged energy density reaches 15 J cm-3 at 690 MV m-1 and power density attains 218 MW cm-3 under 150 Ω resistance at 300 MV m-1, which is far superior to the current dielectric polymers that can be produced at large scales. This work presents a scalable, safe, low-cost, and environment-friendly route toward polymer nanocomposites with superior capacitive performance.

17.
Angew Chem Int Ed Engl ; : e202405781, 2024 May 23.
Article in English | MEDLINE | ID: mdl-38782734

ABSTRACT

Synthesis of bicyclic scaffolds has gained significant attention in drug discovery due to their potential to mimic benzene bioisosteres. Here, we present a mild and scalable Sc(OTf)3-catalyzed [3+2] cycloaddition of bicyclo[1.1.0]butanes (BCBs) with ynamides, yielding a diverse array of polysubstituted 2-amino-bicyclo[2.1.1]hexenes in good to excellent yields. These products offer valuable starting materials for the construction of novel functionalized bicyclo[1.1.0]butanes. Preliminary mechanistic studies indicate that the reaction involves a nucleophilic addition of ynamides to bicyclo[1.1.0]butanes, followed by an intramolecular cyclization of in situ generated enolate and keteniminium ion. We expect that these findings will encourage utilization of complex bioisosteres and foster further investigation into BCB-based cycloaddition chemistry.

18.
J Hypertens ; 2024 May 21.
Article in English | MEDLINE | ID: mdl-38780161

ABSTRACT

OBJECTIVES: Potassium supplementation reduces blood pressure and the occurrence of cardiovascular diseases, with K+-induced natriuresis playing a potential key role in this process. However, whether these beneficial effects occur in diabetes remains unknown. METHODS: In this study, we examined the impact of high-K+ intake on renal Na+/K+ transport by determining the expression of major apical Na+ transporters, diuretics responses (as a proxy for specific Na+ transporter function), urinary Na+/K+ excretion, and plasma Na+/K+ concentrations in db/db mice, a model of type 2 diabetes mellitus. RESULTS: Although db/m mice exhibited increased fractional excretion of sodium (FENa) and fractional excretion of potassium (FEK) under high-K+ intake, these responses were largely blunted in db/db mice, suggesting impaired K+-induced natriuresis and kaliuresis in diabetes. Consequently, high-K+ intake increased plasma K+ levels in db/db mice, which could be attributed to the abnormal activity of sodium-hydrogen exchanger 3 (NHE3), sodium-chloride cotransporter (NCC), and epithelial Na+ channel (ENaC), as high-K+ intake could not effectively decrease NHE3 and NCC and increase ENaC expression and activity in the diabetic group. Inhibition of NCC by hydrochlorothiazide could correct the hyperkalemia in db/db mice fed a high-K+ diet, indicating a key role for NCC in K+-loaded diabetic mice. Treatment with metformin enhanced urinary Na+/K+ excretion and normalized plasma K+ levels in db/db mice with a high-K+ diet, at least partially, by suppressing NCC activity. CONCLUSION: Collectively, the impaired K+-induced natriuresis in diabetic mice under high-K+ intake may be primarily attributed to impaired NCC-mediated renal K+ excretion, despite the role of NHE3.

19.
J Chem Inf Model ; 2024 May 29.
Article in English | MEDLINE | ID: mdl-38808649

ABSTRACT

By performing molecular dynamics (MD), quantum mechanical/molecular mechanical (QM/MM) calculations, and QM cluster calculations, the origin of chemoselectivity of halohydrin dehalogenase (HHDH)-catalyzed ring-opening reactions of epoxide with the nucleophilic reagent NO2- has been explored. Four possible chemoselective pathways were considered, and the computed results indicate that the pathway associated with the nucleophilic attack on the Cα position of epoxide by NO2- is most energetically favorable and has an energy barrier of 12.9 kcal/mol, which is close to 14.1 kcal/mol derived from experimental kinetic data. A hydrogen bonding network formed by residues Ser140, Tyr153, and Arg157 can strengthen the electrophilicity of the active site of the epoxide substrate to affect chemoselectivity. To predict the energy barrier trends of the chemoselective transition states, multiple analyses including distortion analysis and electrophilic Parr function (Pk+) analysis were carried out with or without an enzyme environment. The obtained insights should be valuable for the rational design of enzyme-catalyzed and biomimetic organocatalytic epoxide ring-opening reactions with special chemoselectivity.

20.
Leuk Lymphoma ; : 1-8, 2024 May 30.
Article in English | MEDLINE | ID: mdl-38814179

ABSTRACT

This study explored the impact of different maintenance therapies on survival outcomes in patients with multiple myeloma (MM), focusing on changes in minimal residual disease (MRD) during maintenance. Conducted at a single center, this retrospective study included 259 newly diagnosed MM patients who did not undergo autologous stem cell transplantation (ASCT). The results indicated that patients receiving lenalidomide as maintenance therapy showed significantly better progression-free survival (PFS) and overall survival (OS) compared to those treated with bortezomib or no maintenance therapy. However, bortezomib proved more effective in high-risk MM cases. Patients who were MRD-negative prior to starting maintenance therapy had a better prognosis than MRD-positive patients. Notably, lenalidomide was the most effective regimen irrespective of MRD status. Patients maintaining or achieving MRD-negativity within the first year of lenalidomide treatment exhibited improved prognoses, confirming lenalidomide as the optimal maintenance choice.

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