Emerging therapeutic landscape: Incretin agonists in chronic kidney disease management.

The increasing incidence of chronic kidney disease (CKD) poses a significant public health concern, prompting heightened attention to its treatment. Incretins, including glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide, are intestinal peptides released after nutrient intake, known for their hypoglycemic effects in diabetes management. Recent advancements highlight the promising outcomes of GLP-1 receptor agonists in reducing CKD risk factors and improving renal outcomes. The multifaceted functions of GLP-1, such as its anti-obesity, anti-hypertensive, anti-hyperglycemic, anti-lipid, anti-inflammatory, and endothelial function protective properties, contribute to its potential as a therapeutic agent for CKD. Although experiments suggest the potential benefits of incretin in CKD, a comprehensive understanding of its specific mechanisms is still lacking. This review aims to provide a detailed examination of current evidence and potential future directions, emphasizing the promising yet evolving landscape of incretin agonists in the context of CKD.

The impact of the senescent microenvironment on tumorigenesis: Insights for cancer therapy.

The growing global burden of cancer, especially among people aged 60 years and over, has become a key public health issue. This trend suggests the need for a deeper understanding of the various cancer types in order to develop universally effective treatments. A prospective area of research involves elucidating the interplay between the senescent microenvironment and tumor genesis. Currently, most oncology research focuses on adulthood and tends to ignore the potential role of senescent individuals on tumor progression. Senescent cells produce a senescence-associated secretory phenotype (SASP) that has a dual role in the tumor microenvironment (TME). While SASP components can remodel the TME and thus hinder tumor cell proliferation, they can also promote tumorigenesis and progression via pro-inflammatory and pro-proliferative mechanisms. To address this gap, our review seeks to investigate the influence of senescent microenvironment changes on tumor development and their potential implications for cancer therapies.

BAM15 as a mitochondrial uncoupler: a promising therapeutic agent for diverse diseases.

Subcellular organelles dysfunction is implicated in various diseases, including metabolic diseases, neurodegenerative diseases, cancer, and cardiovascular diseases. BAM15, a selective mitochondrial uncoupler, has emerged as a promising therapeutic agent due to its ability to enhance mitochondrial respiration and metabolic flexibility. By disrupting the coupling between electron transport and ATP synthesis, BAM15 dissipates the proton gradient, leading to increased mitochondrial respiration and energy expenditure. This review provides a comprehensive overview of BAM15, including its mechanism of action and potential therapeutic applications in diverse disease contexts. BAM15 has shown promise in obesity by increasing energy expenditure and reducing fat accumulation. In diabetes, it improves glycemic control and reverses insulin resistance. Additionally, BAM15 has potential in non-alcoholic fatty liver disease, sepsis, and cardiovascular diseases by mitigating oxidative stress, modulating inflammatory responses, and promoting cardioprotection. The safety profile of BAM15 is encouraging, with minimal adverse effects and remarkable tolerability. However, challenges such as its high lipophilicity and the need for alternative delivery methods need to be addressed. Further research is necessary to fully understand the therapeutic potential of BAM15 and optimize its application in clinical settings.

Identification of Potential Indicators for Survival in Patients with Thyroid Cancer Based on Expression of FAM3 Members.

Thyroid cancer (THCA) is a common head and neck malignancy. The family with sequence similarity 3 (FAM3) is a cytokine-like gene family with four members, which is presumed to participate in the development of many cancer types. However, the expression patterns of FAM3s in THCA and their prognostic values, have not yet been established. We investigated differential expressions of FAM3 mRNA and protein in THCA, then validated the findings for FAM3B by immunohistochemistry. We also investigated survival data with respect to FAM3 expression patterns in patients with THCA. FAM3s information regarding their relationships with clinical pathological parameters were obtained and FAM3 mutations were assessed. KEGG and GO pathway regarding FAM3C were obtained using online databases. To investigate potential correlations between FAM3s and immune cell infiltration, we investigated the roles of FAM3s in immune cells of patients with THCA. The mRNA expression of FAM3C were significantly elevated in THCA tissues; high expression levels of FAM3C protein were also observed in THCA tissues. A significant association between the pathological stage and the expression of FAM3C was found in patients with THCA. Patients with THCA who had high mRNA expression levels of FAM3C exhibited significantly more favorable prognosis, compared with patients who had low mRNA expression levels of FAM3C. Overall, FAM3C may play vital roles in the pathogenesis and development of THCA, and these findings constitute novel insights for biomarkers of immunotherapeutic targeted agents and may aid in the identification of prognostic biomarkers for THCA.

Human cytomegalovirus infection is associated with stroke in women: the US National Health and Nutrition Examination Survey 1999-2004.

BACKGROUND: Increasing evidence indicated that infection factors play important roles in stroke development. Human cytomegalovirus (HCMV) infection was positively associated with atherosclerosis and hypertension which are stroke risk factors. Therefore, we aimed to explore the relationship between HCMV infection and stroke using the data of US National Health and Nutrition Examination Survey (NHANES). METHODS: We analysed data on 2844 men and 3257 women in the NHANES 1999-2004. We included participants aged 20-49 years who had valid data on HCMV infection and stroke. RESULTS: 54.1% of participants had serological evidence of HCMV infection and 0.8% of them had a previous diagnosis of stroke. There were ethnic differences in the prevalence of HCMV seropositivity (p<0.001). There was no significant association between HCMV seropositivity and stroke in men in any of the models. In women, HCMV seropositivity was associated with stroke before adjustment (OR=3.45, 95% CI 1.09 to 10.95, p=0.036). After adjusting for race/ethnicity, the association remained significant (OR=4.40, 95% CI 1.37 to 14.09, p=0.014). After further adjustment for body mass index, diabetes, hypercholesterolaemia, hypertension, alcohol consumption, smoking and physical activity, the association still existed (OR=3.58, 95% CI 1.14 to 11.25, p=0.030). The association was significant consistently in adjusted model for age (OR=3.39, 95% CI 1.08 to 10.64, p=0.037). CONCLUSIONS: We found a strong association between HCMV and stroke in women from the nationally representative population-based survey. This provide additional motivation for undertaking the difficult challenge to reduce the prevalence of stroke.

LincRNA-p21 Inhibits Cell Viability and Promotes Cell Apoptosis in Parkinson's Disease through Activating α-Synuclein Expression.

Long intergenic noncoding RNA-p21 (lincRNA-p21) has been reported to be increased in Parkinson's disease (PD). However, the function and underlying mechanisms of lincRNA-p21 remain not clear. In order to explore the role of lincRNA-p21 in PD, we used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce in vivo PD model (C57BL/6 mice) and utilized N-methyl-4-phenylpyridinium (MPP+) to create in vitro PD model (SH-SY5Y cells). Results showed that the expression level of lincRNA-p21 was increased significantly in PD models. High abundance of lincRNA-p21 inhibited viability and promoted apoptosis markedly in SH-SY5Y cells treated with MPP+. Mechanistically, further experiments demonstrated that upregulation of lincRNA-p21 could sponge miR-1277-5p and indirectly increase the expression of α-synuclein to suppress viability and activate apoptosis in SH-SY5Y cells. In short, our study illustrated that lincRNA-p21/miR-1277-5p axis regulated viability and apoptosis in SH-SY5Y cells treated with MPP+ via targeting α-synuclein. LincRNA-p21 might be a novel target for PD.

Application of a modified thoracoabdominal approach that avoids cutting open the costal portion of diaphragm during anterior thoracolumbar spine surgery.

PURPOSE: In the present prospective randomized controlled study, we compared the feasibility and effectiveness of our modified thoracoabdominal approach to anterior thoracolumbar spine surgery without cutting open the costal portion of diaphragm (extradiaphragmatic approach) with the traditional transdiaphragmatic thoracoabdominal approach. The traditional combined thoracoabdominal approach in anterior thoracolumbar surgery for spine tuberculosis is effective but seriously damages the diaphragm and causes various lung complications. We used an extradiaphragmatic approach for complete anterior debridement, bone grafting, and nerve decompression and compared its efficacy and complications with those of the traditional transdiaphragmatic thoracolumbar approach. METHODS: The study included 106 patients with spinal tuberculosis. After a standard preoperative chemotherapy regimen, all patients underwent posterior deformity correction and internal fixation, anterior debridement, decompression, and bone grafting. Patients were divided into the modified extradiaphragmatic thoracolumbar approach group (the modified group) and the traditional transdiaphragmatic thoracolumbar approach group (the traditional group). During the treatment, we strictly followed the standard chemotherapy regimen. RESULTS: The mean follow-up duration was 36.2 months (range 25-38 months). There were significant differences between the two groups in intraoperative blood loss, length of incision, recovery time, and postoperative complications but no significant differences in preoperative and postoperative erythrocyte sedimentation rates and C-reactive protein values, kyphosis, and neurologic function, recovery of ability to live and work, and postoperative healing of bone grafts. CONCLUSION: The modified extradiaphragmatic thoracolumbar approach for anterior thoracolumbar spine surgery is as effective as the traditional approach. However, associated surgical trauma is minimal, and the incidence of pulmonary complications is low.

Chronic Hypoxia-Induced Autophagy Aggravates the Neuropathology of Alzheimer's Disease through AMPK-mTOR Signaling in the APPSwe/PS1dE9 Mouse Model.

Alzheimer's disease (AD) is the most common form of dementia with the accumulation of senile plaques and neurofibrillary tangles in the brain. Autophagy is the key machinery for mammalian cells to degrade damaged organelles and abnormal proteins. Enormous evidence suggests that the autophagy pathway is impaired in AD. Our previous study revealed that hypoxia induced autophagic activation leading to more amyloid-ß production in vitro. In this study, we investigated whether autophagic dysfunction is involved in the hypoxia mediated-pathogenesis of AD. We used APPSwe/PS1dE9 transgenic (Tg) mice and wildtype (Wt) littermates. We documented that chronic hypoxia caused more and larger senile plaques in the brains of Tg mice. In addition, chronic hypoxia induced activation of autophagy in the brains of both Wt and Tg mice, and compared to the normal autophagic flux in Wt mice, the autophagic flux was impaired in the brains of H-Tg mice with a large amount of autophagic vacuole accumulation and significant high level of P62. In an in vitro study, we showed that hypoxia-induced autophagy significantly elevated the level of hAß42. Furthermore, we found that chronic hypoxia activated AMPK and further inhibited the mTOR signaling pathway, while inhibition of AMPK attenuated autophagy induction through the enhancement of mTOR phosphorylation. In short, our study provides new insight into the mechanism underlying chronic hypoxia-mediated AD pathogenesis.

A New VMAT-2 Inhibitor NBI-641449 in the Treatment of Huntington Disease.

AIMS: To evaluate the effectiveness of a new VMAT-2 inhibitor NBI-641449 in controlling hyperkinetic movements of Huntington disease (HD) and to investigate its possible therapeutic effects. METHODS: We applied three different doses of NBI-641449 (1, 10, 100 mg/kg/day) for 2 weeks in 4-month-old YAC128 mice and wild-type (WT) mice. Rotarod performance and locomotive activities were tested during the administration of the drug. The concentration of dopamine (DA) and its metabolites was quantified in the striatal tissues by high-performance liquid chromatography (HPLC). Neuron survival in striatum and huntingtin protein aggregates were assessed with immunostaining. Expression levels of endoplasmic reticulum (ER) stress proteins were detected by immunoblotting. RESULTS: Rotarod performance was significantly improved after treatment with low or middle dose of NBI-641449 in YAC128 mice. Open field test showed that NBI-641449 treatment could attenuate the increased horizontal activity (HACTV), total vertical movement, moving time, and moving distance in YAC128 mice. High dose of NBI-641449 might cause sedative effects in WT and YAC128 mice. HPLC showed that NBI-641449 caused a dose-dependent decrease of DA, 3,4-dihydroxyphenylacetic acid, and homovanillic acid levels in the striatum. NeuN and DARPP-32 immunostaining revealed that NBI-641449 had no significant effect on the neuron survival in the striatum. However, NBI-641449 treatment reduced the huntingtin protein aggregates in the cortex of YAC128 mice. In addition, the levels of ER stress proteins were increased in YAC128 mice, which can be suppressed by NBI-641449. CONCLUSIONS: These findings suggest that this new VMAT-2 inhibitor NBI-641449 may have therapeutic potential for the treatment of HD.

Granular cell tumor of the thyroid: Clinical and pathological characteristics of a rare case in a 14-year-old girl.

Granular cell tumors (GCTs) are soft tissue neoplasms that originate in the nervous system, which may arise anywhere in the body. However, GCTs are extremely uncommon in thyroid tumors, with a favorable prognosis. The diagnosis of GCTs is dependent on pathological and immunohistochemical analysis and at present, surgical resection is considered the only suitable treatment. Regular follow-up after surgery is an important way to monitor treatment outcome and recurrence. The present study describes a new pathological type of thyroid GCTs diagnosed by pathology and immunohistochemistry. A 14-year-old female was referred to the West China Hospital of Sichuan University (Chengdu, China), for thyroid incidentaloma. Laboratory examinations were within the normal range. Thyroid sonography demonstrated a solid hypoechoic mass in the right lobe of the thyroid. Fine needle aspiration cytology showed a suspicious malignant tumor and subsequently a total thyroidectomy was performed. Analysis of frozen sections, from obtained samples, did not facilitate a definite diagnosis. Finally, a thyroid benign granular tumor with atypical changes was diagnosed by postoperative pathology and immunohistochemistry. A 14-month post-operative follow-up showed that the patient experienced a stable recovery and had no signs of recurrence or metastasis. The case emphasizes that the diagnosis of thyroid granular cell tumors is predominantly based on postoperative morphology and immunophenotype. The clinical routine for the differential diagnosis may be due to: (i) neoplasms displaying a granular appearance mimicking granular cell tumors, or (ii) differential diagnosis in the pathological category of granular cell tumors. Further accumulation of such rare cases may be of clinical significance in aiding the diagnosis and treatment of GCTs.

Association of depression with inflammation in hospitalized patients of myocardial infarction.

OBJECTIVE: The aim of this study was to examine the associations between depression and inflammatory markers in patients admitted to the hospital for myocardial infarction. METHODS: Inflammatory cytokines, including high-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α (TNF-α) were assessed in a group of 75 depressed participants (score of ≥ 12) and compared to a control group of 75 nondepressed participants (score < 12), all who had been admitted to the hospital for myocardial infarction. The presence of depressive symptoms was assessed using the Beck Depressive Symptoms Inventory II Scale (BDI-II). RESULTS: Depressed myocardial infarction participants had significantly greater levels of TNF-α (t = 2.070, P < 0.05) compared with control myocardial infarction participants. The BDI-II score was positively correlated with TNF-α levels (r = 0.222, P < 0.05). CONCLUSIONS: These results indicate that the presence of depressive symptoms is positively associated with TNF-α levels among patients who have suffered from myocardial infarction.

Ultra-short-course chemotherapy for spinal tuberculosis: five years of observation.

PURPOSE: This study aimed to explore the feasibility of ultra-short-course chemotherapy in the treatment of spinal tuberculosis. METHODS: One hundred and eighty-five patients with confirmed spinal tuberculosis and surgical indication were included. The chemotherapy regimen was 2SHRZ/XHRZ. According to the duration of the chemotherapy, the patients were divided into two groups, the ultra-short-course chemotherapy group with an average duration of 4.5 months, and the standard chemotherapy group with an average duration of 9 months. The same surgery was performed for patients in the two groups. RESULTS: The duration of the follow-up ranged from 61 to 87 months, with an average of 69.1 months. Erythrocyte sedimentation rate and C-reactive protein, kyphosis and nerve function, recovery of work, and activities of daily living were not significantly different between the two groups before or after treatment; however, the aforementioned indices were significantly different before and after treatment within groups. There was no significant difference in postoperative bone graft healing between the two groups. The drug side effects were significantly different between the two groups. CONCLUSIONS: With thorough focus debridement, bone grafting, and internal fixation, the efficacy of ultra-short chemotherapy was similar to that of standard chemotherapy for the treatment of spinal tuberculosis. The ultra-short-course chemotherapy can shorten the course of treatment and reduce drug side effects.

[Value of oxygenic injury sensitive index in the screening of the early coal workers' pneumoconiosis].

OBJECTIVE: To study the significance of oxidative injury in the screening of coal workers' pneumoconiosis (CWP). METHODS: With the method of nitrate reductase, TBA, et al, the content of NO, MDA and other indexes of peroxidation in plasma lipid were detected in 112 patients suffering from coal workers' pneumoconiosis and 114 healthy coal workers as controls. RESULTS: There were statistical significant between two groups (P < 0.05) with the content or density of MDA, CuZn-SOD, GSH-Px, T-AOC, UA, NO and iNOS except CP. As screening index of pneumoconiosis, there were statistical significant in area under the curve (AUC) of MDA, T-AOC, NO and iNOS between the two groups by ROC. As screening index of pneumoconiosis, MDA, T-AOC, NO and iNOS can be selected as early screening index. Especially, T-AOC was the best index of four indexes (sensitivity is 70.5%, specificity is 68.1%). CONCLUSION: Joint screening of MDA, T-AOC and iNOS is better than single index or series of T-AOC and MDA to the screening of CWP.

[The comparison of efficacy of female sterilization by modified Uchida technique and silver clips in China].

OBJECTIVE: To compare efficacy of female sterilization by modified Uchida technique and silver clips and to evaluate the influence on operation procedure and clinical effect with or without surgery training of service providers. METHODS: A comparative, multicenter clinical trial was performed in 18 county and township-level service centers. Totally 2198 women underwent sterilization from these 18 study center were divided into 1116 women sterilized by modified Uchida technique and 1082 women by silver clips. Those 18 centers were classified into 9 training groups which provide surgical skills of sterilization and other contents and 9 non training groups. Clinical documents of sterilization were recorded. All women were follow-up at 3, 6 and 12 months after surgery. RESULTS: There were no complications during surgery by both sterilization. The failure rate was 2.03% (22/1082) in silver clip method and the mean operative time were (12.4 ± 6.4) minutes in training group and (14.4 ± 8.1) minutes in non training group. In modified Uchida method, the failure rate was 0.18% (2/1116) and the mean operative time were (16.2 ± 4.9) minutes in training group and (19.0 ± 8.6) minutes in non training group. The mean operative time between two groups reached statistical difference (all P < 0.05). Total ended rate in modified Uchida technique were 2.2/hundred women year in training group and 2.5/hundred women year in non training group, and the rate of silver slips were 3.9/hundred women year and 4.8/hundred women year, which did not show significant difference (all P > 0.05). There was no significant difference in acceptability and side effects of all women between two methods (P > 0.05). The training of service providers could influence acceptability of women (P < 0.05). CONCLUSIONS: Clinical efficacy was not influenced by those two methods. The operative time and acceptability were improved by training surgeons in silver clips method.

A comparative study of female sterilization via modified Uchida and silver clip techniques in rural China.

OBJECTIVE: To compare the specific effects of 2 female sterilization methods: the modified Uchida technique and the application of silver clips. METHODS: A total of 2198 women living in rural areas who were still of reproductive age but opting for sterilization were enrolled. The participants were randomly divided into 2 groups, and underwent sterilization by either modified Uchida technique or silver clips. Information on acceptability, operation conditions, effectiveness, adverse effects, and complaints was collected 3, 6, and 12 months after the procedure. RESULTS: No significant difference in effectiveness, adverse effects or chief complaints between the 2 procedures was found. Differences in operative outcome, bleeding volume during the procedure, and operation time were found. CONCLUSION: A shorter operation time and less bleeding for the silver clip method indicated that female sterilization by this technique was as safe as that by modified Uchida technique.

Association of TNF-alpha-238G/A and 308 G/A gene polymorphisms with pulmonary tuberculosis among patients with coal worker's pneumoconiosis.

OBJECTIVES: Tumor necrosis factor-alpha (TNF-alpha) may play an important role in host's immune response to mycobacterium tuberculosis (M. tuberculosis) infection. This study was to investigate the association of TNF-alpha gene polymorphism with pulmonary tuberculosis (TB) among patients with coal worker's pneumoconiosis (CWP). METHODS: A case-control study was conducted in 113 patients with confirmed CWP complicated with pulmonary TB and 113 non-TB controls with CWP. They were matched in gender, age, job, and stage of pneumoconiosis. All participants were interviewed with questionnaires and their blood specimens were collected for genetic determination with informed consent. The TNF-alpha gene polymorphism was determined with polymerase chain reaction of restriction fragment length polymorphism (PCR-RFLP). Frequency of genotypes was assessed for Hardy-Weinberg equilibrium by chi-square test or Fisher's exact probability. Factors influencing the association of individual susceptibility with pulmonary TB were evaluated with logistic regression analysis. Gene-environment interaction was evaluated by a multiplicative model with combined OR. All data were analyzed using SAS version 8.2 software. RESULTS: No significant difference in frequency of the TNF-alpha-308 genotype was found between CWP complicated with pulmonary TB and non-TB controls (chi2 = 5.44, P = 0.07). But difference in frequency of the TNF-alpha-308 A allele was identified between them (chi2 = 5.14, P = 0.02). No significant difference in frequencies of the TNF-alpha-238 genotype and allele (P = 0.23 and P = 0.09, respectively) was found between cases and controls either, with combined (GG and AA) OR of 3.96 (95% confidence interval of 1.30-12.09) at the -308 locus of the TNF-alpha gene, as compared to combination of the TNF-alpha-238 GG and TNF-alpha-308 GG genotypes. Multivariate-adjusted odds ratio of the TNF-alpha-238 GG and TNF-alpha-308 GA genotypes was 1.98 (95% CI of 1.06-3.71) for risk for pulmonary TB in patients with CWP. There was a synergic interaction between the TNF-alpha-308 GG genotype and body mass index (OR = 4.92), as well as an interaction between the TNF-alpha-308 GG genotype and history of BCG immunization or history of TB exposure. And, the interaction of the TNF-alpha-238 GG genotype and history of BCG immunization or TB exposure with risk for pulmonary TB in them was also indicated. CONCLUSIONS: TNF-alpha-308 A allele is associated with an elevated risk for pulmonary TB, whereas TNF-alpha-238 A allele was otherwise.