Metabolic Abnormalities Research Articles

Lactucin ameliorates FFA-induced steatosis in HepG2 cells by modulating mitochondrial homeostasis through the SIRT1/PGC-1α signaling axis

Nonalcoholic fatty liver disease is a complex disease involving abnormal liver metabolism. Its strong association with metabolic dysfunction has led to a change in nomenclature to metabolism dysfunction-associated fatty liver disease (MAFLD). MAFLD pathogenesis involves abnormal accumulation of hepatic lipids that lead to the production of excess free fatty acids (FFAs), which in turn cause an imbalance in hepatic mitochondrial function. Lactucin, a natural compound extracted from Cichorium glandulosum Boiss. et Huet, regulates liver metabolism and protects the liver. However, the potential mechanisms underlying the lactucin-mediated effects in MAFLD require further investigation. In the present study, HepG2 cells were treated with FFAs to establish an in vitro model of MAFLD. Parameters related to lipid accumulation and mitochondrial function, including triglycerides (TG), oil red O-stained lipid droplets, reactive oxygen species (ROS), mitochondrial membrane potential (JC-1), adenine triphosphate (ATP), and complex III were analysed. Morphology of the mitochondria were evaluated by transmission electron microscopy. Furthermore, key proteins in the sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) signalling axis and mitochondrial quality control were analysed. The SIRT1 inhibitor EX-527 was used to verify the key role of the SIRT1 signalling pathway. Western blotting showed that lactucin upregulated the expression of SIRT-1, PGC-1α, Nrf1, Tfam, Mfn2, and Opa1, and promoted mitochondrial biosynthesis and kinetics. The results suggest that lactucin restores mitochondrial dynamic homeostasis by upregulating the SIRT1/PGC-1α signalling axis, thereby reducing FFA-induced lipid accumulation in HepG2 cells.

Genomic instabilities in hepatocellular carcinoma: biomarkers and application in immunotherapies.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers. For patients with advanced HCC, liver function decompensation often occurs, which leads to poor tolerance to chemotherapies and other aggressive treatments. Therefore, it remains critical to develop effective therapeutic strategies for HCC. Etiological factors for HCC are complex and multifaceted, including hepatitis virus infection, alcohol, drug abuse, chronic metabolic abnormalities, and others. Thus, HCC has been categorized as a "genomically unstable" cancer due to the typical manifestation of chromosome breakage and aneuploidy, and oxidative DNA damage. In recent years, immunotherapy has provided a new option for cancer treatments, and the degree of genomic instability positively correlates with immunotherapy efficacies. This article reviews the endogenous and exogenous causes that affect the genomic stability of liver cells; it also updates the current biomarkers and their detection methods for genomic instabilities and relevant applications in cancer immunotherapies. Including genomic instability biomarkers in consideration of cancer treatment options shall increase the patients' well-being.

A novel quinazoline derivative exhibits potent anticancer cytotoxicity via apoptosis and inhibition of angiogenesis in DMBA-induced mammary gland carcinoma.

Mammary gland carcinoma is one of the most prevalent and deadly diseases among women globally. It is a type of solid malignant tumor. In this malignant tumor, the microenvironment becomes hypoxic in rapidly proliferating cancer cells. These cells undergo adaptive changes through the expression of hypoxia-inducible factor-1alpha (HIF-1α) which is regulated by factor inhibiting HIF-1α (FIH-1). Considering this, we hypothesized that the chemical activation of FIH-1 would inhibit the hypoxic activity of HIF-1α in mammary gland carcinoma. A library of 67,609 chemical compounds was virtually screened against FIH-1 based on Lipinski's rule from the ZINC database. The BBAP-8 has been selected based on an excellent docking score (-8.352 Kcal/mol), favorable ADMET, and potential FIH-1 activator profile. Further, its in-vitro cytotoxicity and apoptotic activity were scrutinized against MCF-7 cells and in-vivo activity against 7,12-dimethylbenz[a]anthracene (DMBA) induced mammary gland carcinoma in Wistar rats. It exhibited significant cytotoxicity (IC50 = 16.59 ± 0.49 μM) and activated apoptosis when scrutinized through DAPI, AO/EB, and JC-1 staining. Also, oral administration of BBAP-8 restored hemodynamic changes, normalized tissue architecture, and corrected metabolic abnormalities. The western blot analysis and mRNA expression analysis validated that BBAP-8 has the potential to activate FIH-1 with the downregulation of GLUT-1, VEGF, and Twist-1. Moreover, BBAP-8 fostered apoptosis, when evaluated through BCL-2, BAX, Caspase-8, and Caspase-3. Based on research findings, this implies that BBAP-8 activates FIH-1 and can be effective in chemotherapeutic treatment of mammary gland carcinoma.

The Significance of Comprehensive Metabolic Phenotypes in Cancer Risk: A Japan Multi-Institutional Collaborative Cohort (J-MICC) Study.

The present study investigated the relationship between metabolic phenotypes and the risk of cancer in a Japanese population using the criteria of metabolic phenotypes based on an examination and those based on questionnaires. We used data from 25,357 subjects for examination-based analyses and those from 53,042 subjects for questionnaire-based analyses in the Japan Multi-Institutional Collaborative Cohort Study. Metabolic phenotypes were defined by classifying subjects according to their BMI (obesity: BMI ≥25 kg/m2; normal weight: BMI <25 kg/m2) and the number of metabolic abnormalities. Metabolic abnormalities were defined according to metabolic syndrome components of the Joint Interim Statement Criteria for examination-based analyses and self-reported histories of diabetes, dyslipidemia, and hypertension for questionnaire-based analyses. Cox proportional hazards regression analyses adjusted for potential confounders were performed for total and site-specific cancer incidence according to metabolic phenotypes. Metabolically unhealthy obesity (MUHO) was significantly associated with cancer incidence in both examination-based [HR (95% CI): 1.17 (1.01-1.36)] and questionnaire-based analyses [HR (95% CI): 1.15 (1.04-1.26)]. Regarding site-specific cancer in questionnaire-based analyses, metabolically healthy obesity and MUHO were associated with colorectum and liver cancers in all subjects and with breast cancer in female subjects. Subjects with a metabolically unhealthy normal weight had a higher risk of pancreatic cancer. Moreover, MUHO was associated with corpus uteri cancer in female subjects. This prospective cohort study suggests that metabolic phenotypes are important risk factors for total and some site-specific cancers in Japanese adults.

Exploring mitochondrial blood-based and genetic markers in older adults with mild cognitive impairment and remitted major depressive disorder

Mild cognitive impairment (MCI) is a prodromal stage in aging to possible progression to Alzheimer’s disease and related dementia (ADRD), where co-occurrence of major depressive disorder (MDD) accelerates the progression. Metabolic and mitochondrial abnormalities in ADRD and other neurodegenerative disorders have been widely suggested, while possible mitochondrial dysfunction has been associated with etiopathology of both MCI and MDD. Hence, investigation of mitochondrial markers in MCI, MDD, and presence of both conditions is warranted. In total, 332 older adult participants were included: 168 with MCI, 108 with MCI plus remitted MDD (rMDD), and 56 with rMDD but without MCI. We measured plasma circulating mitochondrial DNA (ccf-mtDNA), lactate, and extracted nuclear mitochondrial encoded (NMt) single-nucleotide variants (SNVs) (n = 312). Non-parametric statistical tests on ccf-mtDNA and lactate levels were performed on the diagnosis, clinical and cardiometabolic variables. Binary sequence kernel association test (SKAT-O) and burden test were performed on NMt-SNV, adjusted for age, race, gender, type II diabetes, and APOE genotype. Lower level of lactate was observed in MCI (KW χ2 = 14.8, P = 0.0024), more specifically, significant differences of lower plasma lactate between MCI only and rMDD, but not between MCI+rMDD and MCI were found, suggesting potential roles in MCI driving lactate lower levels. While higher levels of ccf-mtDNA were observed in APOE-ε4 carrier (χ2 = 5.04, P = 0.05). This relationship was present only in MCI (P = 0.043) and MCI+rMDD groups (P = 0.023). No significant nuclear-encoded mitochondrial gene associations were observed with MCI or MDD. The results suggest decreased level of plasma lactate in individuals with MCI and MCI+rMDD, with inverse correlation with ccf-mtDNA, in addition to effect of APOE-ε4 in further increasing ccf-mtDNA specifically in participants with cognitive impairment. These findings contribute to a deeper understanding of the mitochondrial markers in MCI and MDD, warranting further research to explore the precise roles of mitochondrial abnormalities in the development and progression of MCI.

Are metabolically healthy obese individuals really a benign cardiovascular group? An analysis of 162,590 participants with measures of arterial stiffness in UK BIOBANK

Abstract Background There is conflicting evidence as to whether so called metabolically healthy but overweight and obese individuals are at increased cardiovascular risk or mortality. Purpose We assessed whether metabolic health correlates with vascular health among these individuals using severity of arterial stiffness as a proxy for vascular health and cardiovascular risk. Methods Participants in UK Biobank with body-mass index (BMI) and arterial stiffness index (ASI) recorded at initial assessment between 2006-2010, and free from stroke and myocardial infarction and not underweight (BMI&amp;lt;18.5kg/m2) were included. Participants were stratified by BMI (normal, overweight, obese) and presence of metabolic abnormalities (hypertension, diabetes, dyslipidaemia). The primary outcome was the severity of ASI analysed using multivariate-adjusted linear regression. Results Of 162,590 participants, 55.0% were female, mean age was 57 years (SD 8), 42.5% were overweight and 24.4% obese. Within the normal BMI strata, 50.7% had ≥1 metabolic abnormality. Compared to individuals with normal BMI and no metabolic abnormalities (ref group), increased weight or metabolic abnormalities were similarly associated with higher ASI; adjusted β-coefficient [β] 0.35, 95%CI 0.30 to 0.40 for participants with normal BMI and ≥1 metabolic abnormality; β 0.32, 95%CI 0.26 to 0.37 for overweight participants without metabolic abnormalities. Obese individuals with no metabolic abnormalities had higher ASI (β 0.65; 95%CI 0.57 to 0.74) but was lower than overweight participants with metabolic abnormalities (β 0.80; 95%CI 0.75 to 0.84). Obese participants with metabolic abnormalities had the highest ASI (β 1.07; 95%CI 1.02 to 1.12) among all six metabolic combinations, p&amp;lt;0.001 for each vs ref group. Sensitivity analysis suggested higher ASI with increasing number of metabolic abnormalities within BMI categories. Conclusion Excess weight and metabolic abnormalities, are independently associated with adverse measures of vascular health to a similar degree, suggesting that the so called metabolically healthy obese are not a benign group. Primary prevention strategies should be considered in overweight, or obese individuals even if metabolic abnormalities are absent.

Metabolic alterations in human pulmonary artery smooth muscle cells treated with PDGF-BB.

Metabolic abnormalities are considered to play a key regulatory role in vascular remodeling of pulmonary arterial hypertension. However, to date, there is a paucity of research documenting the changes in metabolome profiles within the supernatants of pulmonary artery smooth muscle cells (PASMC) during their transition from a contractile to a synthetic phenotype. CCK-8 and Edu staining assays were used to evaluate the cell viability and proliferation of human PASMCs. IncuCyte ZOOM imaging system was used to continuously and automatically detect the migration of the PASMCs. A targeted metabolomics profiling was performed to quantitatively analyze 121 metabolites in the supernatant. Orthogonal partial least squares discriminant analysis was used to discriminate between PDGF-BB-induced PASMCs and controls. Metabolite set enrichment analysis was adapted to exploit the most disturbed metabolic pathways. Human PASMCs exhibited a transformation from contractile phenotype to synthetic phenotype after PDGF-BB induction, along with a significant increase in cell viability, proliferation, and migration. Metabolites in the supernatants of PASMCs treated with or without PDGF-BB were well profiled. Eleven metabolites were found to be significantly upregulated, whereas seven metabolites were downregulated in the supernatants of PASMCs induced by PDGF-BB compared to the vehicle-treated cells. Fourteen pathways were involved, and pyruvate metabolism pathway was ranked first with the highest enrichment impact followed by glycolysis/gluconeogenesis and pyrimidine metabolism. Significant and extensive metabolic abnormalities occurred during the phenotypic transformation of PASMCs. Disturbance of pyruvate metabolism pathway might contribute to pulmonary vascular remodeling.

Regulating lipid metabolism in osteoarthritis: a complex area with important future therapeutic potential

Background Osteoarthritis (OA), which is characterized by pain, inflammation and pathological changes, is associated with abnormal lipid metabolism. Extensive studies have been conducted on the potential functions of lipids including cholesterol, fatty acids (FAs) and adipokines. Materials and Methods By searching and screening the literature included in the PubMed and Web of Science databases from 1 January 2019 to 1 January 2024, providing an overview of research conducted on lipid metabolism and OA in the last 5 years. Results In addition to adiponectin, several studies on the effects of lipid metabolism on OA have been consistent and complementary. Total cholesterol, triglycerides, low-density lipoprotein cholesterol, adipsin, leptin, resistin, saturated FAs, monounsaturated FAs, FA-binding protein 4 and the ratios of the FAs hexadecenoylcarnitine (C16:1) to dodecanoylcarnitine and C16:1 to tetradecanoylcarnitine induced mostly deleterious effects, whereas high-density lipoprotein cholesterol and apolipoprotein A/B/D had a positive impact on the health of joints. The situation for polyunsaturated FAs may be more complicated, as omega-3 increases the genetic susceptibility to OA, whereas omega-6 does the opposite. Conclusion: Alterations in lipid or adipokine levels and the resulting pathological changes in cartilage and other tissues (such as bone and synovium) ultimately affect joint pain, inflammation and cartilage degradation. Lipid or adipokine regulation has potential as a future direction for the treatment of OA, this potential avenue of OA treatment requires high-quality randomized controlled trials of combined lipid regulation therapy, and more in-depth in vivo and in vitro studies to confirm the underlying mechanism.

Gene-echocardiography: unmasking the covert role of fatty acid metabolism gene mutations in adult cardiomyopathy

Abstract Background Although the role of fatty acid metabolic deficiencies in cardiomyopathy is established, the precise identity of causative genes and their respective phenotypes in adult cardiomyopathy remains unclear. Methods We implemented a combination of echocardiography and whole exome sequencing in clinically diagnosed cardiomyopathy patients to uncover this relationship. This involved recording cardiac phenotypes, identifying genes associated with disrupted fatty acid metabolism, and subsequently followed up with these patients. Results Out of 802 cardiomyopathy patients, 27 exhibited mutations in genes tied to fatty acid metabolism. Specifically, 16 patients demonstrated a hypertrophic cardiomyopathy (HCM) phenotype, and 11 showed a dilated cardiomyopathy (DCM) phenotype. The implicated genes were SLC22A5 (n=7), ACADVL (n=6), ACADS (n=4), ACADM (n=3), SLC25A20 (n=3), ACADL (n=2), HADH (n=1), and AGK (n=1), with a higher prevalence in males. Among these, the SLC22A5 mutation was predominant and correlated with HCM phenotype. Notably, compound mutations were frequently observed (16/27), leading to earlier disease onset and diminished aortic sinus dimension. Further investigation showed that smaller aortic sinus dimensions resulted from abnormal left ventricular myocardial work. HCM phenotype mutation carriers showed more consistent left ventricular hypertrophy and a higher probability of right ventricular hypertrophy, while DCM phenotype mutation carriers exhibited impaired contractile function across all left ventricle segments. After a 24-month follow-up, the DCM phenotype group demonstrated higher cardiovascular risk, including two fatalities. Conclusion Our investigation highlights the significant prevalence of mutations related to abnormal fatty acid metabolism in adult cardiomyopathy patients, underscoring the utility of a gene-echocardiography approach for diagnosis.

Identification of Key Genes Related to Immune-Lipid Metabolism in Skin Barrier Damage and Analysis of Immune Infiltration.

Several physical and chemical factors regulate skin barrier function. Skin barrier dysfunction causes many inflammatory skin diseases, such as atopic dermatitis and psoriasis. Activation of the immune response may lead to damage to the epidermal barrier. Abnormal lipid metabolism is defined as abnormally high or low values of plasma lipid components such as plasma cholesterol and triglycerides. The mouse skin barrier damage model was used for RNA sequencing. Bioinformatics analysis and validation were performed. Differently expressed genes (DEGs) related to immune and lipid metabolism were screened by differentially expressed gene analysis, and the enriched biological processes and pathways of these genes were identified by GO-KEGG. The interactions between DEGs were confirmed by constructing a PPI network. GSEA, transcription factor regulatory network, and immune infiltration analyses were performed for the 10 genes. Expression validation was performed by public datasets. The expression of key genes in mouse skin tissue was detected by qPCR. The expression of differentially expressed immune cell markers in the skin was detected by immunofluorescence. Based on the trans epidermal water loss (TEWL) score, the expression of key genes was detected by qPCR before skin barrier injury, at 4h and 7d, and at recovery from injury. Il17a, Il6, Tnf, Itgam, and Cxcl1 were immune-related key genes. Pla2g2f, Ptgs2, Plb1, Pla2g3, and Pla2g2d were key genes for lipid metabolism. Database validation and experimental results revealed that the expression trends of these genes were consistent with our analyses. The research value of these genes has been demonstrated through mouse datasets and experimental validation, and future therapeutic approaches may be able to mitigate the disease by targeting these genes to modulate the function of the skin barrier.

Association of obesity and metabolic health status with cerebral small vessel disease in stroke-free individuals

Abstract Background It remains unclear whether obesity itself or metabolic abnormalities coexisting with obesity, are associated with stroke. Purpose We aimed to investigate the association of obesity and metabolic health status with cerebral small vessel disease (SVD) in stroke-free participants from a brain health check-up. Methods We conducted a cross-sectional study of 6088 stroke-free participants who underwent brain magnetic resonance imaging at a brain check-up between 2013 and 2020. Participants were categorised according to sex-specific waist circumference and metabolic health status. A metabolically healthy status was defined as the absence of components of metabolic syndrome other than a large waist circumference, such as high blood pressure, hyperglycaemia, and dyslipidaemia. The total SVD score was derived from four magnetic resonance imaging markers: silent lacunar infarcts, cerebral microbleeds, moderate-to-severe white matter hyperintensities, and enlarged perivascular spaces. Results The mean age of the participants was 55±12 years and 46% were women. The prevalence of metabolically healthy obesity was 650 (11%) and the proportion of metabolically healthy obesity among individuals with obesity was 24%. The prevalence of metabolically unhealthy obesity was 2043 (34%), and the proportion of metabolically unhealthy obesity among individuals with metabolically unhealthy individuals was 58%. The prevalence of moderate-to-severe SVD scores (≥2) was 348 (6%), which was higher in metabolically unhealthy individuals, regardless of obesity status. Compared with the metabolically healthy non-obesity group, the metabolically unhealthy non-obesity (odds ratio 2.22 [95% CI, 1.44–3.42]) and metabolically unhealthy obesity (odds ratio, 2.76 [95% CI, 1.80–4.24]) groups had a significantly higher multivariable-adjusted risk for a total SVD score of ≥2. Further sensitivity analyses using BMI-defined obesity instead of waist circumference-defined obesity yielded similar results. Conclusions Abdominal and general obesity alone are not associated with higher total SVD scores in stroke-free individuals. Unhealthy metabolic components, especially high blood pressure and hyperglycaemia, are important risk factors for SVD.

A IMPORTÂNCIA DA EDUCAÇÃO PERMANENTE PARA OS AGENTES COMUNITÁRIOS DE SAÚDE NO ACOMPANHAMENTO DE PACIENTES COM SÍNDROME METABÓLICA

Metabolic syndrome (MS) is a series of metabolic disorders or abnormalities that together are considered risk factors in the same individual for the development of diabetes and cardiovascular diseases. artery, with the dietary plan being the treatment of first choice. Community health agents play an important role in helping to promote health and prevent diseases through home care, in addition to creating links with the community, promoting humanization, acceptance and accountability. They also provide guidance to the population on the use of and access to health system services. They have great responsibility in educating patients, enhancing health care actions. Community health agents encounter difficulties in carrying out educational work, often caused by the community due to the culture of medicalization, in addition to there being people in the community without comorbidity repressing the capacity of health education to carry out prevention. Therefore, the importance of educational practices is undeniable, as from them society obtains sufficient information to opt for healthier choices and modify their risk behaviors, resulting in a reduction in cases of metabolic syndrome.

Systemic Inflammation Across Metabolic Obesity Phenotypes: A Cross-Sectional Study of Korean Adults Using High-Sensitivity C-Reactive Protein as a Biomarker

Chronic systemic inflammation is a hallmark of obesity. This cross-sectional study aimed to investigate the association between metabolic obesity phenotypes and inflammatory markers in Korean adults (N = 21,112; mean age: 50.9 ± 16.6). Metabolic obesity phenotypes were categorized into metabolically healthy non-obesity (MHNO), metabolically unhealthy non-obesity (MUNO), metabolically healthy obesity (MHO), and metabolically unhealthy obesity (MUO) based on body mass index and the presence of any metabolic abnormalities. High-sensitivity C-reactive protein (hs-CRP) levels were measured. Multiple linear regression was used to determine the association between obesity phenotypes and hs-CRP levels. In the male sample, compared to the MHNO type, the MUNO, MHO, and MUO types were associated with a 22.3% (95% confidence interval; CI: 14.7–30.3%), 15.8% (95% CI: 2.6–30.7%), and 12.5% (95% CI: 3.0–22.9%) increase in the hs-CRP levels, respectively. The association between metabolic obesity types and hs-CRP levels was stronger among the female sample; compared to the MHNO type, the MUNO, MHO, and MUO types were associated with a 30.2% (95% CI: 22.8–38.2%), 16.0% (95% CI: 6.5–26.4%), and 22.8% (95% CI: 13.6–32.8%) increase in the hs-CRP levels, respectively. Our findings indicate a varying profile of systemic inflammation across different metabolic obesity phenotypes.

Short and long-term effects of kidney donation on mineral and bone metabolism

BackgroundLiving kidney donors (LKD) experience an abrupt decline in glomerular filtration rate (GFR) resulting in abnormalities of mineral and bone metabolism (MBD), and this may have implications for skeletal health. We prospectively studied acute and long term MBD adaptation of LKD from two kidney transplant centers (São Paulo, Brazil and Miami, USA).MethodsRenal function and MBD parameters longitudinally after kidney donation (baseline – D0, day 1, 14, 180 and 360 post-operatively) were measured in 74 patients (40 y, 73% female, 54% Brazilian). A subset of 20 donors from Brazil were reassessed after 10 years of nephrectomy.ResultsAt baseline, Brazilian donors presented lower intact FGF23 (20.8 vs. 80.1 pg/mL, P < 0.01) and higher PTH (47.4 vs. 40.1, P = 0.04) than their US counterparts. GFR decreased to 63% of its baseline levels just after donation but improved 10% during the first year. PTH levels increased on D1, returning to baseline levels on D14, while FGF23 remained higher than baseline over the first year. LKD had a significant reduction of serum phosphate on D1, which returned to baseline levels on D180. A higher fractional excretion of phosphate (FEP) was noted since D14. After 10 years of donation, 20 LKD presented a sustained reduction in GFR (74.8 ± 14mL/min). There was a return to baseline in serum FGF23 [21.8 (18–30) pg/mL] and FEP, accompanied by an increase in serum calcium. PTH remained elevated (57.9 ± 18 pg/mL), whereas serum calcitriol and Klotho were lower than before the donation.ConclusionsThe abrupt decline in kidney mass is associated with an increase in PTH and FGF23 that is not explained by phosphate retention. In a long-term evaluation, LKD showed a sustained drop in GFR, with lower serum calcitriol and Klotho, and higher PTH. The effects of these changes should be investigated in further studies.

Novel Perspectives in the Management of Colorectal Cancer: Mechanistic Investigations Into the Reversal of Drug Resistance via Active Constituents Derived From Herbal Medicine.

The high incidence and mortality rate of colorectal cancer have become a significant global health burden. Chemotherapy has been the traditional treatment for colorectal cancer and has demonstrated promising antitumor effects, leading to significant improvements in patient survival. However, the development of chemoresistance poses a major challenge during chemotherapy in colorectal cancer, significantly impeding treatment efficacy and affecting patient prognosis. Despite the development of a variety of novel anticolorectal cancer chemotherapy agents, their effectiveness and side effects vary, possibly due to the complex mechanisms of resistance in colorectal cancer. Abnormal drug metabolism or protein targets are the most direct causes of resistance. Further studies have revealed that these resistance mechanisms involve biochemical processes such as altered protein expression, autophagy, and epithelial-mesenchymal transitions. Herbal active ingredients offer an alternative treatment option and have shown promise in reversing colorectal cancer drug resistance. This paper aims to summarize the role of various biochemical processes and key protein targets in the occurrence and maintenance of resistance mechanisms in colorectal cancer. Additionally, it elaborates on the mechanisms of action of herbal active ingredients in reversing colorectal cancer drug resistance. The article also discusses the limitations and opportunities in developing novel anticolorectal cancer drugs based on herbal medicine.

Circadian Regulation of Lipid Metabolism during Pregnancy

A cluster of metabolic changes occur to provide energy for fetal growth and development during pregnancy. There is a burgeoning body of research highlighting the pivotal role of circadian rhythms in the pathogenesis of metabolic disorders and lipid homeostasis in mammals. Perturbations of the circadian system and lipid metabolism during gestation might be responsible for a variety of adverse reproductive outcomes comprising miscarriage, gestational diabetes mellitus, and preeclampsia. Growing studies have confirmed that resynchronizing circadian rhythms might alleviate metabolic disturbance. However, there is no clear evidence regarding the specific mechanisms by which the diurnal rhythm regulates lipid metabolism during pregnancy. In this review, we summarize previous knowledge on the strong interaction among the circadian clock, lipid metabolism, and pregnancy. Analyzing the circadian clock genes will improve our understanding of how circadian rhythms are implicated in complex lipid metabolic disorders during pregnancy. Exploring the potential of resynchronizing these circadian rhythms to disrupt abnormal lipid metabolism could also result in a breakthrough in reducing adverse pregnancy outcomes.

Study on the Correlation between SLC39A8 Gene and Body Constitution-related Phenotypes and Hearing loss: Based on a Mendelian Randomization analysis

IntroductionWe examined the role of hearing functions as potential mediators in relationships between noise exposures and abnormal body constitution-related results. Additionally, we employed Mendelian randomization (MR) to explore the causative connections between hearing problems and bodily composition.Material and methodsGene connections pertaining to phenotypes of hearing loss and body constitution were obtained from publically available summary data collected from adult population genome-wide association studies. Colocalization analysis was utilized to scrutinize the genetic associations pertaining to age-related hearing impairment (ARHI) liability and BMI within the SLC39A8 locus. For a comprehensive examination, we employed bi-directional MR encompassing both the 'forward' direction (from the composition of the body to hearing) and the 'reverse' direction.ResultsA common causative variable (rs13107325) for BMI and ARHI at the SLC39A8 locus was supported by colocalization analysis, which revealed that the two diseases shared the variant at the SLC39A8 gene. The forward analyses showed that body fat percentage (BFP) was significantly linked with the risk of ARHI [OR =0.95 (95% CI:0.93 to 0.98)] and that waist circumference (WC) was favorably associated with sensorineural hearing loss (SNHL) [OR=0.83 (95% CI:0.72 to 0.97)].ConclusionsWe couldn't find any proof to back up a causal relationship between constitution and HL in the reverse MR Analysis. Colocalization analysis recommended that SLC39A8 variant was often the source of high ARHI and BMI risk. In prospective MR, we discovered causal associations between WC and BFP with SNHL and ARHI, respectively. Therefore, our results suggest lipid metabolic abnormalities leading to adverse health outcome may lead to HL.

Renal Inflammation, Oxidative Stress, and Metabolic Abnormalities During the Initial Stages of Hypertension in Spontaneously Hypertensive Rats

Background: Hypertension is a major cause of mortality worldwide. The kidneys play a crucial role in regulating blood pressure and fluid volume. The relationship between the kidneys and hypertension is complex, involving factors such as the renin–angiotensin system, oxidative stress, and inflammation. This study aims to assess the levels of inflammatory markers, oxidative stress, and metabolic factors in the kidneys, focusing on their potential role in early renal damage and their association with the development of hypertension. Methods: This study was designed to compare the levels of selected inflammatory markers, e.g., interleukins, tumor necrosis factor-α (TNF-α), transforming growth factor, and serine/threonine-protein (mTOR); oxidative stress markers such as malondialdehyde, sulfhydryl group, and glucose (GLC); and metabolic markers among other enzymes, such as alanine transaminase (ALT), aspartate transaminase (AST), hexokinase II (HK-II), and hypoxia-inducible factor-1α (HIF-1α), as well as creatinine in the kidneys of spontaneously hypertensive rats (SHR/NCrl, n = 12) and Wistar Kyoto rats (WKY/NCrl, n = 12). Both juvenile (5 weeks old) and maturing (10 weeks old) specimens were examined using spectrophotometric methods, e.g., ELISA. Results: Juvenile SHRs exhibited reduced renal levels of all studied cytokines and chemokines, with lower oxidative stress and deficits in the mTOR and HK-II levels compared to the age-matched WKYs. Maturing SHRs showed increased renal levels of interleukin-1β (IL-1β), IL-6, IL-18, and TNF-α, alongside elevated carbonyl stress and increased HIF-1α as opposed to their control peers. The levels of all other studied markers were normalized in these animals, except for ALT (increased), ALP, and GLC (both reduced). Conclusions: This study underscores the significant impact of inflammatory, oxidative stress, and metabolic marker changes on renal function. Juvenile SHRs display lower marker levels, indicating an immature immune response and potential subclinical kidney damage that may contribute to hypertension development. In contrast, mature SHRs exhibit chronic inflammation, oxidative dysregulation, and metabolic disturbances, suggesting cellular damage. These changes create a feedback loop that worsens kidney function and accelerates hypertension progression, highlighting the kidneys’ crucial role in both initiating and exacerbating this condition.

Study on serum metabolomics characteristics of obese patients with erectile dysfunction.

Erectile dysfunction (ED) is a common male sexual health problem that can be associated with obesity. This study aimed to identify serum metabolic differences and pathways related to ED in obese men using non-targeted metabolomics techniques. We included 54 obese male patients with (n = 27) and without (n = 27) ED. We collected 5 mL of fasting elbow vein blood and analyzed serum metabolites using ultra-high-performance liquid chromatography-mass spectrometry. Multivariate statistical methods (principal component analysis and orthogonal partial least squares discriminant analysis) were used to identify differential metabolites between the groups. Finally, pathway analysis using the Kyoto encyclopedia of genes and genomes database identified 4 differential metabolic pathways in obese men with ED compared to obese men without ED. A total of 77 differential metabolites were identified in obese men with ED compared to the control group (obese men without ED) using a threshold of variable importance in the projection > 1 and P < .05. Pathway analysis revealed 4 main differences: glycine, serine and threonine metabolism, glycerophospholipid metabolism, aminoacyl-tRNA biosynthesis, and D-glutamine and D-glutamate metabolism. Specific metabolites associated with these pathways included betaine aldehyde, choline, L-threonine, phosphatidylcholine, L-serine, and D-glutamine. Our findings suggest abnormalities in fatty acid metabolism, phospholipid metabolism, and amino acid metabolism between obese men with and without ED. Metabolites such as betaine aldehyde, choline, L-threonine, phosphatidylcholine, L-serine, and D-glutamine may be potential biomarkers for distinguishing obese men with ED.

Chitin Deacetylase 1 Gene as an Optimal RNAi-Based Target for Controlling the Tomato Leaf Miner Tuta absoluta

Chitin is a critical component of both the exoskeleton and internal structures of insects, which can protect insects from mechanical damage, dehydration and pathogen infection, and plays a significant role in the molting process. Chitin deacetylases (CDAs), key enzymes involved in chitin metabolism, are widely distributed among arthropods and microorganisms. In this study, we identified a CDA gene, TaCDA1, in the invasive insect species Tuta absoluta (Meyrick). Sequence analysis demonstrated a high degree of similarity to CDAs in other insects, revealing the presence of three conserved domains. Quantitative analysis showed that the TaCDA1 gene exhibited peak expression during the pupal stage, particularly within the epidermis. The suppression of TaCDA1 expression through RNA interference in T. absoluta pupae significantly impacted the expression of genes associated with chitin metabolism, increasing mortality and developmental abnormalities during the pupa–adult transition and reducing the pupal weight. Furthermore, soaking gene-specific dsRNA resulted in elevated mortality rates during the larva–pupa transition, causing the inability to form new cuticles or undergo ecdysis, as confirmed by subsequent histological observations. The oral administration of dsTaCDA1 + sucrose solution did not significantly impact NtCDA1 expression or the mortality rate compared to the dsGFP + sucrose solution control in the non-target insect Nesidiocoris tenuis. This study demonstrated that TaCDA1 is a potential and safe target for pest control of T. absoluta.