Progressive Metabolic Disease Research Articles

Non-aggregated and water soluble non-peripherally octa substituted Co(II) and Cu(II) phthalocyanines: Synthesis and α-glucosidase inhibitory effects

Type 2 diabetes (T2DM) is a progressive metabolic disease associated with high blood sugar levels that affects 537 million people worldwide. This study aim is to investigate the potential for use in the treatment of T2DM by examining the in vitro glucosidase inhibitory effects of novel synthesized metallophthalocyanines. For this reason, we have synthesized cobalt(II), copper(II) phthalocyanines (3PY-ON-CoQ, 3PY-ON-CuQ) that are both water-soluble and do not aggregate in water. These compounds were characterized by using various spectroscopic methods. The α-glucosidase inhibitory properties of 3PY-ON-CoQ and 3PY-ON-CuQ were carried out using the spectrophotometric method. Then, Lineweaver-Burk and Dixon plots were examined to determine the inhibitory type and constant (Ki). The IC50 values of 3PY-ON-CoQ and 3PY-ON-CuQ were 6.85 ± 1.25 μM and 55.09 ± 2.64 μM, respectively. Both compounds displayed mixed inhibitory effects on α-glucosidase according to Lineweaver-Burk plots. The Ki values of 3PY-ON-CoQ and 3PY-ON-CuQ were calculated as 6.30 ± 1.55 μM and 54.25 ± 1.20 μM, respectively. The results of this work may lead to the discovery of new compounds for the treatment of T2DM.

Aromatic Amino Acids Promote Lipid Metabolism Disorders by Increasing Hepatic Bile Acid Synthesis

BackgroundObesity is a progressive metabolic disease that begins with lipid metabolism disorders. Aromatic amino acids (AAAs), including tryptophan, phenylalanine, and tyrosine, have diverse biological activities as nutrients. However, the underlying mechanisms by which AAAs affect lipid metabolism are unclear. ObjectivesThis study was designed to investigate the possible roles and underlying molecular mechanisms of AAA in the pathogenesis of lipid metabolism disorders. MethodsWe added an AAA mixture to the high-fat diet (HFD) of mice. Glucose tolerance test was recorded. Protein expression of hepatic bile acid (BA) synthase and mRNA expression of BA metabolism-related genes were determined. Hepatic BA profiles and gut microbial were also determined in mice. ResultsThe results showed that AAA significantly increased body weight and white adipose tissue, aggravated liver injury, impaired glucose tolerance and intestinal integrity, and significantly increased hepatic BA synthesis by inhibiting intestinal farnesoid X receptor (FXR). Moreover, AAA increased the content of total BA in the liver and altered the hepatic BA profile, with elevated levels of lithocholic acid, glycochenodeoxycholic acid, and glycoursodeoxycholic acid. AAA markedly increased the levels of proteins involved in BA synthesis (cholesterol 7α-hydroxylase and oxysterol 7α-hydroxylase) and inhibited the intestinal FXR. Gut microbial composition also changed, reducing the abundance of some beneficial bacteria, such as Parvibacter and Lactobacillus. ConclusionsUnder HFD conditions, AAAs stimulate BA synthesis in both the classical and alternative pathways, leading to aggravation of liver injury and fat deposition. Excessive intake of AAA disrupts BA metabolism and contributes to the development of lipid metabolism disorders, suggesting that AAA may be a causative agent of lipid metabolism disorders.

Immune cell balance as potential biomarker of progressing non-alcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a widespread chronic, slowly progressive metabolic multifactorial disease. It is represented by several clinical and morphological forms: steatosis, nonalcoholic steatohepatitis (NASH) (with or without fibrosis), and liver cirrhosis. The search for minimally invasive and cost-effective biomarkers of NAFLD is a key task in the diagnosis, staging of progression, and long-term monitoring of NAFLD. This article discusses the possibility of using immune cell balance as potential minimally invasive peripheral markers of NAFLD progression. In the progression of NASH from steatosis to fibrosis and cirrhosis, inflammation plays an important role because of the activation of Kupffer cells and increased migration of monocytes, dendritic cells, neutrophils, and activated T lymphocytes into the tissues. Macrophages originating from monocytes, with NASH progression, gradually begin to prevail over the pool of resident macrophages. The risk of NASH and fibrosis development in patients with NAFLD increases with the ratio of neutrophils/lymphocytes in the liver. An increase in the Th17 cell count and a decrease in T-regulatory cell count can contribute to increased hepatic steatosis and inflammation development in NAFLD and accelerate the transition from simple steatosis to steatohepatitis and fibrosis. Information on the participation of noncoding RNAs in the regulation of the balance of immune cells in NAFLD is presented, which also allows us to consider them as additional, along with cellular, markers of disease progression.

Early Structural, Biochemical, and Metabolic Responses to Anlotinib in Patients With Progressive Radioactive Iodine Refractory Differentiated Thyroid Cancer

ObjectiveWe aimed to assess the early efficacy of anlotinib in patients with progressive radioactive iodine refractory differentiated thyroid cancer at the structural, biochemical, and metabolic levels. MethodsTen eligible patients were prospectively enrolled to receive anlotinib. Their responses were assessed at 6 weeks. Apart from the structural response according to Response Evaluation Criteria in Solid Tumors version 1.1, the biochemical response was assessed by serum thyroglobulin (Tg), and the metabolic response was assessed by 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) according to the European Organization for Research and Treatment of Cancer criteria. A safety profile was recorded. ResultsStructurally controlled disease (20% partial response + 80% stable disease) was observed in all patients. The median longest diameter of target lesions shrank from 20.8 mm (IQR, 14.9-27.5) to 17.0 mm (IQR, 14.1-23.7) (P < .001), and the average shrinkage rate was −15.1 ± 14.1%. Sharp serum Tg reduction by 72.8 ± 16.4% was observed in 8 measurable patients. The 18F-FDG PET/CT-mapped glucose metabolic response was not quite comparable to the structural response, with 90% of the patients having controlled disease (30% partial metabolic response + 60% stable metabolic disease), whereas 10% presented progressive metabolic disease. The most common treatment-emergent adverse events (AEs) were hypertension (100%) and proteinuria (70%). Most AEs were grade 1 or 2, whereas grade 3 AEs occurred only in hypertension. ConclusionAnlotinib is generally well tolerated and can bring early disease control within the initial 6 weeks of treatment. The sharp biochemical response suggests Tg to be an early sensitive biomarker to anlotinib, whereas the heterogeneous metabolic response might play a complementary role.

Early evaluation of CAR-T cell therapy response in R/R DLBCL patients using 18F-FDG PET/CT.

CD19-targeted chimeric antigen receptor T (CAR-T) cell therapy provides a durable response in patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). The role of fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for early evaluation of response in patients with that immunotherapy was evaluated. Three separate 18F-FDG PET/CT examinations of 53 patients (29 males, 24 females; median 62 years old) with R/R DLBCL were conducted; before bridging therapy [time of decision (TD)], before CAR-T (tisagenlecleucel, n=37; lisocabtagenemaraleucel, n=16) infusion [time of CAR-T infusion (IT)], and one month (M1) after CAR-T infusion. Response was evaluated based on the Deauville 5-point scale and Lugano criteria. Among 21 patients (39.6%) with complete metabolic response (CMR) at IT-PET, 20 were able to continue CMR, while one showed progression at M1-PET. Among 32 patients (60.4%) with non-CMR at IT-PET, 12, 8, 4, and 8 showed CMR, partial metabolic response (PMR), (non-metabolic response (NMR), and progressive metabolic disease (PMD), respectively, at M1-PET as compared with IT-PET. Evaluations of M1-PET as compared with baseline TD-PET indicated 32, 7, 5, and 9 patients with CMR, PMR, NMR, and PMD, respectively. After a median 10.1 months, 26 patients showed progression and 13 had died from DLBCL. The 32 who achieved CMR showed significantly longer progression-free (P<0.0001) and overall survival (P<0.0001) periods as compared to the 21 non-CMR patients. Fluorine-18-FDG PET/CT findings obtained one month after CAR-T cell therapy showed accuracy for early response evaluation and prediction of progression in patients with R/R DLBCL.

The value of 18F-FDG PET/CT in Langerhans cell histiocytosis.

To investigate the value of 18F-FDG PET/CT in diagnosis and disease evaluation of Langerhans cell histiocytosis (LCH). A retrospective analysis of 31 patients with LCH confirmed by histopathology was performed. A systematic analysis of the PET/CT imaging manifestations of LCH was performed, recording patients who were treated and receiving PET/CT for efficacy evaluation. In addition, clinical and laboratory data of LCH patients were collected, and the correlation between these data and PET/CT metabolic parameters was initially investigated. Of the 31 patients, thirty had at least 1 PET/CT positive lesions (96.7%), and one had only skin damage without abnormalities on PET/CT. Of 31 patients, fifteen (48.4%) had single system (SS) disease (9 cases with a single site and 6 cases with multiple sites) and 16 (51.6%) had multisystem (MS) disease (6 low risk and 10 high risk cases). The incidence of LCH lesions in the bone, lymphatic system, pituitary gland, liver, soft tissue, thyroid gland, thymus, and lungs was 20 cases (64.5%), 12 cases (38.7%), 3 cases (9.7%), 2 cases (6.5%), 2 cases (6.5%), 1 case (3.2%), 1 case (3.2%), and 8 cases (25.8%), respectively. A total of 21 PET/CT follow-up scanning were performed in 13 patients receiving chemotherapy, with 13 (61.9%) partial metabolic remission (PMR), 6 (28.6%) progressive metabolic disease (PMD), and 2 (9.5%) stable metabolic disease (SMD), according to PET Response Evaluation Criteria in Solid Tumors (PRECIST) 1.0. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and Lactic Dehydrogenase (LDH) were positively correlated with TTLG (total TLG) (R2 = 0.3256, 0.2409, 0.4205, P < 0.05). The Re-examine SUVmax is positively correlated with re-examine LDH (R2 = 0.7285, P < 0.05). 18F-FDG PET/CT is an effective way to diagnose and evaluate LCH. PET metabolic parameters were associated with laboratory inflammatory markers, suggesting that 18F-FDG PET/CT may be helpful in evaluating disease activity of LCH.

Biotransformed bear bile powder alleviates diet-induced nonalcoholic fatty liver disease in mice by regulating the gut microbiota and reversing lipid metabolism

BackgroundThe pathogenesis of metabolic syndrome was strongly associated with compromised metabolism homeostasis and gut microbiota imbalance. NAFLD is a progressive metabolic liver disease for which effective interventions are lacking. Bile acids exhibited appreciable metabolic regulatory effects and selective antimicrobial activity. Aim of the studyThis study was designed to investigate the effect of BBBP, which mainly contained bile acids, on NAFLD from the perspectives of gut microbiota and metabolomics. Materials and methodsThe present study was initiated on the anti-NAFLD effect of BBBP in HFD-fed mice. The efficacy of BBBP was evaluated by mice phenotypes, liver histopathological analysis and serum lipid and glucose levels. The activation of bile acid receptors such as Nr1h4, Nr1i2 and S1pr2 were detected by qRT-PCR analysis. Subsequently, untargeted metabolomics coupled with microbiomics was used to explore the mechanism of BBBP against NAFLD. Human L02 hepatocytes induced by OA and PA were used to investigate the effect of GABA on reducing lipid accumulation in vitro. ResultsBBBP significantly and dose-dependently alleviated the obese phenotype, lipid accumulation and liver injury in mice subjected to 18 weeks HFD diet. Untargeted metabolomics and microbiomics analysis revealed that BBBP could alleviate the disturbance of lipid and amino acid metabolism and the imbalance of gut microbiota. Furthermore, BBBP oral gavage activated liver bile acid receptors, as indicated by elevated mRNA levels of Nr1h4, Nr1i2 and S1pr2. Surprisingly, we determined that BBBP, which mainly contained bile acids that possessed antimicrobial activity, could promote the growth of Lactobacillus. Correlation analysis showed a remarkable correlation between Lactobacillus and endogenous metabolites such as valine, serine, glutamine, et al. Among them, GABA which could be produced by Lactobacillus significantly reduced the lipid accumulation in L02 cells. ConclusionsThe role of BBBP in regulating lipid metabolism might be achieved by activating bile acid receptors, or partially by promoting the levels of Lactobacillus and its metabolites such as GABA. Our study provided evidence that BBBP could be a novel therapeutic candidate for the treatment of NAFLD.

The nurse’s role in recognizing dermatological changes in individuals with diabetes mellitus

Diabetes is a chronic, progressive metabolic disease that has now reached pandemic proportions. It’s estimated that 10.5% of the world’s population has diabetes, making it a global challenge that requires attention and innovative strategies from healthcare systems worldwide. While macrovascular complications remain the leading cause of death in diabetes patients, this study provides a detailed description of dermatological changes in these individuals, with a particular emphasis on the severity of diabetic foot conditions. Within the realm of dermatological manifestations, specific changes such as acanthosis nigricans, diabetic dermopathy, and xerosis are thoroughly described, and they are all specific for individuals with type 2 diabetes. Other manifestations, such as diabetic blisters and vitiligo, which are more common in individuals with type 1 diabetes, are also analysed. The study places a special focus on the crucial role of nurses in recognizing skin changes in diabetes patients. It highlights the importance of continuous education about precise insulin application and emphasises the need for regular systematic skin examinations, particularly in areas that are not easily visible to the patient, such as the feet or back. Nurse educators, like physicians, also share the responsibility for demonstrating self-examination skills or conducting joint examinations of these areas during consultations. Ultimately, this study advocates for an active partnership between healthcare professionals and individuals with diabetes to collectively address the challenges presented by diabetes, particularly in terms of dermatological changes.

Disturbances in Nitric Oxide Cycle and Related Molecular Pathways in Clear Cell Renal Cell Carcinoma.

It is important to note that maintaining adequate levels of nitric oxide (NO), the turnover, and the oxidation level of nitrogen are essential for the optimal progression of cellular processes, and alterations in the NO cycle indicate a crucial step in the onset and progression of multiple diseases. Cellular accumulation of NO and reactive nitrogen species in many types of tumour cells is expressed by an increased susceptibility to oxidative stress in the tumour microenvironment. Clear cell renal cell carcinoma (ccRCC) is a progressive metabolic disease in which tumour cells can adapt to metabolic reprogramming to enhance NO production in the tumour space. Understanding the factors governing NO biosynthesis metabolites in ccRCC represents a relevant, valuable approach to studying NO-based anticancer therapy. Exploring the molecular processes mediated by NO, related disturbances in molecular pathways, and NO-mediated signalling pathways in ccRCC could have significant therapeutic implications in managing and treating this condition.

The remodeling of metabolic brain pattern in patients with extracranial diffuse large B-cell lymphoma

BackgroundOwing to the advances in diagnosis and therapy, survival or remission rates for lymphoma have improved prominently. Apart from the lymphoma- and chemotherapy-related somatic symptom burden, increasing attention has been drawn to the health-related quality of life. The application of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) has been routinely recommended for the staging and response assessment of FDG-avid lymphoma. However, up till now, only a few researches have investigated the brain metabolic impairments in patients with pre-treatment lymphoma. The determination of the lymphoma-related metabolic brain pattern would facilitate exploring the tailored therapeutic regimen to alleviate not only the physiological, but also the psychological symptoms. In this retrospective study, we aimed to establish the diffuse large B-cell lymphoma-related pattern (DLBCLRP) of metabolic brain network and investigate the correlations between DLBCLRP and several indexes of the staging and response assessment.ResultsThe established DLBCLRP was characterized by the increased metabolic activity in bilateral cerebellum, brainstem, thalamus, striatum, hippocampus, amygdala, parahippocampal gyrus and right middle temporal gyrus and by the decreased metabolic activity in bilateral occipital lobe, parietal lobe, anterior cingulate gyrus, midcingulate cortex and medial frontal gyrus. Significant difference in the baseline expression of DLBCLRP was found among complete metabolic response (CMR), partial metabolic response (PMR) and progressive metabolic disease (PMD) groups (P < 0.01). DLBCLRP expressions were also significantly or tended to be positively correlated with international prognostic index (IPI) (rs = 0.306, P < 0.05), lg(total metabolic tumor volume, TMTV) (r = 0.298, P < 0.05) and lg(total lesion glycolysis, TLG) (r = 0.233, P = 0.064). Though no significant correlation of DLBCLRP expression was found with Ann Arbor staging or tumor SUVmax (P > 0.05), the post-treatment declines of DLBCLRP expression were significantly positively correlated with Ann Arbor staging (rs = 0.284, P < 0.05) and IPI (rs = 0.297, P < 0.05).ConclusionsThe proposed DLBCLRP would lay the foundation for further investigating the cerebral dysfunction related to DLBCL itself and/or treatments. Besides, the expression of DLBCLRP was associated with the tumor burden of lymphoma, implying a potential biomarker for prognosis.

The Prognostic Role of [18F]FDG PET/CT in Patients with Advanced Cutaneous Squamous Cell Carcinoma Submitted to Cemiplimab Immunotherapy: A Single-Center Retrospective Study.

Background: Baseline 2-deoxy-2[18F]fluoro-d-glucose ([18F]FDG) positron emission tomography (PET)-derived parameters and 12-week metabolic response were investigated as prognostic factors in advanced cutaneous squamous cell carcinoma (cSCC) submitted to cemiplimab immunotherapy. Materials and Methods: Clinical records of 25 cSCC patients receiving cemiplimab, submitted to [18F]FDG positron emission tomography/computed tomography (PET/CT) at baseline and after ∼12 weeks, were retrospectively reviewed. The Kaplan-Meier (KM) method was applied to analyze differences in event-free survival (EFS), and Cox regression analysis was employed to identify the prognostic factors. Results: At the 12-week PET/CT evaluation, 16 patients (64%) were classified as responders (complete or partial response) and 9 (36%) as nonresponders ("unconfirmed progressive metabolic disease") according to immune PET Response Criteria in Solid Tumors (iPERCIST). By KM analysis, baseline metabolic tumor volume (MTV) and total lesion glycolysis (TLG) significantly correlated with the EFS (p < 0.05). Furthermore, the KM analysis showed that the lack of metabolic response at 12 weeks was associated with meaningfully shorter EFS (7.2 ± 1 months in nonresponders vs. 20.3 ± 2.3 months in responders). In Cox multivariate analysis, metabolic response at 12 weeks remained the only predictor of the EFS (p < 0.05). Conclusions: Baseline tumor load (i.e., MTV and TLG) and metabolic response at 12 weeks may have a prognostic impact in cSCC patients treated with cemiplimab.

Diabetic Pneumopathy- A Novel Diabetes-associated Complication: Pathophysiology, the Underlying Mechanism and Combination Medication.

The "diabetic lung" has been identified as a possible target organ in diabetes, with abnormalities in ventilation control, bronchomotor tone, lung volume, pulmonary diffusing capacity, and neuroadrenergic bronchial innervation. This review summarizes studies related to diabetic pneumopathy, pathophysiology and a number of pulmonary disorders including type 1 and type 2 diabetes. Electronic searches were conducted on databases such as Pub Med, Wiley Online Library (WOL), Scopus, Elsevier, ScienceDirect, and Google Scholar using standard keywords "diabetes," "diabetes Pneumopathy," "Pathophysiology," "Lung diseases," "lung infection" for review articles published between 1978 to 2023 very few previous review articles based their focus on diabetic pneumopathy and its pathophysiology. Globally, the incidence of diabetes mellitus has been rising. It is a chronic, progressive metabolic disease. The "diabetic lung" may serve as a model of accelerated ageing since diabetics' rate of respiratory function deterioration is two to three-times higher than that of normal, non-smoking people. Diabetes-induced pulmonary dysfunction has not gained the attention it deserves due to a lack of proven causality and changes in cellular properties. The mechanism underlying a particular lung illness can still only be partially activated by diabetes but there is evidence that hyperglycemia is linked to pulmonary fibrosis in diabetic people.

Urine-derived stem cell therapy for diabetes mellitus and its complications: progress and challenges.

Diabetes mellitus (DM) is a chronic and relentlessly progressive metabolic disease characterized by a relative or absolute deficiency of insulin in the body, leading to increased production of advanced glycosylation end products that further enhance oxidative and nitrosative stresses, often leading to multiple macrovascular (cardiovascular disease) and microvascular (e.g., diabetic nephropathy, diabetic retinopathy, and neuropathy) complications, representing the ninth leading cause of death worldwide. Existing medical treatments do not provide a complete cure for DM; thus, stem cell transplantation therapy has become the focus of research on DM and its complications. Urine-derived stem cells (USCs), which are isolated from fresh urine and have biological properties similar to those of mesenchymal stem cells (MSCs), were demonstrated to exert antiapoptotic, antifibrotic, anti-inflammatory, and proangiogenic effects through direct differentiation or paracrine mechanisms and potentially treat patients with DM. USCs also have the advantages of simple noninvasive sample collection procedures, minimal ethical issues, low cost, and easy cell isolation methods and thus have received more attention in regenerative therapies in recent years. This review outlines the biological properties of USCs and the research progress and current limitations of their role in DM and related complications. In summary, USCs have shown good versatility in treating hyperglycemia-impaired target organs in preclinical models, and many challenges remain in translating USC therapies to the clinic.

FRI027 Regulation Of A Novel Sortilin Splice Variant Expression In Human Diabetic Adipocytes By GLP-1 To Maintain Glucose Homeostasis

Abstract Disclosure: N.A. Patel: None. R.S. Patel: None. A. Liu: None. Type 2 diabetes mellitus (T2DM) is a chronic and progressive metabolic disease with no cure. 37.3 million Americans have T2DM as of 2021 and 96 million (1 in 3) are prediabetic. Globally 462 million people are estimated to be living with T2DM. T2DM is a complex, polygenic metabolic disease characterized by hyperglycemia and insulin resistance. Adipocytes play a crucial role in glucose homeostasis. In response to insulin, translocation of major glucose transporter-4 (Glut4) from cytoplasm to the plasma membrane facilitates uptake of glucose into the adipocytes. Sortilin, an important constituent of Glut4 storage vesicles, binds to Glut4 with its luminal domain while its C-terminal tail guides intracellular trafficking. In insulin resistant adipocytes, glucose uptake is impaired. In this study, we used human adipose stem cells (hASC) from diabetic (DM) and nondiabetic (NDM) donors and differentiated them in vitro to mature adipocytes. We report that in addition to constitutively spliced full-length sortilin (Sort_FL), we identified an alternatively spliced sortilin variant in human adipocytes. Results show that alternative exon inclusion resulted in inclusion of STOP codon which produced a truncated C-terminal (Sort_T) protein whose expression was significantly increased in DM adipocytes. We elucidated the role and function of Sort_T and our results show that hyperglycemic conditions promoted an increase in Sort_T levels in NDM adipocytes. Overexpression of Sort_T in NDM adipocytes resulted in reduced insulin-stimulated Glut4 translocation and decreased glucose uptake. However, overexpression of Sort_FL does not rescue glucose uptake in DM adipocytes. Computational modeling and molecular dynamics results suggested that Glut4 bound tightly to both Sort_T and Sort_FL. This was validated using co-immunoprecipitation assays which demonstrated robust binding of Sort_T to Glut4. Immunocytochemistry was performed to determine localization of sortilin variants in DM and NDM adipocytes. Results demonstrated that Glut4 co-localized with both Sort_T and Sort_FL and Pearson’s coefficient demonstrated increased Sort_T co-localization with Glut4 in DM adipocytes. Incretin hormone glucagon-like peptide-1 (GLP1) and its analog liraglutide is used to manage T2DM. We evaluated the effect of GLP1 and liraglutide treatment in DM adipocytes on sortilin variant expression and our results demonstrate decreased Sort_T levels at physiological doses (8nM). Using a sortilin splicing minigene, our results demonstrate that GLP1 regulates splicing of Sort_T pre-mRNA and splice factor SRSF10 is involved in GLP1-mediated sortilin alternative splicing in adipocytes. Our study concludes that Sort_T expression in diabetic adipocytes hinders glucose metabolism and Sort_T is a target of GLP1 for maintaining glucose homeostasis. Presentation: Friday, June 16, 2023

Isorhynchophylline improves lipid metabolism disorder by mediating a circadian rhythm gene Bmal1 in spontaneously hypertensive rat.

Hypertension is a progressive metabolic disease characterized by circadian regulation of lipid metabolism disorder. Identifying specific lipid components and maintaining circadian homeostasis of lipid metabolism might be a promising therapeutic strategy for hypertension. Isorhynchophylline (IRP) can regulate lipid metabolism; however, the underlying mechanism of IRP in improving lipid metabolism rhythm disorder is still unclear. The lipid circadian biomarkers and abnormal metabolic pathways intervened by IRP were investigated using diurnal lipidomic research methods. The 24-h circadian changes in mRNA and protein expression levels of circadian genes, including Bmal1, Clock, Cry1, Cry2, Per1, and Per2, and lipid metabolism-related factors (PPARα and LPL) were determined using RT-PCR and western blot analyses, respectively. The underlying mechanisms were intensively investigated by inhibiting Bmal1. Molecular docking and drug affinity responsive target stability analyses were performed to assess the binding affinity of IRP and Bmal1. IRP treatment could effectively improve 24-h blood pressure, ameliorate the lipid metabolic rhythm disorder, reverse the expression levels of circadian rhythm genes, and regulate lipid metabolism-related genes (PPARα and LPL) by mediating Bmal1. This study highlighted the potential effects of IRP in maintaining the circadian homeostasis of lipid metabolism and the treatment of hypertension.

Protective effect of phytoestrogens on nonalcoholic fatty liver disease in postmenopausal women.

Non-alcoholic fatty liver disease (NAFLD) is a progressive metabolic disease characterized by hepatic steatosis, inflammation, and fibrosis that seriously endangers global public health. Epidemiological studies have shown that the incidence of non-alcoholic fatty liver disease in postmenopausal women has significantly increased. Studies have shown that estrogen deficiency is the main reason for this situation, and supplementing estrogen has become a new direction for preventing the occurrence of postmenopausal fatty liver. However, although classical estrogen replacement therapy can reduce the incidence of postmenopausal NAFLD, it has the risk of increasing stroke and cardiovascular diseases, so it is not suitable for the treatment of postmenopausal NAFLD. More and more recent studies have provided evidence that phytoestrogens are a promising method for the treatment of postmenopausal NAFLD. However, the mechanism of phytoestrogens in preventing and treating postmenopausal NAFLD is still unclear. This paper summarizes the clinical and basic research evidence of phytoestrogens and reviews the potential therapeutic effects of phytoestrogens in postmenopausal NAFLD from six angles: enhancing lipid metabolism in liver and adipose tissue, enhancing glucose metabolism, reducing oxidative stress, reducing the inflammatory response, regulating intestinal flora, and blocking liver fibrosis (Graphical Abstract).

Organosulfurs, S-allyl cysteine and N-acetyl cysteine sequester di-carbonyls and reduces carbonyl stress in HT22 cells

Diabetes, characterized by high blood glucose level, is a progressive metabolic disease that leads to serious health complications. One of the major pathological consequences associated with diabetes is the accumulation of highly reactive carbonyl compounds called advanced glycation end products (AGEs). Most of the AGEs are dicarbonyls and have the potential to covalently modify proteins especially at the lysine residues in a non-enzymatic fashion (a process termed as glycation) resulting in the functional impairment and/or toxic gain in function. Therefore, non-toxic small molecules that can inhibit glycation are of interest for the therapeutic intervention of diabetes. In the present communication, we have investigated the effect of organosulfurs (S-allyl cysteine, SAC and N-acetyl cysteine, NAC) that are major principal components of Allium sativa against the glycation of different proteins. We discovered that both SAC and NAC are potent anti-glycating agents. We also found that both SAC and NAC reduce ROS level and inhibit apoptosis caused by protein glycation.

Prognostic value of [18F]-FDG PET/CT in patients with meta-static breast cancer treated with cyclin-dependent inhibitors.

The addition of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) to endocrine therapy impressively improved the outcome of patients with hormone receptor-positive metastatic breast cancer. Despite their great efficacy, not all patients respond to treatment and many of them develop acquired resistance. The aim of this retrospective study was to assess the role of [18F]-FDG PET/CT in predicting PFS and OS in breast cancer patients treated with CDK4/6i. 114 patients who performed an [18F]-FDG PET/CT scan before (PET1) and 2-6 months (PET2) after starting treatment were retrospectively enrolled. Metabolic response was evaluated by EORTC, PERCIST and Deauville Score and correlated to PFS and OS. In patients who did not progress at PET2 (n = 90), PFS rates were not significantly different between classes of response by EORTC and PERCIST. Conversely, patients showing a Deauville score ≤3 had a longer PFS (median PFS 42 vs 21.0 months; p = 0.008). A higher total metabolic tumor volume at PET1 (TMTV1) was also associated with a shorter PFS (median 18 vs 42 months; p = 0.0026). TMTV1 and Deauville score were the only independent prognostic factors for PFS at multivariate analysis and their combination stratified the population in four definite classes of relapse risk. Conversely, the above parameters did not affect OS which was only influenced by a progressive metabolic disease at PET2 (3-years survival rate 29.8 vs 84.9%; p<0.0001). TMTV and metabolic response by Deauville score were significant prognostic factors for PFS in patients with breast cancer treated with CDK4/6i. Their determination could help physicians to select patients who may need a closer follow up.

Comparación del valor pronóstico de diferentes criterios de respuesta metabólica determinados por PET/TC en pacientes con cáncer de mama metastásico en tratamiento con inhibidores de CDK 4/6

PurposeThis study evaluates the prognostic role of different [18F]FDG PET/CT metabolic response criteria in metastatic breast cancer (MBC) patients treated with cyclin-dependent kinase 4/6 inhibitors (CDK 4/6). Materials and methodsWe retrospectively evaluated the data of MBC patients treated with CDK 4/6 inhibitors who underwent an [18F]FDG PET/CT scan before starting and during treatment. [18F]FDG PET/CT response was assessed with the European Organization for Research and Treatment of Cancer, PET response criteria in solid tumors (PERCIST), and whole-body total lesion glycolysis (WBTLG) criteria. Fleiss kappa was computed to assess the agreement between metabolic response criteria. The endpoint of the study was progression-free survival (PFS). PFS data were analyzed by the Kaplan–Meier method and compared using the log-rank test. ResultsThe study included 16 MBC patients who received CDK 4/6 inhibitors therapy. According to PERCIST, partial metabolic response (PMR) was found in seven patients, stable metabolic disease (SMD) in seven patients, and progressive metabolic disease (PMD) in two patients. According to the European Organization for Research and Treatment of Cancer, PMR was detected in eight patients, SMD in seven patients, and PMD in one patient. According to WBTLG, PMR was found in 10 patients, SMD in four patients, and PMD in two patients. There was a fair agreement between the three criteria. While progression was detected in seven of the patients during follow-up, no progression was detected in nine of them. Kaplan–Meier analysis revealed that the responders according to WBTLG showed significantly longer PFS than non-responders. ConclusionTreatment response according to WBTLG criteria during treatment appears to be associated with prolonged PFS in patients treated with CDK 4/6 inhibitors for MBC.

A holistic view of muscle metabolic reprogramming through personalized metabolic modeling in newly diagnosed diabetic patients.

Type 2 diabetes mellitus (T2DM) is a challenging and progressive metabolic disease caused by insulin resistance. Skeletal muscle is the major insulin-sensitive tissue that plays a pivotal role in blood sugar homeostasis. Dysfunction of muscle metabolism is implicated in the disturbance of glucose homeostasis, the development of insulin resistance, and T2DM. Understanding metabolism reprogramming in newly diagnosed patients provides opportunities for early diagnosis and treatment of T2DM as a challenging disease to manage. Here, we applied a system biology approach to investigate metabolic dysregulations associated with the early stage of T2DM. We first reconstructed a human muscle-specific metabolic model. The model was applied for personalized metabolic modeling and analyses in newly diagnosed patients. We found that several pathways and metabolites, mainly implicating in amino acids and lipids metabolisms, were dysregulated. Our results indicated the significance of perturbation of pathways implicated in building membrane and extracellular matrix (ECM). Dysfunctional metabolism in these pathways possibly interrupts the signaling process and develops insulin resistance. We also applied a machine learning method to predict potential metabolite markers of insulin resistance in skeletal muscle. 13 exchange metabolites were predicted as the potential markers. The efficiency of these markers in discriminating insulin-resistant muscle was successfully validated.