Metabolic Manifestations Research Articles

Circulating Fetuin-A concentrations in rheumatic diseases: asystematic review and meta-analysis.

Rheumatic diseases (RDs) include a broad group of disabling conditions with different phenotypes, from autoimmune to autoinflammatory, degenerative, metabolic or mixed manifestations. With the continuous efforts to identify therapeutic targets for new biologic drugs to treat overt clinical manifestations, research is also focusing on the discovery of new biomarkers to diagnose and manage early disease stages. In this context, we conducted a systematic review and meta-analysis of Fetuin-A (FtA), a glycoprotein synthesized by the liver that participates in several biological processes and has been proposed as a biomarker for several disorders, including rheumatoid arthritis. A systematic search in PubMed, Scopus and Web of Science, from inception to the 24th of August 2024, led to the identification of 13 manuscripts from 219 records; six additional studies were identified through reference hand-search, for a total of 19 studies. There was a significant decrease in FtA concentrations in RD patients (standardized mean difference, SMD = -.91; 95% CI -1.43 to -.39, p = .001), with no substantial contribution from any individual study nor publication bias. The effect size was significantly associated with erythrocyte sedimentation rate, various lipid fractions, geographical area of study conduction, study design and specific type of RD. In conclusion, our study identified significant reductions in FtA concentrations in RD patients versus healthy controls. These alterations were significantly associated with specific study and patient characteristics. Further research is required to identify the exact pathophysiological mechanisms underlying these alterations and the possible utility of measuring FtA for the diagnosis and management of RDs.

Gastrodin ameliorates diabetic nephropathy by activating the AMPK/Nrf2 pathway.

Diabetic nephropathy (DN) is a leading cause of end-stage kidney failure, contributing to elevated morbidity and mortality rates in individuals with diabetes. Despite its potential renoprotective effects, the molecular mechanism by which gastrodin (GSTD) impacts DN remains unclear. To investigate this, mice were initially induced with DN via intraperitoneal streptozotocin (STZ) injection (50mg/kg) and subsequently treated with varying doses of GSTD (5, 10, 20mg/kg). Furthermore, the potential molecular mechanism of GSTD in mitigating DN was explored in vivo in conjunction with compound C, an inhibitor of 5'-AMP-activated protein kinase (AMPK). Subsequently, the blood weight, fasting blood glucose levels, and renal injury markers of DN-afflicted mice were assessed. Additionally, renal tissues were subjected to quantitative reverse-transcriptase-polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) to evaluate inflammatory factor levels, colorimetric assays to measure renal malondialdehyde (MDA) levels, and immunoblotting analysis to examine AMPK/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. The results demonstrated that a 6-week GSTD regimen effectively improved metabolic manifestations associated with DN, including reductions in fasting blood glucose levels, 24-hour urine output, renal indices, amelioration of glomerular histopathological abnormalities, diminished glycogen accumulation, and fibrosis. Furthermore, DN-afflicted renal tissues exhibited decreased MDA levels and elevated expression of AMPK/Nrf2 pathway-associated proteins. The beneficial effects of GSTD on DN and its protein modulation were reversed upon co-intervention with compound C. Together, our findings imply that GSTD improves DN by activating the AMPK/Nrf2 pathway, thereby mitigating STZ-induced renal damage, inflammatory responses, and oxidative stress.

Comparison of Metabolic Syndrome, Autoimmune and Viral Distinctive Inflammatory Related Conditions as Affected by Body Mass Index.

Background: Metabolic inflammation (MI), long COVID (LC) and systemic lupus erythematosus (SLE) share some metabolic common manifestations and inflammatory pathophysiological similarities. Health-related quality of life (HRQoL) and metabolic age are indicators of health status. The "METAINFLAMMATION-CM Y2020/BIO-6600" project, a prospective controlled study, aimed to identify differential diagnostic tools and clinical features among three inflammatory conditions by comparing obesity status (low BMI vs. high BMI). Methods: A total of 272 adults of both Caucasian and Hispanic descent, diagnosed with MI, LC or SLE, and a range of BMI, were recruited. Clinical and phenotypic traits were measured to analyze body composition, metabolic and inflammatory markers, HRQoL data, metabolic age and lifestyle habits using a 3 × 2 (disease × BMI) factorial design. Results: Some inflammatory related variables, such as fibrinogen, RDW (red cell blood distribution width), ESR (erythrocyte sedimentation rate) and NLR (neutrophil/lymphocyte ratio), showed effect modifications depending on the BMI and disease type. In relation to HRQoL, the Physical Component Summary (PCS12) showed no relevant changes, while the Mental Component Summary (MCS12) showed a significant effect modification according to the disease type and BMI (p < 0.05). Furthermore, a significant interaction was identified between the disease type and BMI in relation to metabolic age (p = 0.02). Conclusions: Assessing the impact of BMI on these three inflammatory diseases may help to prevent clinical complications and to design personalized treatments, especially for patients with SLE, who have a worse prognosis with an increased BMI compared to the other two inflammatory diseases.

7255 Tirzepatide Helps Achieve Glycemic Control and Lower Triglycerides in Seven Patients with Lipodystrophy

Abstract Disclosure: R. Meral: None. E.D. Frontera: None. M. Celik Guler: None. M.C. Foss de Freitas: None. N. Nachawi: None. D.T. Broome: Consulting Fee; Self; Tayco, Inc.. Research Investigator; Self; Novo Nordisk, Fractyl Laboratories, Rhythm Pharmaceuticals. S.I. Taylor: None. E.A. Oral: Advisory Board Member; Self; Amryt, Regeneron Pharmaceuticals. Consulting Fee; Self; Regeneron Pharmaceuticals, Amryt, Third Rock Ventures. Grant Recipient; Self; Regeneron Pharmaceuticals, Amryt. Research Investigator; Self; Novo Nordisk, Fractyl, Ionis Pharmaceuticals Inc., GI Dynamics, Rhythm Pharmaceuticals. Other; Self; Amryt. Lipodystrophy encompasses a group of rare disorders associated with severe metabolic disease. These disorders are defined by abnormal distribution of fat, with near-total (generalized lipodystrophy, GL) or partial (partial lipodystrophy, PL; i.e. familial partial lipodystrophy, FPLD) absence of adipocyte mass leading to a decreased ability to store triglycerides safely. Excess triglycerides are more likely to be stored in ectopic tissues such as hepatocytes, which leads to the metabolic manifestations of the disease state. Patients with GL have near absent levels of leptin hormone and leptin replacement therapy leads to dramatic improvement, which has mainly been attributed to a reduction in caloric intake. Patients with PL are not as leptin deficient and their response to leptin replacement therapy has been variable. We hypothesized that the clinical use of tirzepatide in patients with lipodystrophy may lead to favorable outcomes through the reduction of caloric intake. We closely observed 7 patients who were prescribed tirzepatide for their diabetes with information presented respectively [Age: 44; 54; 34; 53; 44; 46; 38 years | Sex: F; F; F; F; F; M; F | Subtype: FPLD type 1; FPLD type 2; FPLD type 1; Acquired GL; FPLD type 2; FPLD type 1; FPLD type 3]. At baseline, all patients had poor control of their disease despite aggressive medical therapy (except patient #5). Follow-up durations varied due to the observational nature of the study [follow-up duration (months): 6; 12; 7; 3; 8; 9; 5]. Reductions in A1c, triglycerides, and body mass index (BMI) were observed [A1c (%): 13.4-&amp;gt;7.1; 7.1-&amp;gt;6.6; 7.6-&amp;gt;5.2; 8.7-&amp;gt;6.9; 5.4-&amp;gt;5.1; 8.9-&amp;gt;7.8; 9.7-&amp;gt;7.1 | triglycerides (mg/dL): 539-&amp;gt;339; 164-&amp;gt;109; 367-&amp;gt;NA; 151-&amp;gt;113; 388-&amp;gt;101; 459-&amp;gt;319; 4081-&amp;gt;259 | BMI (Kg/m2): 25.0-&amp;gt;24.5; 30.6-&amp;gt;28.3; 37.7-&amp;gt;33.9; 22.8-&amp;gt;20.9; 27.6-&amp;gt;23.4; 40.1-&amp;gt;37.9; 24.0-&amp;gt;24.9]. Those who were on insulin had decreased daily requirements [total daily insulin requirement (units): 160-&amp;gt;25; 82-&amp;gt;18; not on insulin; 85-&amp;gt;0; not on insulin; 280-&amp;gt;200; 124-&amp;gt;111]. All patients reported a reduction in their daily food intake. Treatment related complications were limited to known gastrointestinal issues which the patients rated as tolerable. Based on our results, a randomized controlled trial to test the efficacy of tirzepatide in patients with lipodystrophy may be warranted. Presentation: 6/3/2024

Effectiveness and acceptability of different lifestyle interventions for women with polycystic ovary syndrome: protocol for a systematic review and network meta-analysis.

Women with polycystic ovary syndrome (PCOS) experience various metabolic, endocrine, reproductive and psychosocial manifestations. Lifestyle modification is crucial for the management of PCOS to reduce long-term complications. Nonetheless, the efficacy and acceptability of lifestyle interventions differs, and there are no uniform methods of clinical application. Hence, a systematic review and network meta-analysis (NMA) are needed to explore the efficacy and acceptability of lifestyle interventions to inform clinical practice. Ten databases (Cochrane Gynaecology and Fertility Specialised Register, Cochrane Register of Studies Online, PubMed, EMBASE (Excerpta Medica Database), PsycINFO, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Chinese National Knowledge Infrastructure, WanFang, VIP, and Sinomed) and four clinical trial registry platforms will be searched to identify literature published in English or Chinese reporting results of randomised clinical trials conducted to evaluate the effects of lifestyle interventions for women with PCOS. The reference lists of the included studies will be manually searched. Primary outcomes will include biochemical and clinical hyperandrogenism, recruitment and retention rates. Secondary outcomes will encompass menstrual regularity, ovulation, anthropometry and quality of life. Literature selection and extraction of data will be performed independently by at least two researchers. An NMA random-effects model will be implemented for amalgamating evidence. All treatments will be ranked based on the value of p. OpenBUGS will be used for Bayesian modelling, with output verifications generated in Stata and R. The quality of evidence supporting network estimates of major outcomes will also be appraised using the Grading of Recommendations Assessment, Development, and Evaluation framework. Ethical approval is not required for this review as no data will be collected from human participants. Results will be presented in a peer-reviewed publication. CRD42024499819.

The combination of 18F-fluorodeoxyglucose and 18F 9-fluoropropyl-(+)-dihydrotetrabenazine positron emission tomography for distinguishing between early-onset and late-onset idiopathic Parkinson disease and analyzing influencing factors.

The classification of Parkinson disease by age of onset has proven to be a valuable method for subtyping, given its practical application in clinical settings. However, the interactions between the metabolic brain changes, dopaminergic dysfunction, and clinical manifestations in patients with early-onset (early-iPD) and late-onset (late-iPD) idiopathic Parkinson disease have not been adequately evaluated. Therefore, this study aimed to investigate the difference in cerebral metabolism and presynaptic dopaminergic function between patients with early-iPD and those with late-onset disease using 18F-fluorodeoxyglucose (18F-FDG) and [18F] 9-fluoropropyl-(+)-dihydrotetrabenazine (18F-FP-DTBZ) positron emission tomography (PET). Furthermore, the goal was to further explore the correlation between imaging measurements and clinical manifestations in the early and late idiopathic patients with Parkinson disease. This cross-sectional study included 80 patients with idiopathic Parkinson disease and 29 healthy control participants who underwent 18F-FDG and18F-FP-DTBZ PET imaging at Xuanwu Hospital, Capital Medical University from August 2022 to August 2023. The patients were categorized into early-iPD (n=27) and late-iPD (n=53) groups based on an age threshold of 50 years. The mean standardized uptake value of 18F-FDG and the standardized uptake value ratio (SUVR) of 18F-FP-DTBZ were compared between the early-iPD and late-iPD groups using unpaired Student t-tests. Furthermore, pairwise correlations among cerebral metabolism, dopaminergic function, and corresponding clinical ratings in all patients were conducted using Pearson correlation analysis. Patients with late-iPD exhibited a significant metabolic decrease in the frontal, parietal, and temporal cortex, along with the globus pallidus, putamen, thalamus, and cerebellum, compared to those with early-iPD in 18F-FDG PET imaging (all P values <0.05). Furthermore, the 18F-FP-DTBZ binding potential was significantly lower in the contralateral caudate and anterior putamen of patients with late-iPD compared to those with early-iPD (contralateral caudate: 3.16±1.2 vs. 2.63±0.7, P=0.020; contralateral anterior putamen: 2.49±1.2 vs. 2.05±0.7, P=0.040). Further analysis of the correlations between imaging clinical features revealed that glucose metabolism increases and dopaminergic function decreases with higher motor ratings. 18F-FDG and 18F-FP-DTBZ PET offer an objective molecular imaging basis for distinguishing between early-onset and late-onset idiopathic with Parkinson disease. Additionally, correlation analysis between imaging and clinical data represents a new approach for exploring the potential applications in future studies involving patients with early-iPD and late-iPD.

The IgLON family of cell adhesion molecules expressed in developing neural circuits ensure the proper functioning of the sensory system in mice

Deletions and malfunctions of the IgLON family of cell adhesion molecules are associated with anatomical, behavioral, and metabolic manifestations of neuropsychiatric disorders. We have previously shown that IgLON genes are expressed in sensory nuclei/pathways and that IgLON proteins modulate sensory processing. Here, we examined the expression of IgLON alternative promoter-specific isoforms during embryonic development and studied the sensory consequences of the anatomical changes when one of the IgLON genes, Negr1, is knocked out. At the embryonal age of E12.5 and E13.5, various IgLONs were distributed differentially and dynamically in the developing sensory areas within the central and peripheral nervous system, as well as in limbs and mammary glands. Sensory tests showed that Negr1 deficiency causes differences in vestibular function and temperature sensitivity in the knockout mice. Sex-specific differences were noted across olfaction, vestibular functioning, temperature regulation, and mechanical sensitivity. Our findings highlight the involvement of IgLON molecules during sensory circuit formation and suggest Negr1’s critical role in somatosensory processing.

The mineralocorticoid system, cardiometabolic health and its interplay with adipose tissue.

The mineralocorticoid system, comprising the renin-angiotensin-aldosterone system (RAAS) and associated receptors, is traditionally viewed as a regulator of sodium and fluid balance and blood pressure (BP), with the main mineralocorticoid hormone aldosterone acting via the mineralocorticoid receptor (MR) in distal renal tubules. Over the past few decades, there has been a wider understanding of the role of the mineralocorticoid system in regulating both classical BP-dependent and non-BP-dependent systemic effects. Mounting evidence indicates the novel role of the mineralocorticoid system in cardiometabolic health, with excess mineralocorticoid system activity being associated with adiposity, diabetes, insulin resistance and cardiovascular diseases independent of its effect on BP, and RAAS blockade and MR antagonists offering protection against cardiometabolic dysfunction. The metabolic manifestations of mineralocorticoid system overactivation are mainly mediated by their interactions with adipose tissue, which orchestrates energy, lipids, and glucose homeostasis via effects on the functions of brown and white adipocytes and immune cells. Adipose tissue can, in turn, influence mineralocorticoid system activity by harboring its own RAAS system and by releasing mineralocorticoid-secretory factors/adipokines, resulting in further progression of cardiometabolic dysfunction. This article discusses the interplay between the mineralocorticoid system and adipose tissue in the pathophysiology of cardiometabolic diseases.

Antipsychotic medication in people with intellectual disability and schizophrenia: A 25-year updated systematic review and cross-sectional study.

To determine the efficacy and safety of antipsychotic medication for treating individuals with a dual diagnosis of intellectual disability (ID) and schizophrenia. We systematically reviewed the literature to explore the risks and benefits of antipsychotics for schizophrenia in ID. In addition, a cross-sectional retrospective study on the tolerance profiles of a representative ID and schizophrenia cohort was conducted. From the systematic search, we retained 18 articles detailing information on 24 cases. In almost all cases, the antipsychotic improved psychotic symptoms (e.g., hallucinations, delusions, disorganization). Negative manifestations were also improved (blunted affects, amotivation, poor rapport), as were challenging behaviors in a few cases. The most commonly reported side effects were neurological (extra-pyramidal, movement disorder, epilepsy) and metabolic manifestations. In the retrospective cross-sectional study, we reported data on 112 participants with comorbid ID and schizophrenia. In all, 103 participants were antipsychotic-treated, of which 39% were on antipsychotic monotherapy. Of these, 35% were in the obesity range, 25% in the hyperglycemic range, and 25% in the dyslipidemia range. The body mass index did not differ between the groups. This study provides an initial evidence base underpinning the efficacy of antipsychotic drugs on schizophrenia in the ID population. Nevertheless, there may be an increased risk of metabolic side effects, hence, close monitoring of blood glucose, lipids, and weight should be implemented when prescribing antipsychotics to this population.

The interplay between oxidative stress, zinc, and metabolic dysfunction in polycystic ovarian syndrome.

Polycystic ovarian syndrome (PCOS) is a functional endocrine disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology that has been associated with chronic disease and comorbidities including adverse metabolic and cardiac disorders. This review aims to evaluate the role of oxidative stress and zinc in the metabolic dysfunction observed in PCOS, with a focus on insulin resistance. Recent studies indicate that oxidative stress markers are elevated in PCOS and correlate with hyperandrogenemia, obesity, and insulin resistance. Zinc, an essential trace element, is crucial for metabolic processes, particularly in the pancreas for beta-cell function and glucagon secretion. Insufficient zinc levels have been linked to diabetes, obesity, and lipid metabolism disorders. This review aims to highlight the interplay between oxidative stress, zinc, and metabolic dysfunction in PCOS, suggesting that zinc supplementation could mitigate some metabolic and endocrine manifestations of PCOS.

Abstract P307: A Review Of The Burden, Management And Outcomes Of Patients With Aldosterone Dysregulation

Introduction: Aldosterone dysregulation (excess aldosterone production) is a complex physiological driver of uncontrolled hypertension as well as cardiovascular (CV) and kidney outcomes. Understanding the clinical and economic burden of excess aldosterone in routine practice is critical to optimizing treatment and improving long-term outcomes. This review examines the burden of excess aldosterone production as a driver of disease and its impact on clinical and economic outcomes. Hypothesis: Excess aldosterone production has a broad impact on long-term outcomes, and left untreated, contributes to worsened patient outcomes. Methods: A targeted literature review was conducted to identify articles on the burden, management and outcomes of patients with excess aldosterone production (2013 – 2024) with 27 manuscripts included. Results: More studies document the impact of excess aldosterone on organ function in the cardiovascular system and kidney (10, 8 manuscripts) compared to liver (1 manuscript). Excess aldosterone levels and aldosterone-induced oxidative stress and inflammation are associated with increased risk of CV events including myocardial infarction, heart failure, stroke, and increased morbidity and mortality. For example, Framingham Offspring Study showed increased CV disease risk with each rise in serum aldosterone levels (HR, 1.11; 95% CI, 1.02–1.21). Kidney, hepatic and metabolic manifestations are also well-documented, with implications for progression to chronic kidney disease, liver disease and metabolic syndrome. Another study reported an 11% increased risk of CKD progression associated with each doubling of serum aldosterone. Current pharmacological interventions for hypertension, including mineralocorticoid receptor antagonists, were not reported to restore normal aldosterone levels. No literature was found on the economic burden of excess aldosterone or the association between excess aldosterone production and clinical outcomes independent of blood pressure control. Conclusions: Currently available literature emphasizes the broad impact of excess aldosterone production on CV, kidney, hepatic, and metabolic outcomes. The impact on outcomes indicates that excess aldosterone production is underappreciated, with prognostic implications beyond primary aldosteronism. Current hypertension treatments do not address excess aldosterone production. These findings underscore the unmet need for novel management strategies that target excess aldosterone production.

Clinical evaluation of the efficiency of combined phytotherapy in the postoperative period in patients with uterus cancer

As it is well known, that operative procedures which influence on ovary functions and relieve the patient of some suffering and danger from diseases, are realized by pronounced changes in hormonal self-regulation, homeostasis disturbance, deep psycho-emotional disorders, which leads to a change in the quality of life, an increased risk of long-term complications development (cardiac vascular pathology, osteoporosis, etc.).Some authors explain the changes in neurovegetative and endocrine homeostasis after hysterectomy not only by the insufficient development of collateral blood flow, but also by the removal of one of the links of the self-regulatory system – APUD – the uterine system, which causes the disorders in hypothalamic-pituitary-ovarian relationships. Menopausal symptoms with the appearance of neurovegetative, psychoemotional disorders, urological disorders, sexual dysfunction, as well as metabolic manifestations do not always provide an opportunity to assess the parameters of a woman’s health, which are combined into the concept of quality of life.The article presents the results of a study on the use of Cimicifuga racemosa for the treatment and prevention of post-hysterectomy syndrome in patients with uterine cancer in the postoperative period.The objective: to study the clinical effectiveness of the drug, which contains the estrogen receptor modulator Cimicifuga racemosa, in patients after surgical treatment for hormone-dependent uterine tumors.Materials and methods. The study included 50 uterine cancer patients after hysterectomy. 30 patients (main group) of them had rehabilitation therapy in the postoperative period (postoperative antibacterial prophylaxis, analgesic therapy, vaginal sanation) and, starting from the second month, they additionally received a herbal preparation with an extract of Cimicifuga racemosa, 1 tablet 1 time a day for 4 months.The control group included 20 women who received only rehabilitation therapy after surgery.Quality of life was assessed after 6 months of therapy based on a comprehensive assessment using the modified MENQOL scale and the study of such important indicators as energy, sleep, emotional reactions, social isolation, physical activity, and pain.All types of statistical processing were performed using the standard package «Statistica for Windows – 10».Results. The use of selective combined herbal therapy of the post-hysterectomy syndrome in patients with hormone-dependent tumors after 6 months of treatment leads to a decrease in the frequency of hot flashes by 63.3%, profuse sweating by 63.4%, sleep disturbances by 43.3%, increased fatigue by 40.0%, depressive disorders – by 36.7% and irritability – by 33.3%.Additional use of the herbal preparation with Cimicifuga racemosa extract reliably (p&lt;0.05) reduces the manifestations of post-hysterectomy syndrome, improves the quality of life, is well tolerated and has no side effects.Conclusions. The use of selective combined herbal therapy in the postoperative period in patients with cancer of the uterine body allows to reliably improve the quality of life of patients and reduce the clinical manifestations of post-hysterectomy syndrome, which is especially relevant in patients with cancer of the uterine body, for whom replacement hormone therapy is contraindicated. Selective herbal therapy is well tolerated by patients and can be used for a long time.

Genetic variants of KISS1 gene in association with polycystic ovary syndrome– A meta-analysis

Polycystic ovary syndrome (PCOS) is a widely diagnosed syndrome associated with clinical and metabolic manifestations and even many cases of infertility. Sexual hormone imbalance can be considered as PCOS causal factor. Thus, kisspeptin (KISS1) regulating gonadotropin-releasing hormone (GnRH) levels plays a critical role in this syndrome. This study aimed to investigate the association of KISS1 genetic polymorphisms with PCOS using meta-analysis protocols. In accordance with PRISMA guidelines, systematic search of scientific databases was conducted to find included articles and then meta-analysis was performed using Review Manager 5.4 in dominant, recessive, and allelic models of inheritance. This meta-analysis included 2165 PCOS patients and 2301 healthy reproductive-aged female genotyped for five different polymorphisms of KISS1. In recessive and allelic models, three genetic variations specifically showed significant association with PCOS. This concerns rs12998 (G → A) which was proved as associated with higher risk of PCOS in recessive (p = 0.0002) and allelic models (P = 0.02). In addition, rs372790354 despite the small number of studies was associated with this syndrome in allelic model (P = 0.03). In additive model, rs4889 was shown as associated with higher PCOS risk (P = 0.02). This meta-analysis suggests rs4889, rs12998 and rs372790354 genetic variations in KISS1 as risk factors of PCOS. Results will improve our knowledge about PCOS and form a basis for future trials trying to find new markers for its prognosis and therapy.

Recapitulating familial hypercholesterolemia in a mouse model by knock-in patient-specific LDLR mutation.

Familial hypercholesterolemia (FH) is one of the most prevalent monogenetic disorders leading to cardiovascular disease (CVD) worldwide. Mutations in Ldlr, encoding a membrane-spanning protein, account for the majority of FH cases. No effective and safe clinical treatments are available for FH. Adenine base editor (ABE)-mediated molecular therapy is a promising therapeutic strategy to treat genetic diseases caused by point mutations, with evidence of successful treatment in mouse disease models. However, due to the differences in the genomes between mice and humans, ABE with specific sgRNA, a key gene correction component, cannot be directly used to treat FH patients. Thus, we generated a knock-in mouse model harboring the partial patient-specific fragment and including the Ldlr W490X mutation. LdlrW490X/W490X mice recapitulated cholesterol metabolic disorder and clinical manifestations of atherosclerosis associated with FH patients, including high plasma low-density lipoprotein cholesterol levels and lipid deposition in aortic vessels. Additionally, we showed that the mutant Ldlr gene could be repaired using ABE with the cellular model. Taken together, these results pave the way for ABE-mediated molecular therapy for FH.

SperMD: the expression atlas of sperm maturation

The impairment of sperm maturation is one of the major pathogenic factors in male subfertility, a serious medical and social problem affecting millions of global couples. Regrettably, the existing research on sperm maturation is slow, limited, and fragmented, largely attributable to the lack of a global molecular view. To fill the data gap, we newly established a database, namely the Sperm Maturation Database (SperMD, http://bio-add.org/SperMD). SperMD integrates heterogeneous multi-omics data (170 transcriptomes, 91 proteomes, and five human metabolomes) to illustrate the transcriptional, translational, and metabolic manifestations during the entire lifespan of sperm maturation. These data involve almost all crucial scenarios related to sperm maturation, including the tissue components of the epididymal microenvironment, cell constituents of tissues, different pathological states, and so on. To the best of our knowledge, SperMD could be one of the limited repositories that provide focused and comprehensive information on sperm maturation. Easy-to-use web services are also implemented to enhance the experience of data retrieval and molecular comparison between humans and mice. Furthermore, the manuscript illustrates an example application demonstrated to systematically characterize novel gene functions in sperm maturation. Nevertheless, SperMD undertakes the endeavor to integrate the islanding omics data, offering a panoramic molecular view of how the spermatozoa gain full reproductive abilities. It will serve as a valuable resource for the systematic exploration of sperm maturation and for prioritizing the biomarkers and targets for precise diagnosis and therapy of male subfertility.

Adipose Tissue Dysfunction in PCOS

Polycystic Ovary Syndrome (PCOS) is one of the most common endocrine diseases among women of reproductive age; however, its aetiology is unclear. PCOS is linked to many metabolic manifestations and alterations such as obesity, insulin resistance, and cardiovascular diseases (CVD). Women with PCOS have intra-ovarian and systemic changes in their metabolite levels. Adipose tissue dysfunction plays a significant role in the pathophysiology of PCOS. Adipose tissue growth is disrupted by metabolic stress, leading to hypertrophy of adipocytes, which begin to express stress signals. Adipose tissue secretes autocrine and paracrine factors, called adipokines or adipocytokines. Adiponectin is an adipocyte-derived protein abundant in the bloodstream. Plasma adiponectin concentration is low in women with PCOS, obesity, CVD, and hypertension. Other adipocytokines with altered secretion in PCOS include leptin, resistin, apelin, visfatin, IL-6, IL-8, and TNF-α. Hormonal imbalance, untimely action of high LH, and consequent hyperandrogenism in women with PCOS may cause metabolic defects associated with adipose tissue dysfunction; however, there are no reports on the role of higher LH levels in adipose dysfunction and altered adipokine secretion. New medications with therapeutic potential have been developed that target adipokines for the treatment of PCOS. This review discusses the association between PCOS and altered adipokine production as a consequence of adipose dysfunction.

Genetic variations in IKZF3, LET7-a2, and CDKN2B-AS1: Exploring associations with metabolic syndrome susceptibility and clinical manifestations.

Metabolic syndrome (MetS) increases the risk of atherosclerosis and diabetes, but there are no approved predictive markers. This study assessed the role of specific genetic variations in MetS susceptibility and their impact on clinical manifestations. In this study, a genotype-phenotype assessment was performed for IKZF3 (rs907091), microRNA-let-7a-2 (rs1143770), and lncRNA-CDKN2B-AS1 (rs1333045). Analyses indicate that while rs907091 and rs1143770 may have potential associations with MetS susceptibility and an increased risk of atherosclerosis and diabetes, there is an observed trend suggesting that the rs1333045 CC genotype may be associated with a decreased risk of MetS. The genotypes and allele frequencies of rs1333045 were significantly different between studied groups (OR = 0.56, 95% CI 0.38-0.81, p = 0.002, and OR = 0.71, 95% CI 0.55-0.92, p = 0.008), with the CC genotype displaying increased levels of HDL. Furthermore, the rs907091 TT genotype was associated with increased triglyceride, cholesterol, and HOMA index in MetS patients. Subjects with the CC genotype for rs1143770 had higher HbA1c and BMI. In silico analyses illustrated that rs907091 C remarkably influences the secondary structure and the target site of a broad spectrum of microRNAs, especially hsa-miR-4497. Moreover, rs1333045 creates a binding site for seven different microRNAs. Further studies on other populations may help confirm these SNPs as useful predictive markers in assessing the MetS risk.

Multiomic analysis in fibroblasts of patients with inborn errors of cobalamin metabolism reveals concordance with clinical and metabolic variability

The high variability in clinical and metabolic presentations of inborn errors of cobalamin (cbl) metabolism (IECM), such as the cblC/epicblC types with combined deficits in methylmalonyl-coA mutase (MUT) and methionine synthase (MS), are not well understood. They could be explained by the impaired expression/activity of enzymes from other metabolic pathways. We performed metabolomic, genomic, proteomic, and post-translational modification (PTM) analyses in fibroblasts from three cblC cases and one epi-cblC case compared with three cblG cases with specific MS deficits and control fibroblasts. CblC patients had metabolic profilings consistent with altered urea cycle, glycine, and energy mitochondrial metabolism. Metabolomic analysis showed partial disruption and increased glutamate/ketoglutarate anaplerotic pathway of the tricarboxylic acid cycle (TCA), in patient fibroblasts. RNA-seq analysis showed decreased expression of MT-TT (mitochondrial tRNA threonine), MT-TP (mitochondrial tRNA proline), OXCT1 (succinyl CoA:3-oxoacid CoA transferase deficiency), and MT-CO1 (cytochrome C oxidase subunit 1). Proteomic changes were observed for key mitochondrial enzymes, including NADH:ubiquinone oxidoreductase subunit A8 (NDUFA8), carnitine palmitoyltransferase 2 (CPT2), and ubiquinol-cytochrome C reductase, complex III subunit X (UQCR10). Propionaldehyde addition in ornithine aminotransferase was the predominant PTM in cblC cells and could be related with the dramatic cellular increase in propionate and methylglyoxalate. It is consistent with the decreased concentration of ornithine reported in 3 cblC cases. Whether the changes detected after multi-omic analyses underlies clinical features in cblC and cblG types of IECM, such as peripheral and central neuropathy, cardiomyopathy, pulmonary hypertension, development delay, remains to be investigated. The omics-related effects of IECM on other enzymes and metabolic pathways are consistent with the diversity and variability of their age-related metabolic and clinical manifestations. PTMs are expected to produce cumulative effects, which could explain the influence of age on neurological manifestations. French Agence Nationale de la Recherche (Projects PREDICTS and EpiGONE) and Inserm.

GDF-15 levels in patients with polycystic ovary syndrome treated with metformin: a combined clinical and in silico pathway analysis.

Polycystic ovary syndrome (PCOS) is an endocrine disease characterized by metabolic, reproductive, and psychological manifestations. Growth and differentiation factor 15 (GDF-15) is a cytokine associated with metabolic and inflammatory disorders. Metformin is commonly used for the treatment of PCOS. We investigated the relationship between GDF-15 levels and PCOS, the effect of metformin on GDF-15 levels, and potential biologic pathways related to GDF-15. The study included 35 women with PCOS and 32 women without PCOS (controls). Both groups were compared in terms of GDF-15 levels. Additional analysis was conducted on samples from 22 women with PCOS who were treated with either metformin (n = 7) or placebo (n = 15), retrieved from a previous randomized, controlled trial. Levels of GDF-15 were measured using MILLIPLEX. The biologic pathways related to GDF-15 were evaluated using the databases STRING, SIGNOR, and Pathway Commons. The statistical analysis was conducted using the software SPSS. Levels of GDF-15 were higher in the PCOS group compared with the non-PCOS group (p = 0.039). Among women with PCOS, GDF-15 levels were higher in those treated with metformin compared with placebo (p = 0.007). The proteins related to GDF-15 overlapped between the databases, and a significant interaction was found between GDF-15 and proteins related to PCOS and its complications, including those related to estrogen response, oxidative stress, ovarian infertility, interleukin (IL)-18, IL-4, the ratio of advanced glycation end products to their receptor (AGE/RAGE), leptin, transforming growth factor beta (TGF-β), adipogenesis, and insulin. The findings of the present study suggest a relationship between GDF-15 and PCOS and a potential increase in GDF-15 levels with metformin treatment. An additional finding was that GDF-15 could be involved in biologic pathways related to PCOS complications.

Inulin-type fructans with different degrees of polymerization improve insulin resistance, metabolic parameters, and hormonal status in overweight and obese women with polycystic ovary syndrome: A randomized double-blind, placebo-controlled clinical trial.

Polycystic ovary syndrome (PCOS) is associated with reproductive disorders and adverse cardiometabolic risk factors that can negatively impact the general health of women. Inulin-type fructans (ITFs) are proposed to beneficially affect risk factors associated with metabolic disorders. Whether ITFs can help with the management of PCOS by modifying insulin resistance (IR) and androgen levels has not yet been explored. The aim of this study was to investigate the effects of ITFs with different degrees of polymerization on insulin resistance, blood lipids, anthropometric measures, and hormonal status in overweight and obese women with PCOS. In a randomized double-blind placebo-controlled trial, seventy-five women with PCOS aged 18-40 years old were randomly assigned to receive 10 g/day of high-performance inulin (HPI) or oligofructose-enriched inulin (OEI) or maltodextrin for 12 weeks. Biochemical and clinical outcomes were measured at baseline and after the intervention. Participants in the HPI and OEI groups experienced improvements in waist circumference, total testosterone, free androgen index, sex hormone-binding globulin, and triglycerides compared to the placebo group. Also, the number of women with irregular menses or oligomenorrhoea decreased significantly in both ITF groups. Participants in the HPI group reported lower body mass, fasting insulin, and HOMA-IR, as well as a higher quantitative insulin sensitivity check index. ITF supplementation, especially with long-chain ITFs, when given for 12 weeks may improve metabolic outcomes, androgen status and clinical manifestations in women with PCOS.