Metabolic Abnormalities Research Articles

Application of proton magnetic resonance spectroscopy in metabolic alterations of prefrontal white and gray matter in depression adolescents

BACKGROUND Cases of depression among adolescents are gradually increasing. The study of the physiological basis of cognitive function from a biochemical perspective has therefore been garnering increasing attention. Depression has been hypothesized to be associated with the brain biochemical metabolism of the anterior cingulate gyrus, frontal lobe white matter, and the thalamus. AIM To explore the application of proton magnetic resonance spectroscopy (1H-MRS) in the metabolic alterations in the prefrontal white matter (PWM) and gray matter (GM) in adolescents with depression. METHODS 1H-MRS was performed for semi-quantitative analysis of the biochemical metabolites N-acetylaspartate (NAA), choline (Cho) complexes, creatine (Cr), and myo-inositol (mI) in bilateral PWM, anterior cingulate GM, and thalami of 31 adolescent patients with depression (research group) and 35 healthy adolescents (control group), and the NAA/Cr, Cho/Cr, and mI/Cr ratios were calculated. Meanwhile, Hamilton Depression Scale (HAMD) and Wechsler Memory Scale were used to assess the degree of depression and memory function in all adolescents. The correlation of brain metabolite levels with scale scores was also analyzed. RESULTS The research group had markedly higher HAMD-24 scores and lower memory quotient (MQ) compared with the control group (P < 0.05). Adolescents with depression were found to have lower bilateral PWM NAA/Cr and Cho/Cr ratios compared with healthy adolescents (P < 0.05). The mI/Cr ratios were found to be similar in both groups (P > 0.05). The bilateral anterior cingulate GM NAA/Cr, Cho/Cr, and mI/Cr also did not demonstrate marked differences (P > 0.05). No statistical inter-group difference was determined in NAA/Cr of the bilateral thalami (P > 0.05), while bilateral thalamic Cho/Cr and mI/Cr were reduced in teenagers with depression compared with healthy adolescents (P < 0.05). A significant negative correlation was observed between the HAMD-24 scores in adolescents with depression with bilateral PWM NAA/Cr and Cho/Cr and were inversely linked to bilateral thalamic Cho/Cr and mI/Cr (P < 0.05). In adolescents with depressions, MQ positively correlated with right PWH NAA/Cr, left PWH Cho/Cr, and bilateral thalamic Cho/Cr and mI/Cr. CONCLUSION PWM and thalamic metabolic abnormalities might influence teen depression, and the reduction in bilateral PWM NAA/Cr and Cho/Cr could be related to the neuropathology of adolescents with depression suffering from memory impairment. There exists a possibility of dysfunction of nerve cell membrane phospholipids in the thalami of adolescent patients with depression.

Skin as a mirror of metabolic syndrome: Do some dermatoses alarm internal metabolic sinister?

Metabolic syndrome is a group of abnormalities in metabolism including hypertension, central obesity, insulin resistance and dyslipidaemia. Etiopathogenesis is multifactorial including genetic and environmental factors. It is more prevalent in recent decade due to sedentary lifestyle with unhygienic food habits and cause increased prevalence in younger age group. This abnormal metabolism leads to oxidative stress in body involving multiple inflammatory pathways. There are so many dermatoses which are associated with metabolic syndrome due to common factors are involved in etiopathogenesis. These includes psoriasis, acne vulgaris, acanthosis nigricans, hidradenitis suppurativa, atopic dermatitis, androgenetic alopecia, lichen planus. There is increased risk of developing diabetes mellitus and damage to cardiovascular system. Early diagnosis and management are required to reduce risk of complications. These includes active lifestyle, dietary changes and medications.

Role of metabolic syndrome and lifestyle factors in endometrial cancer risk and prevention

Introduction: The incidence of endometrial cancer, the sixth most common cancer among women, has been rising, especially in developed countries, possibly due to the obesity and diabetes pandemic. The aim of this review is to investigate the connection between metabolic syndrome, its individual components and endometrial cancer risk and to explore the role of lifestyle factors in endometrial cancer prevention. Materials and methods: For this review, we included studies regarding endometrial cancer and metabolic syndrome, obesity, diabetes and hyperglycemia, hypertension, dyslipidemia and several lifestyle factors, from 1994 to 2024. State of knowledge: This paper reviews existing literature on the relationship between metabolic syndrome and endometrial cancer, highlighting the significant role of central obesity, hyperglycemia and diabetes, dyslipidemia, and hypertension as risk factors. Evidence consistently demonstrates that individuals with metabolic syndrome, and its components individually, are at a heightened risk of developing endometrial cancer compared to those without metabolic abnormalities. Biological mechanisms linking metabolic syndrome’s components to endometrial cancer involve complex interplays between metabolic, hormonal or inflammatory factors and signalling pathways. Lifestyle interventions focusing on weight management, physical activity, and eating habits play an important role in reducing endometrial cancer risk and improving overall health outcomes. Conclusion: An understanding of the relationship between metabolic syndrome and endometrial cancer is crucial for improving risk stratification, early detection, and prevention strategies. Addressing metabolic abnormalities and promoting healthy lifestyle behaviours are essential actions against the rising incidence and burden of endometrial cancer.

CORRELATION OF LEPTIN AND ADIPONECTIN LEVELS WITH METABOLIC AND HORMONAL PROFILES IN PCOS PATIENTS: A COMPARATIVE STUDY WITH NORMAL CONTROLS

Objective: Polycystic Ovary Syndrome (PCOS) is a common endocrine disorder characterized by metabolic and reproductive abnormalities, including insulin resistance and hyperandrogenism. Leptin and adiponectin, two adipokines involved in metabolic regulation, are known to be dysregulated in PCOS. This study aims to investigate the correlation between leptin and adiponectin levels and their association with metabolic and hormonal profiles in PCOS patients compared to healthy controls. Methods: A prospective, observational study was conducted involving 120 women diagnosed with PCOS and 50 healthy controls. Leptin and adiponectin levels were measured using enzyme-linked immunosorbent assay (ELISA). The adiponectin-to-leptin ratio (ALR) was calculated, and correlations with BMI, LH/FSH ratio, and other metabolic parameters were analyzed. Data were analyzed using appropriate statistical methods. Results: Leptin levels were significantly higher in the PCOS group compared to controls (25.34 ng/ml vs. 11.16 ng/ml, p<0.0001), while adiponectin levels were significantly lower (2.93 mcg/ml vs. 21.44 mcg/ml, p<0.0001). The adiponectin-to-leptin ratio was markedly reduced in PCOS patients (0.13 vs. 2.05, p<0.0001). A significant correlation was observed between the adiponectin/leptin ratio and the LH/FSH ratio (r = 0.2138, p = 0.019). Conclusion: This study highlights the dysregulation of leptin and adiponectin in PCOS, suggesting their potential role in metabolic and reproductive dysfunction. The adiponectin-to-leptin ratio emerges as a promising biomarker for insulin resistance and metabolic risk in PCOS patients.

Metabolic Abnormality and Sleep Disturbance are Associated with Clinical Severity of Patients with Schizophrenia

Metabolic Abnormality and Sleep Disturbance are Associated with Clinical Severity of Patients with Schizophrenia

Novel perspectives on the link between obesity and cancer risk: from mechanisms to clinical implications.

Existing epidemiologic and clinical studies have demonstrated that obesity is associated with the risk of a variety of cancers. In recent years, an increasing number of experimental and clinical studies have unraveled the complex relationship between obesity and cancer risk and the underlying mechanisms. Obesity-induced abnormalities in immunity and biochemical metabolism, including chronic inflammation, hormonal disorders, dysregulation of adipokines, and microbial dysbiosis, may be important contributors to cancer development and progression. These contributors play different roles in cancer development and progression at different sites. Lifestyle changes, weight loss medications, and bariatric surgery are key approaches for weight-centered, obesity-related cancer prevention. Treatment of obesity-related inflammation and hormonal or metabolic dysregulation with medications has also shown promise in preventing obesity-related cancers. In this review, we summarize the mechanisms through which obesity affects the risk of cancer at different sites and explore intervention strategies for the prevention of obesity-associated cancers, concluding with unresolved questions and future directions regarding the link between obesity and cancer. The aim is to provide valuable theoretical foundations and insights for the in-depth exploration of the complex relationship between obesity and cancer risk and its clinical applications.

Lipid metabolism-related gene signature predicts prognosis and unveils novel anti-tumor drugs in specific type of diffuse large B cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma which possess highly aggressive and heterogeneous. Despite advances in understanding heterogeneity and development of novel targeted agents, the prognosis of DLBCL patients remains unsatisfied. Lipids are crucial components of biological membranes and signal transduction while accumulating evidence has supported the vital roles of abnormal lipid metabolism in tumorigenesis. Furthermore, some related pathways could serve as prognostic biomarkers and potential therapeutic targets. However, the clinical significance of abnormal lipid metabolism reprogramming in DLBCL has not been investigated. In the current study, we developed a prognostic risk model for DLBCL based on the abnormal expressed lipid metabolism genes and moreover based on our risk model we classified patients with DLBCL into novel subtypes and identified potential drugs for DLBCL patients with certain lipid metabolism profiles. We utilized univariate Cox regression analysis to identify the prognosis-related lipid metabolism genes, and then performed LASSO Cox regression to identify prognostic related lipid metabolism related genes. Multivariate cox regression was used to establish the prognostic model. Patients were divided in to high and low risk groups based on the median risk score. Immune cell infiltration and GSEA were used to identify the pathways between high and low risk groups. Oncopredict algorithm was utilized to identify potential drug for high-risk patients. In vitro cell apoptosis and viability analysis were employed to verify the specific tumor inhibition effects of AZD5153. Nineteen survival related lipid metabolism genes TMEM176B, LAYN, RAB6B, MMP9, ATAD3B, SLC2A11, CD3E, SLIT2, SLC2A13, SLC43A3, CD6, SIRPG, NEK6, LCP2, CTTN, CXCL2, SNX22, BCL6 and FABP4 were identified and subjected to build the prognostic model which was further verified in four external microarray cohorts and one RNA seq cohorts. Tumor immune microenvironment analysis and GSEA results showed that the activation of MYC targets genes rather than immunosuppression contribute to the poor survival outcome of patients in the high-risk group. AZD5153, a novel bivalent BET bromodomain inhibitor which could inhibit the transcription of MYC and E2F exhibited specific antitumor function for cells with high-risk score. Our results provide the first lipid metabolism-based gene signature for predicting the survival of patients with DLBCL. Furthermore, by determining novel subtypes with our lipid metabolism prognostic model we illustrated that drugs that compromising MYC target genes rather than immune checkpoint inhibitors may be beneficial to DLBCL patients with certain lipid metabolism profiles.

Targeting Glucose Metabolism: A Novel Therapeutic Approach for Parkinson’s Disease

Glucose metabolism is essential for the maintenance and function of the central nervous system. Although the brain constitutes only 2% of the body weight, it consumes approximately 20% of the body’s total energy, predominantly derived from glucose. This high energy demand of the brain underscores its reliance on glucose to fuel various functions, including neuronal activity, synaptic transmission, and the maintenance of ion gradients necessary for nerve impulse transmission. Increasing evidence shows that many neurodegenerative diseases, including Parkinson’s disease (PD), are associated with abnormalities in glucose metabolism. PD is characterized by the progressive loss of dopaminergic neurons in the substantia nigra, accompanied by the accumulation of α-synuclein protein aggregates. These pathological features are exacerbated by mitochondrial dysfunction, oxidative stress, and neuroinflammation, all of which are influenced by glucose metabolism disruptions. Emerging evidence suggests that targeting glucose metabolism could offer therapeutic benefits for PD. Several antidiabetic drugs have shown promise in animal models and clinical trials for mitigating the symptoms and progression of PD. This review explores the current understanding of the association between PD and glucose metabolism, emphasizing the potential of antidiabetic medications as a novel therapeutic approach. By improving glucose uptake and utilization, enhancing mitochondrial function, and reducing neuroinflammation, these drugs could address key pathophysiological mechanisms in PD, offering hope for more effective management of this debilitating disease.

Impaired Iron Metabolism and Cerebral Perfusion Patterns in Unilateral Middle Cerebral Artery Stenosis or Occlusion: Insights from Quantitative Susceptibility mapping.

Cerebral hypoperfusion caused by stenosis or occlusion of the middle cerebral artery (MCA) may be followed by impaired iron metabolism. We explored the association between iron changes of gray matter (GM) nuclei subregions and different cerebral perfusion patterns in patients with chronic unilateral middle cerebral artery (MCA) stenosis or occlusion using quantitative susceptibility imaging (QSM). Sixty-one patients with unilateral MCA stenosis or occlusion were recruited and scored with Alberta-Stroke-Program-Early-CT-Score (ASPECTS) based on relative cerebral blood flow (rCBF) measurements to calculate the number of corresponding hypoperfusion subregions, and then divided into an extensive-hypoperfusion group (EH group), regional-hypoperfusion group (RH group), and normal-perfusion group (Control group) accordingly. The measured magnetic susceptibility of GM nuclei subregions was compared between the lesion and contralateral side for each group and among the three groups. Correlation analysis was performed to assess the relationships of magnetic susceptibility of GM nuclei with mean rCBF, National-Institutes-of-Health-stroke-scale (NIHSS) and modified-Rankin-scale (mRS) scores. Magnetic susceptibility in the putamen (PU) and globus pallidus (GP) at the lesion side was higher in the EH and RH groups compared with the contralateral side (all P < 0.05). Susceptibility in the lesion side PU and GP showed negative correlations with mean rCBF and positive correlations with NIHSS and mRS scores (all P < 0.05). Our findings demonstrate that chronic cerebral hypoperfusion might be one cause of cerebral abnormal iron metabolism. In addition, magnetic susceptibility of PU and GP seems to be correlated with stroke scale scores, suggesting that iron deposition may play an important role in neurologic deficits after ischemic stroke.

Copper homeostasis and neurodegenerative diseases

Copper, one of the most prolific transition metals in the body, required for normal brain physiological activity and allows various functions to work normally through its range of concentrations. Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins, including copper transporters (CTR1 and CTR2), the two copper ion transporters the Cu -transporting ATPase 1 (ATP7A) and Cu-transporting beta (ATP7B), and the three copper chaperones ATOX1, CCS, and COX17. Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue. Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins, including ceruloplasmin and metallothionein, is involved in the pathogenesis of neurodegenerative disorders. However, the exact mechanisms underlying these processes are not known. Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress. Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction. Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation, with elevated levels activating several critical inflammatory pathways. Additionally, copper can bind aberrantly to several neuronal proteins, including alpha-synuclein, tau, superoxide dismutase 1, and huntingtin, thereby inducing neurotoxicity and ultimately cell death. This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases, with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis. By synthesizing the current findings on the functions of copper in oxidative stress, neuroinflammation, mitochondrial dysfunction, and protein misfolding, we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders, such as Wilson's disease, Menkes' disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Potential clinically significant therapeutic targets, including superoxide dismutase 1, D-penicillamine (DPA), and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline (PBT2), along with their associated therapeutic agents, are further discussed. Ultimately, we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.

Exploring the interaction between the gut microbiota and cyclic adenosine monophosphate-protein kinase A signaling pathway: a potential therapeutic approach for neurodegenerative diseases

The interaction between the gut microbiota and cyclic adenosine monophosphate (cAMP)- protein kinase A (PKA) signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enhances communication along the gut–brain axis. The gut microbiota influences the cAMP-PKA signaling pathway through its metabolites, which activates the vagus nerve and modulates the immune and neuroendocrine systems. Conversely, alterations in the cAMP-PKA signaling pathway can affect the composition of the gut microbiota, creating a dynamic network of microbial-host interactions. This reciprocal regulation affects neurodevelopment, neurotransmitter control, and behavioral traits, thus playing a role in the modulation of neurological diseases. The coordinated activity of the gut microbiota and the cAMP-PKA signaling pathway regulates processes such as amyloid-β protein aggregation, mitochondrial dysfunction, abnormal energy metabolism, microglial activation, oxidative stress, and neurotransmitter release, which collectively influence the onset and progression of neurological diseases. This study explores the complex interplay between the gut microbiota and cAMP-PKA signaling pathway, along with its implications for potential therapeutic interventions in neurological diseases. Recent pharmacological research has shown that restoring the balance between gut flora and cAMP-PKA signaling pathway may improve outcomes in neurodegenerative diseases and emotional disorders. This can be achieved through various methods such as dietary modifications, probiotic supplements, Chinese herbal extracts, combinations of Chinese herbs, and innovative dosage forms. These findings suggest that regulating the gut microbiota and cAMP-PKA signaling pathway may provide valuable evidence for developing novel therapeutic approaches for neurodegenerative diseases.

PCSK9 in metabolism and diseases.

PCSK9 is a serine protease that regulates plasma levels of low-density lipoprotein (LDL) and cholesterol by mediating the endolysosomal degradation of LDL receptor (LDLR) in the liver. When PCSK9 functions unchecked, it leads to increased degradation of LDLR, resulting in elevated circulatory levels of LDL and cholesterol. This dysregulation contributes to lipid and cholesterol metabolism abnormalities, foam cell formation, and the development of various diseases, including cardiovascular disease (CVD), viral infections, cancer, and sepsis. Emerging clinical and experimental evidence highlights an imperative role for PCSK9 in metabolic anomalies such as hypercholesterolemia and hyperlipidemia, as well as inflammation, and disturbances in mitochondrial homeostasis. Moreover, metabolic hormones - including insulin, glucagon, adipokines, natriuretic peptides, and sex steroids - regulate the expression and circulatory levels of PCSK9, thus influencing cardiovascular and metabolic functions. In this comprehensive review, we aim to elucidate the regulatory role of PCSK9 in lipid and cholesterol metabolism, pathophysiology of diseases such as CVD, infections, cancer, and sepsis, as well as its pharmaceutical and non-pharmaceutical targeting for therapeutic management of these conditions.

Study on the molecular mechanism of atopic dermatitis in mice based on skin and serum metabolomic analysis.

Atopic dermatitis (AD) is a common chronic inflammatory dermatosis. However, the exact molecular mechanism underlying the development of AD remain largely unclear. To investigate comprehensive metabolomic alterations in serum and skin tissue between 2,4-dinitrofluorobenzene (DNFB)-induced AD-like mice and healthy controls, aiming to identify the potential disease biomarkers and explore the molecular mechanisms of AD. In this study, Untargeted metabolomics analysis was used to investigate both skin and serum metabolic abnormalities of 2,4-dinitrofluorobenzene (DNFB)-induced AD-like mice. Then, the metabolic differences among the groups were determined through the application of multivariate analysis. Additionally, the selection of predictive biomarkers was accomplished using the receiver operating characteristic (ROC) module. Our findings showed that levels of 220 metabolites in the skin and 94 metabolites in the serum were different in AD-like mice that were treated with DNFB compared to control mice. Uracil, N-Acetyl-L-methionine, deoxyadenosine monophoosphate, 2-acetyl-l-alkyl-sn-glycero-3-phosphcholine, and prostaglandin D2 are considered potential biomarkers of AD as obtained by integrating skin and serum differential metabolite results. Metabolomic data analysis showed that the metabolic pathways in which skin and serum are involved together include histidine metabolism, pyrimidine metabolism, alanine, aspartate, and glutamate metabolism. Our research explained the possible molecular mechanism of AD at the metabolite level and provided potential targets for the development of clinical drugs for AD.

IGF2BP1 accelerates the aerobic glycolysis to boost its immune escape in hepatocellular carcinoma microenvironment

IntroductionEnergy metabolism abnormity emerges as a crucial factor that facilitates tumorigenesis by accelerating aerobic glycolysis. However, the function of N6-methyladenosine (m6A) on hepatocellular carcinoma (HCC) aerobic glycolysis and immune escape is still unclear. Here, this investigation was intended to elucidate the regulation of m6A ‘reader’ IGF2BP1 involved in HCC aerobic glycolysis and immune escape.MethodsThe aerobic glycolysis was tested by glucose uptake, lactate, ATP generation and ECAR. The CD8+ T cell-mediated killing effect was tested by cytotoxicity, IFN-γ and granzyme B. The molecular interaction was confirmed by luciferase reporter assay, immunoprecipitation assay and chromatin immunoprecipitation (ChIP)-PCR.ResultsElevated IGF2BP1 expression was associated with poor prognosis in HCC patients. Functionally, IGF2BP1 emerged as an oncogenic factor that accelerated HCC aerobic glycolysis (glucose uptake, lactate, ATP generation and ECAR) and oxaliplatin resistance. Meanwhile, IGF2BP1 repressed the activated CD8+ T cell-mediated killing effect (cytotoxicity, IFN-γ and granzyme B) and apoptosis of HCC cells, indicating a suppressed cytotoxic T-cell response. By recognizing and binding to the m6A-modified sites on c-Myc mRNA, IGF2BP1 enhanced the stability of c-Myc mRNA, consequently upregulating c-Myc expression. In addition, transcription factor c-Myc targeted the programmed death ligand 1 (PD-L1) promoter region to strengthen its transcription.DiscussionTaken together, this study illustrates IGF2BP1 as a potential therapeutic target in HCC, aiming to disrupt the interplay between aberrant metabolism and immune escape.

Emerging Role of Ubiquitin Proteasome System and Autophagy in Pediatric Demyelinating Leukodystrophies and Therapeutic Opportunity

Leukodystrophies represent a heterogeneous group of disorders characterized by specific genetic mutations, metabolic abnormalities, and degeneration of white matter in the central nervous system. These disorders are classified into several categories, with X-linked adrenoleukodystrophy (X-ALD), metachromatic leukodystrophy (MLD), and globoid cell leukodystrophy (GLD) being the most prevalent demyelinating leukodystrophies in pediatric populations. Maintaining proteostasis, which is critical for normal cellular function, relies fundamentally on the ubiquitin–proteasome system (UPS) and autophagy for the degradation of misfolded and damaged proteins. Compelling evidence has highlighted the critical roles of UPS and autophagy dysfunction in the pathogenesis of neurodegenerative diseases. Given the complex and poorly understood pathomechanisms underlying demyelinating leukodystrophies, coupled with the pressing need for effective therapeutic strategies, this review aims to systemically analyze the molecular and pathological evidence linking UPS and autophagy dysfunction to demyelinating leukodystrophies, specifically X-ALD and GLD. Furthermore, we will assess the therapeutic potential of autophagy modulators in the management of X-ALD and GLD, with the objective to inspire further research into therapeutic approaches that target autophagy and UPS pathways. Novel therapies that enhance autophagy and UPS function hold promise as complementary regimens in combination therapies aimed at achieving comprehensive correction of the pathogenic mechanisms in demyelinating leukodystrophies.

Lactobacillus paracasei 259 alleviates hyperuricemia in rats by decreasing uric acid and modulating the gut microbiota

Hyperuricemia (HUA) is a metabolic disease arising from abnormal purine metabolism. It contributes to an increased risk of kidney damage. The present study aimed to investigate the uric acid (UA)-lowering effects of Lactobacillus paracasei 259 isolated from yak yogurt and explore its underlying mechanisms. Our results revealed that L. paracasei 259 decreased the UA levels in rats and inhibited the serum activities of xanthine oxidase. In addition, L. paracasei 259 reduced the levels of pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6) in the kidney and altered the expressions of UA transporters (ABC transporter 2 (ABCG2), PDZ domain containing 1 (PDZK1), urate transporter 1 (URAT1), and sodium-phosphate cotransporter type 4 (NPT4)) to near normal levels. Moreover, it increased the abundance of beneficial bacteria in the gut and recovered the gut microbiota composition, promoting the production of short-chain fatty acids (SCFAs). These findings suggested that L. paracasei 259 can potentially be used to decrease UA levels, repair kidney damage, regulate gut microbiota, and alleviate HUA.

Phosphate metabolism: its impact on disorders of mineral metabolism.

Regulatory molecules typically work cooperatively to ensure the efficient functioning of hormonal systems. Examples include LH and FSH in reproductive biology, insulin and glucagon in glucose metabolism. Similarly, calcium and phosphorus are important regulators of skeletal homeostasis. In the circulation, these molecules are under the control of PTH, 1,25(OHD), and FGF23. In turn, these hormones depend upon a mutual and complex interplay among themselves. For example, alterations in calcium metabolism influence phosphorus homeostasis, as occurs in primary hyperparathyroidism (PHPT). Not as well recognized is the influence that abnormalities in phosphorus metabolism can have on calcium homeostasis. In this review, we call attention to the impact that abnormalities in phosphorus can have on calcium metabolism.

Base-editing corrects metabolic abnormalities in a humanized mouse model for glycogen storage disease type-Ia

Glycogen storage disease type-Ia patients, deficient in the G6PC1 gene encoding glucose-6-phosphatase-α, lack blood glucose control, resulting in life-threatening hypoglycemia. Here we show our humanized mouse model, huR83C, carrying the pathogenic G6PC1-R83C variant displays the phenotype of glycogen storage disease type-Ia and dies prematurely. We evaluate the efficacy of BEAM-301, a formulation of lipid nanoparticles containing a newly-engineered adenine base editor, to correct the G6PC1-R83C variant in huR83C mice and monitor phenotypic correction through one year. BEAM-301 can correct up to ~60% of the G6PC1-R83C variant in liver cells, restores blood glucose control, improves metabolic abnormalities of the disease, and confers long-term survival to the mice. Interestingly, just ~10% base correction is therapeutic. The durable pharmacological efficacy of base editing in huR83C mice supports the development of BEAM-301 as a potential therapeutic for homozygous and compound heterozygous glycogen storage disease type-Ia patients carrying the G6PC1-R83C variant.

Identification of Estrogen-Responsive Proteins in Mouse Seminal Vesicles Through Mass Spectrometry-Based Proteomics

Background: Although estrogenic compounds promise therapeutic potential in treating various conditions, concerns regarding their endocrine-disrupting effects have been raised. Current methodologies for screening estrogenicity in rodent models are limited to the female-specific uterotrophic bioassay. Studies have reported enlargement of the seminal vesicles in orchiectomized males treated with estrogens. However, identifying estrogenicity strictly through changes in wet weights is uninformative regarding the molecular mechanisms of these agents. Therefore, protein-based biomarkers can complement and improve the sensitivity of weight-based assessments. To this end, we present a discovery-driven proteomic analysis of 17β-estradiol’s effects on the seminal vesicles. Methods: We treated orchidectomized mice with the hormone for five days and used the vehicle-treated group as a control. Seminal vesicles were analyzed by shotgun approach using data-dependent nanoflow liquid chromatography–tandem mass spectrometry and label-free quantification. Proteins found to be differentially expressed between the two groups were processed through a bioinformatics pipeline focusing on pathway analyses and assembly of protein interaction networks. Results: Out of 668 identified proteins that passed rigorous validation criteria, 133 were regulated significantly by 17β-estradiol. Ingenuity Pathway Analysis® linked them to several hormone-affected pathways, including those associated with immune function such as neutrophil degranulation. The altered protein interaction networks were also related to functions including endocrine disruption, abnormal metabolism, and therapeutic effects. Conclusions: We identified several potential biomarkers for estrogenicity in mouse seminal vesicles, many of them not previously linked with exogenous 17β-estradiol exposure.

Role of intestinal testosterone-degrading bacteria and 3/17β-HSD in the pathogenesis of testosterone deficiency-induced hyperlipidemia in males

Testosterone deficiency can cause abnormal lipid metabolism in men, leading to hyperlipidemia. We identified the testosterone-degrading bacterium Pseudomonas nitroreducens in the fecal samples of male patients with hyperlipidemia. Gastric administration of P. nitroreducens in mice led to testosterone deficiency and elevated blood lipid levels. Whole-genome sequencing of P. nitroreducens revealed the presence of 3/17β-hydroxysteroid dehydrogenase (3/17β-HSD), a gene responsible for testosterone degradation, which is also associated with hyperlipidemia. Microbiota analysis of fecal samples collected from 158 patients with hyperlipidemia and 151 controls revealed that the relative abundance of P. nitroreducens and 3/17β-HSD in the fecal samples of patients with hyperlipidemia was significantly higher than that in controls. These results suggest that P. nitroreducens and 3/17β-HSD may be related to the onset of testosterone deficiency-induced hyperlipidemia. Therefore, treatments targeted at eradicating testosterone-degrading bacteria are a potential future option for patients with testosterone-induced hyperlipidemia and should thus be studied further.