Impaired Metabolism Research Articles

The Role of Inflammatory and Nutritional Indices in Postmenopausal Osteoporosis: A Retrospective Study

Background: Postmenopausal osteoporosis is characterized by impaired bone metabolism, inflammation, and nutritional deficiencies. This study aimed to evaluate the potential of inflammatory and nutritional markers in identifying decreased bone mineral density (BMD) in postmenopausal women. Methods: This cross-sectional study retrospectively analyzed postmenopausal women from January 2018 and December 2023. A total of 368 women were divided into three groups based on T-scores: 61 women with osteoporosis (T-score ≤ −2.5), 153 women with osteopenia (−1 > T-score > −2.5), and 154 women with normal BMD (T-score > −1). Inflammatory and nutritional biomarkers included the neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), monocyte/lymphocyte ratio (MLR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), pan-immune inflammation value (PIV), geriatric nutritional risk index (GNRI), triglycerides, total cholesterol, and body weight index (TCBI), prognosis nutritional index (PNI), hemoglobin, albumin, lymphocyte, and platelet (HALP) score, 25-OH Vitamin D level, Na, K, Ca, Mg, and their ratios. Results: The GNRI was significantly lower in the osteoporosis group compared to the control group. The NLR, PLR, SII, SIRI, PIV, TCBI, PNI, and HALP were similar between the groups. The GNRI and TCBI showed a positive correlation with T-scores. The Mg level was lower in the osteoporosis group than in the control group and osteopenia group, and the Na/Mg ratio was higher. Additionally, the Ca/Mg ratio was lower in the osteoporosis group than in the control group. The T-score was positively correlated with Mg and Ca/Mg, while the Na/Mg ratio showed a significant negative correlation. Vitamin D, other minerals, and their ratios did not show significant differences between the groups. Conclusions: Our findings suggest that the GNRI could serve as a useful indicator for assessing bone health and the risk of osteoporosis. Furthermore, maintaining appropriate levels of Mg and balanced Na/Mg and Ca/Mg ratios appears crucial for BMD.

Maternal lipid mobilization is essential for embryonic development in the malaria vector Anopheles gambiae.

Lipid metabolism is an essential component in reproductive physiology. While lipid mobilization has been implicated in the growth of Plasmodium falciparum malaria parasites in their Anopheles vectors, the role of this process in the reproductive biology of these mosquitoes remains elusive. Here, we show that impairing lipolysis in Anopheles gambiae, the major malaria vectors, leads to embryonic lethality. Embryos derived from females in which we silenced the triglyceride lipase AgTL2 or the lipid storage droplet AgLSD1 develop normally during early embryogenesis but fail to hatch due to severely impaired metabolism. Embryonic lethality is efficiently recapitulated by exposing adult females to broad-spectrum lipase inhibitors prior to blood feeding, unveiling lipolysis as a potential target for inducing mosquito sterility. Our findings provide mechanistic insights into the importance of maternal lipid mobilization in embryonic health that may inform studies on human reproduction.

Role of LIPIN 1 in regulating metabolic homeostasis in the retinal pigment epithelium.

Dysregulated lipid metabolism, characterized by the accumulation of lipid deposits on Bruch's membrane and in drusen, is considered a key pathogenic event in age-related macular degeneration (AMD). The imbalance of lipid production, usage, and transport in local tissues, particularly in the retinal pigment epithelium (RPE), is increasingly recognized as crucial in AMD development. However, the molecular mechanisms governing lipid metabolism in the RPE remain elusive. LIPIN1, a multifunctional protein acting as both a modulator of transcription factors and a phosphatidate phosphatase (PAP1), is known to play important regulatory roles in lipid metabolism and related biological functions, such as inflammatory responses. While deficits in LIPIN1 have been linked to multiple diseases, its specific roles in the retina and RPE remain unclear. In this study, we investigated LIPIN1 in RPE integrity and function using a tissue-specific knockout animal model. The clinical and histological examinations revealed age-dependent degeneration in the RPE and the retina, along with impaired lipid metabolism. Bulk RNA sequencing indicated a disturbance in lipid metabolic pathways. Moreover, these animals exhibited inflammatory markers reminiscent of human AMD features, including deposition of IgG and C3d on Bruch's membrane. Collectively, our findings indicate that LIPIN1 is a critical component of the complex regulatory network of lipid homeostasis in the RPE. Disruption of LIPIN1-mediated regulation impaired lipid balance and contributed to AMD-related pathogenic changes.

The first case of a competitive basketball player affected by carnitine palmitoyl transferase II deficiency presenting an undescribed compound heterozygous genetic mutation.

The risk of exercise-induced rhabdomyolysis, followed by abrupt creatine kinase (CK) augmentation, associated with carnitine palmitoyl transferase II (CPTII) deficiency causes patients to abstain from physical training. However, the exercise adjustment to the disease-induced metabolic impairment, accompanied by a tailored nutritional and supplementation strategy, could make sporting activity feasible, even at a competitive level. Here, we report the case of an 18-year-old male basketball player at a competitive level diagnosed for CPTII deficiency after a rhabdomyolytic event. Subsequent genetic analysis revealed the previously unreported c.1741C > T genetic mutation. The patient underwent a battery of tests to evaluate nutrition (indirect calorimetry; 8-day food records), hydration (bioimpedance analysis), and the use of energy substrates during exercise (cardiopulmonary exercise test, CPET). Inadequate macronutrients distribution with respect to the reference values for CPTII deficiency, an optimal hydration status, and a non-physiological prevalence of carbohydrates consumption all along the CPET, accentuated with workload augmentation, were found. Based on the results, the patient was provided with a personalized nutritional (carbohydrate = 50-55%, fat = 20%, and protein = 25-30% of total energy) and supplementation (medium-chain triglycerides, β-alanine, and creatine citrate) plan, and indications on the exercise intensity to be adopted to avoid the contribution of fat to energy production. Monitoring of CK for the five months following the resumption of sporting activity shows that the patient no longer had rhabdomyolysis. These findings suggest that tailoring exercise, nutrition and supplementation upon the disease-induced metabolic limitation makes sport activity at a competitive level feasible in a CPTII-deficient patient, prompting further analysis on larger cohorts.

Heightened cholesterol 25-hydroxylase expression in aged lung during Streptococcus pneumoniae

IntroductionAlveolar macrophages (AM) are critical effectors of the immune response and are essential for host responses to Streptococcus pneumoniae. Changes in lipid metabolism in AM can alter cellular function and biology. Impaired metabolism can contribute to excessive lipid accumulation and pro-inflammatory signaling. Our current study was designed to examine the role of cholesterol 25-hydroxylase (Ch25h), a redox enzyme that catalyzes the oxidation of cholesterol to 25-hydroxycholesterol (25-HC), in modulating AM responses in the aged lung during S. pneumoniae infection.MethodsTo observe the impact of aging on Ch25h expression in AM during infection, in vitro and in vivo murine models of S. pneumoniae were used.ResultsAt baseline and in response to infection, cholesterol metabolism significantly altered in aged AM, which corresponded with increased lipid droplet formation. In vitro, treatment of aged macrophages with Ch25 h-specific siRNA improved S. pneumoniae clearance and enhanced phagocytic receptor expression. In vivo siRNA targeting significantly reduced Ch25h expression in aged lungs and improved clinical parameters during S. pneumoniae infection. Reduction of Ch25h was associated with changes in phagocytosis and antibacterial signaling, correlated with changes in cholesterol metabolism, and increased S. pneumoniae clearance.DiscussionThe results of our current study demonstrate that Ch25h plays an essential role in modulating aged AM responses to S. pneumoniae.

Circulatory response to exercise relative to oxygen uptake assessed in the follow-up of patients with fatty acid beta-oxidation disorders.

Patients with fatty acid oxidation disorders (FAODs) experience muscle symptoms due to impaired ATP metabolism and the toxicity of accumulated mitochondrial FAO substrates or intermediates, especially during catabolic states. A major issue is the absence of specific and sensible biomarkers to evaluate metabolic equilibrium. The relationship between cardiac output (Q) and oxygen consumption (VO2) during incremental exercise (dQ/dVO2) provides an indirect surrogate of mitochondrial function. A high dQ/dVO2 slope indicates impaired oxidative phosphorylation in skeletal muscle during exercise. Our study aimed to evaluate dQ/dVO2 as a potential marker of the severity of FAODs. We retrospectively collected clinical, laboratory parameters and treatment data for FAOD patients over 6 years old, including a disease severity score, plasma acylcarnitines and cardiopulmonary exercise tests with Q measurement via thoracic bioelectrical impedance. FAO flux was measured in whole blood and in myoblasts when available. We included 27 FAOD patients followed from 2015 to 2022, with deficiencies in LCHAD (n = 10), CPT2 (n = 6), VLCAD (n = 7), or MADD (n = 4). CPT2 deficient patients with severe scores had the highest C18:1-, C16-, C18-acylcarnitines, and dQ/dVO2. In these patients, dQ/dVO2 was positively correlated with C18:1, C16, and C18 acylcarnitines. In a linear multivariate regression model, dQ/dVO2 was significantly associated with the severity score (B = 0.831, p = 0.008) and triheptanoin treatment (B = -0.547, p = 0.025). dQ/dVO2 and plasma long-chain acylcarnitines might be useful to monitor CPT2D, as these parameters associate with our clinical severity score and could reflect altered mitochondrial functions.

Fibro-adipogenic progenitor cells in skeletal muscle unloading: metabolic and functional impairments

BackgroundSkeletal muscle resident fibro-adipogenic progenitor cells (FAPs) control skeletal muscle regeneration providing a supportive role for muscle stem cells. Altered FAPs characteristics have been shown for a number of pathological conditions, but the influence of temporary functional unloading of healthy skeletal muscle on FAPs remains poorly studied. This work is aimed to investigate how skeletal muscle disuse affects the functionality and metabolism of FAPs.MethodsHindlimb suspension (HS) rat model employed to investigate muscle response to decreased usage. FAPs were purified from m. soleus functioning muscle (Contr) and after functional unloading for 7 and 14 days (HS7 and HS14). FAPs were expanded in vitro, and tested for: immunophenotype; in vitro expansion rate, and migration activity; ability to differentiate into adipocytes in vitro; metabolic changes. Crosstalk between FAPs and muscle stem cells was estimated by influence of medium conditioned by FAP’s on migration and myogenesis of C2C12 myoblasts. To reveal the molecular mechanisms behind unloading-induced alterations in FAP’s functionality transcriptome analysis was performed.ResultsFAPs isolated from Contr and HS muscles exhibited phenotype of MSC cells. FAPs in vitro expansion rate and migration were altered by functional unloading conditions. All samples of FAPs demonstrated the ability to adipogenic differentiation in vitro, however, HS FAPs formed fat droplets of smaller volume and transcriptome analysis showed fatty acids metabolism and PPAR signaling suppression. Skeletal muscle unloading resulted in metabolic reprogramming of FAPs: decreased spare respiratory capacity, decreased OCR/ECAR ratio detected in both HS7 and HS14 samples point to reduced oxygen consumption, decreased potential for substrate oxidation and a shift to glycolytic metabolism. Furthermore, C2C12 cultures treated with medium conditioned by FAPs showed diverse alterations: while the HS7 FAPs-derived paracrine factors supported the myoblasts fusion, the HS14-derived medium stimulated proliferation of C2C12 myoblasts; these observations were supported by increased expression of cytokines detected by transcriptome analysis.Conclusionthe results obtained in this work show that the skeletal muscle functional unloading affects properties of FAPs in time-dependent manner: in atrophying skeletal muscle FAPs act as the sensors for the regulatory signals that may stimulate the metabolic and transcriptional reprogramming to preserve FAPs properties associated with maintenance of skeletal muscle homeostasis during unloading and in course of rehabilitation.

Nicotinamide riboside targets mitochondrial unfolded protein response to reduce alcohol-induced damage in Kupffer cells.

The pathogenesis of alcohol-related liver disease (ALD) is closely linked to mitochondrial dysfunction and impaired cellular energy metabolism. In this study, we explored how ethanol triggers inflammation, oxidative stress, and mitochondrial dysfunction in Kupffer cells, i.e.hepatic resident macrophages, primarily focusing on the mitochondrial unfolded protein response (UPRmt) using immortalized mouse Kupffer cells (ImKCs) and mouse primary KCs. The UPRmt is a cellular defense mechanism activated in response to the perturbation of mitochondrial proteostasis to maintain mitochondrial integrity and function by upregulating the expression of mitochondrial chaperones and proteases. We also determined whether nicotinamide riboside (NR), a NAD+ precursor, could mitigate ethanol-triggered cellular damage. When ImKCs were exposed to 80 mm ethanol for 72 h, they displayed inflammation, oxidative stress, and impaired mitochondrial function with decreased mitochondrial content and deformed mitochondrial crista structure. NR, however, counteracted the effects of ethanol. Furthermore, ethanol increased mRNA and protein levels of UPRmt genes, such as mitochondrial chaperones and proteases, which were attenuated by NR. Notably, the ethanol-induced shift in the entry of activating transcription factor 5 (ATF5), a putative transcriptional regulator of UPRmt, to the nucleus from the mitochondria was abolished by NR. The induction of UPRmt genes by ethanol was significantly repressed when Atf5 was knocked down, indicating the role of ATF5 in the induction of UPRmt genes in ImKCs exposed to ethanol. We also confirmed the induction of UPRmt gene expression in mouse and human livers exposed to alcohol. Our findings demonstrate the ability of NR to alleviate ethanol-induced oxidative stress, inflammation, and mitochondrial dysfunction, partly by modulating the ATF5-dependent UPRmt pathway in ImKCs, suggesting its potential for ALD therapy. © 2024 The Pathological Society of Great Britain and Ireland.

Impact of daily fasting duration on body composition and cardiometabolic risk factors during a time-restricted eating protocol: a randomized controlled trial

BackgroundTime-restricted eating (TRE) is a dietary regimen that limits food intake for at least 12 h daily. Unlike other fasting protocols, TRE does not dictate what or how much to eat but rather focuses on the timing of meals. This approach has been previously demonstrated to improve body composition in individuals with obesity or metabolic impairments. However, its impact on body composition and cardiometabolic factors in healthy individuals remains unclear. Furthermore, the optimal fasting duration is still debated. Thus, we aimed to compare the effects of 8 weeks of different fasting durations on body composition and biochemical parameters in metabolically healthy, non-trained individuals using a parallel randomized controlled trial.MethodsForty-one volunteers were randomly assigned to one of the four experimental groups: TRE 16:8 (16 h of fasting,8 h of eating), TRE 14:10 (14 h of fasting,10 h of eating), TRE 12:12 (12 h of fasting,12 h of eating) or a normal diet group (ND; no dietary restriction). Participants underwent body composition measurements and blood tests for lipid profiles (i.e., total cholesterol, LDL, HDL, and triglycerides), fasting glucose, leptin, and anabolic hormones (i.e., insulin and testosterone) levels. Data were analyzed using both intention-to-treat (ITT) and per-protocol (PP) analysis to account for compliance. A two-way ANOVA for repeated measures was employed to assess interactions between time and group.ResultsIn the ITT analysis, TRE 16:8 reduced body mass (-2.46%, p = 0.003) and absolute fat mass (-8.65%, p = 0.001) with no changes in lean soft tissue and in calorie intake. These results were consistent with the PP analysis which included 8 participants in TRE 16:8, 5 in TRE 14:10, 9 in TRE 12:12, and the entire ND group. Participants in the TRE 16:8 group spontaneously reduced their total caloric intake, although this reduction was not statistically significant. None of the other measurements significantly changed after 8 weeks.ConclusionsOur results suggest that a 16-hour fasting window, even without caloric restriction, may be a viable strategy for improving body composition in healthy and non-trained individuals, whereas a shorter fasting period may be insufficient to produce significant changes in a healthy population.Trial registrationNCT, NCT04503005. Registered 4 August 2020, https://clinicaltrials.gov/study/NCT04503005.

The Multifaceted Role of the Polyphenol Curcumin: A Focus on Type 2 Diabetes Mellitus

Abstract: Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disorder characterized by chronic hyperglycemia, which often co-exists with other metabolic impairments. This condition can damage various tissues and organs, resulting in the development of severe complications, both microvascular, such as retinopathy, nephropathy, and neuropathy, and macrovascular, responsible for an increased risk of cardiovascular diseases. Curcumin is the main bioactive molecule found in the rhizomes of turmeric. Many studies have reported curcumin to exhibit antioxidant, anti-inflammatory, anti-infectious, and anti-cancer properties; thus, there is an increasing interest in exploiting these properties in order to prevent the rise or the progression of T2DM, as well as its possible associated conditions. In this review, we have presented the current state-ofart regarding the clinical trials that have involved curcumin administration and analyzed the possible mechanisms by which curcumin might exert the beneficial effects observed in literature.

Zinc ions facilitate metabolic bioenergetic recovery post spinal cord injury by activating microglial mitophagy through the STAT3-FOXO3a-SOD2 pathway

Spinal cord injury (SCI) is a devastating condition of the central nervous system (CNS) with high global rates of disability and mortality, and no effective cure currently available. Microglia play a critical role in the progression of SCI, and enhancing their metabolic function may facilitate tissue repair and recovery. Mitochondrial dysfunction is a key feature of metabolic impairment, with the regulation of autophagy being essential for maintaining mitochondrial homeostasis and cell survival. The transcription factor Forkhead box O3a (FOXO3a) is integral to cellular metabolism, mitochondrial dysfunction, and oxidative stress responses, yet its role in post-SCI microglial metabolism remains underexplored. In this study, single-cell RNA sequencing reveals the crucial involvement of the FOXO signaling pathway in zinc ion-mediated enhancement of microglial metabolism. Mechanistically, oxidative stress-induced reactive oxygen species (ROS) accumulation exacerbates metabolic dysfunction by promoting excessive mitochondrial fission and impairing mitophagy. Importantly, zinc ions induce the nuclear translocation of FOXO3a, leading to its activation as a transcription factor. This activation enhances mitochondrial autophagy and fusion processes, thereby restoring microglial metabolic capacity. Our findings suggest that the zinc ion regulation of the STAT3-FOXO3a-SOD2 axis is pivotal in modulating mitochondrial gene expression, which governs microglial energy homeostasis and improves the spinal cord microenvironment, potentially enhancing neuronal survival. These insights highlight a promising therapeutic target for SCI.

The assessment of the composition of the microbiota of the facial skin in patients with seborrheic dermatitis and metabolic syndrome

Our study revealed associations with dysregulation of the community of commensals connected with seborrheic dermatitis, metabolic syndrome (MS) and type 2 diabetes mellitus.The aim of the study was to identify the association of the severity of SD and changes in the bacterial composition of the skin microbiota in patients with facial SD, with facial SD and metabolic syndrome and in patients with facial SD with MS and type 2 diabetes mellitus.Material and methods.The study included 90 patients with seborrheic dermatitis, divided into 3 groups . The severity of the disease was determined by SEDASI score . Metabolic syndrome was diagnosed based on the criteria of NCEP ATP III. The diagnosis of diabetes mellitus was established according to the diagnostic criteria of diabetes mellitus and other glycemic disorders . A modified Leming-Notman dense medium was used to isolate yeast fungi of Malassezia spp. The cultures were obtained according to the Gold’s method. The species identification from clinical isolates was carried out using the mass spectrometry method on the MALDI-TOF MS "Biotyper RTC" device.Results.Significant changes in the number of bacterial species were observed in patients with moderate to severe diabetes mellitus. We found that the colonization of microorganisms on the facial skin significantly increased in patients of groups 2 and 3, compared with group 1. Among the isolated staphylococci in patients of groups 2 and 3, the growth of S. аureus, S. epidermidis, and S. hominis prevailed.Conclusion.The severity of the duration and widespread lesions on the facial skin in patients with seborrheic dermatitis, metabolic syndrome and with seborrheic dermatitis, metabolic syndrome and type 2 diabetes mellitus are interrelated with dysbiosis of the microbiota. The growth of microorganisms in patients with seborrheic dermatitis and impaired carbohydrate metabolism is associated with severe facial SD and plays a significant role in the pathogenesis of the disease.

Ruminococcus gnavus in the gut: driver, contributor, or innocent bystander in steatotic liver disease?

The human gut microbiome plays a crucial role in regulating intestinal and systemic health, impacting host immune response and metabolic function. Dysbiosis of the gut microbiome is linked to various diseases, including steatotic liver diseases. Metabolic dysfunction-associated steatotic liver disease (MASLD), a chronic liver disease characterized by excess hepatic lipid content and impaired metabolism, is the leading cause of liver disease worldwide. Among the gut microbes, Ruminococcus gnavus (R. gnavus) has garnered attention for its association with inflammatory and metabolic diseases. While R. gnavus abundance correlates to liver fat accumulation, further research is needed to identify a causal role or therapeutic intervention in steatotic liver disease. This review surveys our current understanding of R. gnavus in the development and progression of steatotic liver diseases, highlighting its potential mechanisms through metabolite secretion, and emphasizes the need for comprehensive microbiome analyses and longitudinal studies to better understand R. gnavus' impact on liver health. This knowledge could pave the way for targeted interventions aimed at modulating gut microbiota to treat and prevent MASLD and its comorbidities.

Understanding the biological processes of kidney carcinogenesis: an integrative multi-omics approach

Biological mechanisms related to cancer development can leave distinct molecular fingerprints in tumours. By leveraging multi-omics and epidemiological information, we can unveil relationships between carcinogenesis processes that would otherwise remain hidden. Our integrative analysis of DNA methylome, transcriptome, and somatic mutation profiles of kidney tumours linked ageing, epithelial–mesenchymal transition (EMT), and xenobiotic metabolism to kidney carcinogenesis. Ageing process was represented by associations with cellular mitotic clocks such as epiTOC2, SBS1, telomere length, and PBRM1 and SETD2 mutations, which ticked faster as tumours progressed. We identified a relationship between BAP1 driver mutations and the epigenetic upregulation of EMT genes (IL20RB and WT1), correlating with increased tumour immune infiltration, advanced stage, and poorer patient survival. We also observed an interaction between epigenetic silencing of the xenobiotic metabolism gene GSTP1 and tobacco use, suggesting a link to genotoxic effects and impaired xenobiotic metabolism. Our pan-cancer analysis showed these relationships in other tumour types. Our study enhances the understanding of kidney carcinogenesis and its relation to risk factors and progression, with implications for other tumour types.

Recent Studies on Heterocyclic Cholinesterase Inhibitors Against Alzheimer's Disease.

Alzheimer's disease is a progressive and neurodegenerative disease characterized by impairment in emotion, language, memory and cognitive judgment. There are many factors related to Alzheimer's disease, such as amyloid beta plaques (Aβ) due to impaired metabolism of amyloid precursor protein (APP), tau hyperphosphorylation and accumulation of neurofibrillary tangles, and disruption of the cholinergic system. Disruption of the cholinergic system responsible for cognitive function and memory processes is one of the important causes of Alzheimer's disease. Therefore, cholinesterase (acetylcholinesterase and butyrylcholinesterase) inhibitors that maintain choline (acetylcholine and butyrylcholine) levels in the synaptic gap play an important role in the symptomatic treatment of Alzheimer's disease. Numerous studies have been carried out against Alzheimer's disease involving acetylcholinesterase and butyrylcholinesterase inhibitors. However, there are very few drugs (tacrine, rivastigmine, galantamine and donepezil) approved as cholinesterase inhibitors. Therefore, cholinesterase inhibitors are needed against Alzheimer's disease. This review is focused on using heterocyclic rings that show remarkable cholinesterase inhibitory activity for Alzheimer's disease. In this review, chemical structures and structure-activity relationships of recently reported cholinesterase inhibitors are emphasized. This review will give important ideas to medicinal chemists in the discovery and development of potent cholinesterase inhibitors in their future studies.

Sex and Age Differences in the Impact of Metabolic Syndrome on Heart Failure Development

Metabolic syndrome (MetS), a cluster of metabolic dysregulations, is recognized as a significant risk factor for the development of heart failure (HF). The pathophysiological mechanisms linking MetS to HF are complex and multifaceted, with the components of MetS contributing to cardiac deterioration through impaired myocardial energy metabolism, increased inflammation, and endothelial dysfunction. Numerous clinical studies have confirmed the relationship between MetS and HF. Multiple studies have demonstrated that the impact of MetS on HF varies by sex and age. Metabolic disorders, including MetS, have a greater impact on HF incidence in younger adults compared to the elderly population and in women compared to men. Although the reasons for these differences are not yet fully understood, recognizing the sex- and age-related variations is crucial for developing targeted strategies to prevent HF in individuals with MetS. Future research should continue to investigate the underlying mechanisms behind these variations and identify optimal management approaches that account for both sex and age in reducing HF risk.

MBX 2109, a Once-Weekly Parathyroid Hormone Replacement Therapy Prodrug: Phase 1, First-in-Human, Randomized Trial.

Hypoparathyroidism denotes parathyroid hormone (PTH) deficiency and impaired mineral metabolism. MBX 2109, a novel prodrug yielding a biologically active PTH peptide agonist (PTH[1-32], extended by a fatty acylated Lys33), is being developed as a long-acting, once-weekly PTH replacement therapy. Here, we report the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of MBX 2109 in healthy volunteers. This phase 1, randomized, double-blind, placebo-controlled, multiple ascending-dose study (NCT05158335) enrolled healthy adults, who were randomized 4:1 to receive MBX 2109 (200, 400, 600, and 900 μg; n = 8) or placebo (n = 2) by subcutaneous administration once weekly for 4 doses (days 1, 8, 15, and 22). The primary endpoint was safety and tolerability. Key secondary endpoints were PK and PD. Overall, 40 participants (MBX 2109 n = 32, placebo n = 8) were randomized (mean age, 43.3 years; 22.5% female). Treatment-emergent adverse events (TEAEs) occurred in 50%-88% of MBX 2109 groups and in 25% of placebo participants. In the MBX 2109 groups, no severe or serious TEAEs were observed. Injection-site reaction was the most common treatment-related TEAE. The half-lives were 79-95 hours for MBX 2109 and 184-213 hours for the fatty-acylated biologically active PTH peptide, which showed dose- and time-dependent exposure increases. The sustained-action PTH prodrug MBX 2109 was well tolerated with no unexpected, off-target safety issues. The long half-life and flat exposure profile of MBX 2109's biologically active PTH agonist supports once-weekly administration. MBX 2109 doses were identified for future studies.

Depression like-behavior and memory loss induced by methylglyoxal is associated with tryptophan depletion and oxidative stress: a new in vivo model of neurodegeneration

BackgroundDepression and memory loss are prevalent neurodegenerative disorders, with diabetic patients facing an elevated risk of brain dysfunction. Methylglyoxal (MGO) formation, which is heightened in diabetes owing to hyperglycemia and gut dysbiosis, may serve as a critical link between diabetes and brain diseases. Despite the high prevalence of MGO, the precise mechanisms underlying MGO-induced depression and memory loss remain unclear.ResultsWe investigated the effect of MGO stress on depression like-behavior and memory loss to elucidate the potential interplay between MGO-induced tryptophan (Trp) metabolism impairment and oxidative stress in the brain. It demonstrates that MGO induces depression-like behavior in mice, as confirmed by the OFT, TST, FST, SPT, and EPM behavioral tests. MGO led to the depletion of Trp and related neurotransmitters as 5-HT, EPI, and DA in the mouse brain. Additionally, MGO reduced the cell count in the DG, CA1, and CA3 hippocampal regions and modulated TPH2 levels in the brain. Notably, co-treatment with MGO and Trp mirrored the effects observed after Trp-null treatment in neurons, including reduced TPH1 and TPH2 levels and inhibition of neuronal outgrowth. Furthermore, MGO significantly altered the expression of key proteins associated with neurodegeneration, such as p-Tau, p-GSK-3β, APP, oAβ, BDNF, NGF, and p-TrkB. Concurrently, MGO activated MAPKs through ROS induction, triggering a redox imbalance by downregulating Nrf-2, Ho-1, TXNRD1, Trx, Sirt-3, and Sirt-5 expression levels, NAD+, and CAT activity in the mouse brain. This led to an accelerated neuroinflammatory response, as evidenced by increased expression of Iba-1, p-NF-κB, and the secretion of IL-6 and TNF-α. Importantly, Trp treatment ameliorated MGO-induced depression like-behavior and memory loss in mice and markedly mitigated increased expression of p-Tau, APP, p-ERK1/2, p-pJNK, and p-NF-κB in the brain. Likewise, Trp treatment also induced the expression of MGO detoxifying factors GLO-I and GLO-II and CAT activity, suggesting the induction of an antioxidant system and reduced inflammation by inhibiting IL-6 and TNF-α secretion.ConclusionsOur data revealed that MGO-induced depression like-behavior and memory deficits resulted from disturbances in Trp, 5-HT, BDNF, and NGF levels, increased p-Tau and APP expression, neuroinflammation, and impaired redox status (Nrf-2/Ho-1/TXNRD1/Sirt3/5) in the brain.

Isolating the direct effects of growth hormone on lifespan and metabolism in mice.

Prior studies have shown that interrupting the growth hormone/insulin-like growth factor-I (GH/IGF-I) signaling axis extends laboratory mouse lifespan, but confounding effects of additional gene or hormone deficiencies that exist in commonly used models of GH/IGF-I interruption obscure the specific effect of GH on longevity. We address this issue by using mice with a specific knockout of the GH gene and show that both males and females on a mixed genetic background display extended lifespans resulting from GH deficiency. Our physiological assessment of these mice revealed that in addition to weighing significantly less and displaying significantly greater body fat (as a percentage of body weight), GH deficient mice display significant impairments in glucose metabolism and preferential fat utilization. These data provide strong evidence that GH deficiency is directly responsible for the altered nutrient utilization and extended lifespan that is commonly observed in mouse models of GH/IGF-I interruption.

Juvenile Parkinsonism Associated With Dihydropyrimidinase Deficiency.

Juvenile parkinsonism is an exceedingly rare condition in which clinical signs of parkinsonism manifest before 21 years of age. Although the genetic underpinnings of this disorder are increasingly recognized, the full range of inherited metabolic contributors remains undefined. We present the first case of levodopa-responsive juvenile parkinsonism associated with dihydropyrimidinase deficiency caused by a novel DPYS variant. A 13-year-old patient presented with rapid progression of dysphagia, dysarthria, and loss of ambulation over 18 months. Whole-exome sequencing revealed compound heterozygous variants in the DPYS gene (NM_001385: c.1393C>T, p.R465X, and c.905G>A, p.R302Q). In silico analysis predicted both variants to be pathogenic. Further urinary metabolome analysis demonstrated markedly elevated dihydrouracil and dihydrothymine levels, confirming impaired pyrimidine metabolism. Levodopa treatment effectively relieved the patient's motor symptoms. This report identifies DPYS as a novel genetic cause of juvenile parkinsonism and underscores the potential efficacy of levodopa therapy in managing motor dysfunction in DYPS-related parkinsonism.