Ferroptosis and iron metabolism in diabetes: Pathogenesis, associated complications, and therapeutic implications.

Diabetes mellitus is a complex chronic disease, considered as one of the most common metabolic disorders worldwide, posing a major threat to global public health. Ferroptosis emerges as a novel mechanism of programmed cell death, distinct from apoptosis, necrosis, and autophagy, driven by iron-dependent lipid peroxidation accumulation and GPx4 downregulation. A mounting body of evidence highlights the interconnection between iron metabolism, ferroptosis, and diabetes pathogenesis, encompassing complications like diabetic nephropathy, cardiomyopathy, and neuropathy. Moreover, ferroptosis inhibitors hold promise as potential pharmacological targets for mitigating diabetes-related complications. A better understanding of the role of ferroptosis in diabetes may lead to an improvement in global diabetes management. In this review, we delve into the intricate relationship between ferroptosis and diabetes development, exploring associated complications and current pharmacological treatments.

Higher serum uric acid as a risk factor for frailty in older adults: A nationwide population-based study.

BACKGROUND: Uric acid (UA), the terminal breakdown product of purine metabolism, possesses contradictory roles, functioning both as an inflammatory mediator and as an antioxidant. Its clinical relevance, particularly in geriatric populations, remains a topic of ongoing debate. Aiming to elucidate whether circulating UA is detrimental or beneficial to human health, we investigate the association between serum UA concentrations and the frailty index-a comprehensive measure of biological aging in a nationally representative cohort of community-dwelling older adults. METHODS: We conducted a population-based, cross-sectional study utilizing data from the Korea National Health and Nutrition Examination Survey. The sample included 4268 participants aged 65 years and above. A deficit accumulation frailty index (FI) was constructed using 38 items that assess physical, cognitive, psychological, and social domains. Based on the FI, participants were categorized into non-frail (FI ≤ 0.15), pre-frail (0.15 < FI ≤ 0.25), or frail (FI > 0.25). Serum UA levels were quantified through a colorimetric enzymatic assay. RESULTS: After controlling for confounders such as age, sex, socioeconomic status (including income and education level), lifestyle factors (smoking status), and medical history (hypertension, diabetes, dyslipidemia, stroke, cardiovascular diseases), and body mass index, serum UA levels were observed to be significantly higher in frail participants compared with their non-frail counterparts (P < 0.001). Furthermore, serum UA concentrations demonstrated a positive correlation with the FI (P < 0.001), and the odds ratio for frailty per 1 mg/dL increase in serum UA was 1.22 (P < 0.001). Additionally, older adults in the highest quartile of UA levels exhibited a significantly higher FI and 1.66-fold increased odds of frailty compared with those in the lowest quartile (P = 0.011 and P = 0.005, respectively). CONCLUSIONS: These findings suggest that elevated circulating UA levels may act as a pro-aging factor rather than an anti-aging one in older adults, highlighting its potential role in accelerating biological aging. The data further support the utility of serum UA as a potential blood-based biomarker for frailty in this demographic, contributing to the expanding evidence on its significance in geriatric health assessments.

Polar Lipids Supplementation Enhances Basal Excitatory Synaptic Transmission in Primary Cortical Neuron.

SCOPE: Polar lipids, such as gangliosides and phospholipids, are fundamental structural components that play critical roles in the development and maturation of neurons in the brain. Recent evidence has demonstrated that dietary intakes of polar lipids in early life are associated with improved cognitive outcomes during infancy and adolescence. However, the specific mechanisms through which these lipids impact cognition remain unclear. METHODS AND RESULTS: This study examines the direct physiological impact of polar lipid supplementation, in the form of buttermilk powder, on primary cortical neuron growth and maturation. The changes are measured with postsynaptic current response recordings, immunohistochemical examination of functional synapse localization and numbers, and the biochemical quantification of receptors responsible for neuronal synaptic neurotransmission. Chronic exposure to polar lipids increases primary mouse cortical neuron basal excitatory synapse response strength attributed to enhanced dendritic complexity and an altered expression of the excitatory α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit 2 (GluR2). CONCLUSION: The present finding suggests that dietary polar lipids improve human cognition through an enhancement of neuronal maturation and/or function.

Protein Arginine Methyltransferases: Emerging Targets in Cardiovascular and Metabolic Disease.

Cardiovascular diseases (CVDs) and metabolic disorders stand as formidable challenges that significantly impact the clinical outcomes and living quality for afflicted individuals. An intricate comprehension of the underlying mechanisms is paramount for the development of efficacious therapeutic strategies. Protein arginine methyltransferases (PRMTs), a class of enzymes responsible for the precise regulation of protein methylation, have ascended to pivotal roles and emerged as crucial regulators within the intrinsic pathophysiology of these diseases. Herein, we review recent advancements in research elucidating on the multifaceted involvements of PRMTs in cardiovascular system and metabolic diseases, contributing significantly to deepen our understanding of the pathogenesis and progression of these maladies. In addition, this review provides a comprehensive analysis to unveil the distinctive roles of PRMTs across diverse cell types implicated in cardiovascular and metabolic disorders, which holds great potential to reveal novel therapeutic interventions targeting PRMTs, thus presenting promising perspectives to effectively address the substantial global burden imposed by CVDs and metabolic disorders.

The implicated role of GDF15 in gastrointestinal cancer.

BACKGROUND: Growth differentiation factor 15 (GDF15), a stress-responsive cytokine from transforming growth factor superfamily, is highly expressed in mammalian tissues, including pancreas, stomach and intestine under pathological conditions. In particular, elevated levels of GDF15 might play an important role in the development and progression of various gastrointestinal cancers (GCs), suggesting its potential as a promising target for disease prediction and treatment. METHODS: In this review, systematic reviews addressing the role of GDF15 in GCs were updated, along with the latest clinical trials focussing on the GDF15-associated digestive malignancies. RESULTS: The multiple cellular pathways through which GDF15 is involved in the regulation of physiological and pathological conditions were first summarized. Then, GDF15 was also established as a valuable clinical index, functioning as a predictive marker in diverse GCs. Notably, latest clinical treatments targeting GDF15 were also highlighted, demonstrating its promising potential in mitigating and curing digestive malignancies. CONCLUSIONS: This review unveils the pivotal roles of GDF15 and its potential as a promising target in the pathogenesis of GCs, which may provide insightful directions for future investigations.

Loss of SREBP-1c ameliorates iron-induced liver fibrosis by decreasing lipocalin-2.

Sterol regulatory element-binding protein (SREBP)-1c is involved in cellular lipid homeostasis and cholesterol biosynthesis and is highly increased in nonalcoholic steatohepatitis (NASH). However, the molecular mechanism by which SREBP-1c regulates hepatic stellate cells (HSCs) activation in NASH animal models and patients have not been fully elucidated. In this study, we examined the role of SREBP-1c in NASH and the regulation of LCN2 gene expression. Wild-type and SREBP-1c knockout (1cKO) mice were fed a high-fat/high-sucrose diet, treated with carbon tetrachloride (CCl4), and subjected to lipocalin-2 (LCN2) overexpression. The role of LCN2 in NASH progression was assessed using mouse primary hepatocytes, Kupffer cells, and HSCs. LCN2 expression was examined in samples from normal patients and those with NASH. LCN2 gene expression and secretion increased in CCl4-induced liver fibrosis mice model, and SREBP-1c regulated LCN2 gene transcription. Moreover, treatment with holo-LCN2 stimulated intracellular iron accumulation and fibrosis-related gene expression in mouse primary HSCs, but these effects were not observed in 1cKO HSCs, indicating that SREBP-1c-induced LCN2 expression and secretion could stimulate HSCs activation through iron accumulation. Furthermore, LCN2 expression was strongly correlated with inflammation and fibrosis in patients with NASH. Our findings indicate that SREBP-1c regulates Lcn2 gene expression, contributing to diet-induced NASH. Reduced Lcn2 expression in 1cKO mice protects against NASH development. Therefore, the activation of Lcn2 by SREBP-1c establishes a new connection between iron and lipid metabolism, affecting inflammation and HSCs activation. These findings may lead to new therapeutic strategies for NASH.

Gut microbiota-generated metabolites: missing puzzles to hosts' health, diseases, and aging.

The gut microbiota, an intricate community of bacteria residing in the gastrointestinal system, assumes a pivotal role in various physiological processes. Beyond its function in food breakdown and nutrient absorption, gut microbiota exerts a profound influence on immune and metabolic modulation by producing diverse gut microbiota-generated metabolites (GMGMs). These small molecules hold potential to impact host health via multiple pathways, which exhibit remarkable diversity, and have gained increasing attention in recent studies. Here, we elucidate the intricate implications and significant impacts of four specific metabolites, Urolithin A (UA), equol, Trimethylamine N-oxide (TMAO), and imidazole propionate, in shaping human health. Meanwhile, we also look into the advanced research on GMGMs, which demonstrate promising curative effects and hold great potential for further clinical therapies. Notably, the emergence of positive outcomes from clinical trials involving GMGMs, typified by UA, emphasizes their promising prospects in the pursuit of improved health and longevity. Collectively, the multifaceted impacts of GMGMs present intriguing avenues for future research and therapeutic interventions. [BMB Reports 2024; 57(5): 207-215].

CDKN2 expression is a potential biomarker for T cell exhaustion in hepatocellular carcinoma.

Hepatocellular Carcinoma (HCC), the predominant primary hepatic malignancy, is the prime contributor to mortality. Despite the availability of multiple surgical interventions, patient outcomes remain suboptimal. Immunotherapies have emerged as effective strategies for HCC treatment with multiple clinical advantages. However, their curative efficacy is not always satisfactory, limited by the dysfunctional T cell status. Thus, there is a pressing need to discover novel potential biomarkers indicative of T cell exhaustion (Tex) for personalized immunotherapies. One promising target is Cyclin-dependent kinase inhibitor 2 (CDKN2) gene, a key cell cycle regulator with aberrant expression in HCC. However, its specific involvement remains unclear. Herein, we assessed the potential of CDKN2 expression as a promising biomarker for HCC progression, particularly for exhausted T cells. Our transcriptome analysis of CDKN2 in HCC revealed its significant role involving in HCC development. Remarkably, single-cell transcriptomic analysis revealed a notable correlation between CDKN2 expression, particularly CDKN2A, and Tex markers, which was further validated by a human cohort study using human HCC tissue microarray, highlighting CDKN2 expression as a potential biomarker for Tex within the intricate landscape of HCC progression. These findings provide novel perspectives that hold promise for addressing the unmet therapeutic need within HCC treatment. [BMB Reports 2024; 57(6): 287-292].

Inhibition of SIRT7 overcomes sorafenib acquired resistance by suppressing ERK1/2 phosphorylation via the DDX3X-mediated NLRP3 inflammasome in hepatocellular carcinoma.

AIMS: Sirtuin 7 (SIRT7) plays an important role in tumor development, and has been characterized as a potent regulator of cellular stress. However, the effect of SIRT7 on sorafenib acquired resistance remains unclear and a possible anti-tumor mechanism beyond this process in HCC has not been clarified. We examined the therapeutic potential of SIRT7 and determined whether it functions synergistically with sorafenib to overcome chemoresistance. METHODS: Cancer Genome Atlas-liver HCC data and unbiased gene set enrichment analyses were used to identify SIRT7 as a potential effector molecule in sorafenib acquired resistance. Two types of SIRT7 chemical inhibitors were developed to evaluate its therapeutic properties when synergized with sorafenib. Mass spectrometry was performed to discover a direct target of SIRT7, DDX3X, and DDX3X deacetylation levels and protein stability were explored. Moreover, an in vivo xenograft model was used to confirm anti-tumor effect of SIRT7 and DDX3X chemical inhibitors combined with sorafenib. RESULTS: SIRT7 inhibition mediated DDX3X depletion can re-sensitize acquired sorafenib resistance by disrupting NLRP3 inflammasome assembly, finally suppressing hyperactive ERK1/2 signaling in response to NLRP3 inflammasome-mediated IL-1ß inhibition. CONCLUSIONS: SIRT7 is responsible for sorafenib acquired resistance, and its inhibition would be beneficial when combined with sorafenib by suppressing hyperactive pro-cell survival ERK1/2 signaling.

Effect of Voice and Articulation Parameters of a Home-Based Serious Game for Speech Therapy in Children With Articulation Disorder: Prospective Single-Arm Clinical Trial.

BACKGROUND: Articulation disorder decreases the clarity of language and causes a decrease in children's learning and social ability. The demand for non-face-to-face treatment is increasing owing to the limited number of therapists and geographical or economic constraints. Non-face-to-face speech therapy programs using serious games have been proposed as an alternative. OBJECTIVE: The aim of this study is to investigate the efficacy of home therapy on logopedic and phoniatric abilities in children with articulation disorder using the Smart Speech game interface. METHODS: This study is a prospective single-arm clinical trial. Children with articulation disorders, whose Urimal Test of Articulation and Phonology (U-TAP) was -2 SDs or less and the Receptive and Expressive Vocabulary Test score was -1 SD or more, were enrolled. A preliminary evaluation (E0) was conducted to check whether the children had articulation disorders, and for the next 4 weeks, they lived their usual lifestyle without other treatments. Prior to the beginning of the training, a pre-evaluation (E1) was performed, and the children trained at home for ≥30 minutes per day, ≥5 times a week, over 4 weeks (a total of 20 sessions). The Smart Speech program comprised oral exercise training, breathing training, and speech training; the difficulty and type of the training were configured differently according to the participants' articulation error, exercise, and vocal ability. After the training, postevaluation (E2) was performed using the same method. Finally, 8 weeks later, postevaluation (E3) was performed as a follow-up. A voice evaluation included parameters such as maximum phonation time (MPT), fundamental frequency (F0), jitter, peak air pressure (relative average perturbation), pitch, intensity, and voice onset time. Articulation parameters included a percentage of correct consonants (PCC; U-TAP word-unit PCC, U-TAP sentence-unit PCC, and three-position articulation test) and alternate motion evaluation (diadochokinesis, DDK). Data obtained during each evaluation (E1-E2-E3) were compared. RESULTS: A total of 13 children with articulation disorders aged 4-10 years were enrolled in the study. In voice parameters, MPT, jitter, and pitch showed significant changes in repeated-measures ANOVA. However, only MPT showed significant changes during E1-E2 (P=.007) and E1-E3 (P=.004) in post hoc tests. Other voice parameters did not show significant changes. In articulation parameters, U-TAP, three-position articulation test (TA), and DDK showed significant changes in repeated-measures ANOVA. In post hoc tests, U-TAP (word, sentence) and TA showed significant changes during E1-E2 (P=.003, .04, and .01) and E1-E3 (P=.001, .03, and .003), and DDK showed significant changes during E1-E2 only (P=.03). CONCLUSIONS: Home-based serious games can be considered an alternative treatment method to improve language function. TRIAL REGISTRATION: Clinical Research Information Service KCT0006448; https://cris.nih.go.kr/cris/search/detailSearch.do/20119.

A CRISPR activation screen identifies MUC-21 as critical for resistance to NK and T cell-mediated cytotoxicity.

BACKGROUND: Immunotherapy has significantly advanced cancer treatments, but many patients do not respond to it, partly due to immunosuppressive mechanisms used by tumor cells. These cells employ immunosuppressive ligands to evade detection and elimination by the immune system. Therefore, the discovery and characterization of novel immunosuppressive ligands that facilitate immune evasion are crucial for developing more potent anti-cancer therapies. METHODS: We conducted gain-of-function screens using a CRISPRa (CRISPR activation) library that covered the entire human transmembrane sub-genome to identify surface molecules capable of hindering NK-mediated cytotoxicity. The immunosuppressive role and mechanism of MUC21 were validated using NK and T cell mediated cytotoxicity assays. Bioinformatics tools were employed to assess the clinical implications of mucin-21 (MUC21) in cancer cell immunity. RESULTS: Our genetic screens revealed that MUC21 expression on cancer cell surfaces inhibits both the cytotoxic activity of NK cells and antibody-dependent cellular cytotoxicity, but not affecting complement-dependent cytotoxicity. Additionally, MUC21 expression hinders T cell activation by impeding antigen recognition, thereby diminishing the effectiveness of the immune checkpoint inhibitor, anti-PD-L1. Moreover, MUC21 expression suppress the antitumor function of both CAR-T cells and CAR-NK cells. Mechanistically, MUC21 facilitates immune evasion by creating steric hindrance, preventing interactions between cancer and immune cells. Bioinformatics analysis revealed elevated MUC21 expression in lung cancer, which correlated with reduced infiltration and activation of cytotoxic immune cells. Intriguingly, MUC21 expression was higher in non-small cell lung cancer (NSCLC) tumors that were non-responsive to anti-PD-(L)1 treatment compared to responsive tumors. CONCLUSIONS: These findings indicate that surface MUC21 serves as a potent immunosuppressive ligand, shielding cancer cells from NK and CD8+T cell attacks. This suggests that inhibiting MUC21 could be a promising strategy to improve cancer immunotherapy.

Integrative Evaluation of the Clinical Significance Underlying Protein Arginine Methyltransferases in Hepatocellular Carcinoma.

HCC is a major contributor to cancer-related mortality worldwide. Curative treatments are available for a minority of patients diagnosed at early stages; however, only a few multikinase inhibitors are available and are marginally effective in advanced cases, highlighting the need for novel therapeutic targets. One potential target is the protein arginine methyltransferase, which catalyzes various forms of arginine methylation and is often overexpressed in various cancers. However, the diverse expression patterns and clinical values of PRMTs in HCC remain unclear. In the present study, we evaluated the transcriptional expression of PRMTs in HCC cohorts using publicly available datasets. Our results revealed a significant association between PRMTs and prognosis in HCC patients with diverse clinical characteristics and backgrounds. This highlights the promising potential of PRMTs as prognostic biomarkers in patients with HCC. In particular, single-cell RNA (scRNA) sequencing analysis coupled with another human cohort study highlighted the pivotal role of PRMT1 in HCC progression, particularly in the context of Tex. Translating these findings into specific therapeutic decisions may address the unmet therapeutic needs of patients with HCC.

Mitochondria-associated programmed cell death as a therapeutic target for age-related disease.

Mitochondria, ubiquitous double-membrane-bound organelles, regulate energy production, support cellular activities, harbor metabolic pathways, and, paradoxically, mediate cell fate. Evidence has shown mitochondria as points of convergence for diverse cell death-inducing pathways that trigger the various mechanisms underlying apoptotic and nonapoptotic programmed cell death. Thus, dysfunctional cellular pathways eventually lead or contribute to various age-related diseases, such as neurodegenerative, cardiovascular and metabolic diseases. Thus, mitochondrion-associated programmed cell death-based treatments show great therapeutic potential, providing novel insights in clinical trials. This review discusses mitochondrial quality control networks with activity triggered by stimuli and that maintain cellular homeostasis via mitohormesis, the mitochondrial unfolded protein response, and mitophagy. The review also presents details on various forms of mitochondria-associated programmed cell death, including apoptosis, necroptosis, ferroptosis, pyroptosis, parthanatos, and paraptosis, and highlights their involvement in age-related disease pathogenesis, collectively suggesting therapeutic directions for further research.

Thrap3 promotes nonalcoholic fatty liver disease by suppressing AMPK-mediated autophagy.

Autophagy functions in cellular quality control and metabolic regulation. Dysregulation of autophagy is one of the major pathogenic factors contributing to the progression of nonalcoholic fatty liver disease (NAFLD). Autophagy is involved in the breakdown of intracellular lipids and the maintenance of healthy mitochondria in NAFLD. However, the mechanisms underlying autophagy dysregulation in NAFLD remain unclear. Here, we demonstrate that the hepatic expression level of Thrap3 was significantly increased in NAFLD conditions. Liver-specific Thrap3 knockout improved lipid accumulation and metabolic properties in a high-fat diet (HFD)-induced NAFLD model. Furthermore, Thrap3 deficiency enhanced autophagy and mitochondrial function. Interestingly, Thrap3 knockout increased the cytosolic translocation of AMPK from the nucleus and enhanced its activation through physical interaction. The translocation of AMPK was regulated by direct binding with AMPK and the C-terminal domain of Thrap3. Our results indicate a role for Thrap3 in NAFLD progression and suggest that Thrap3 is a potential target for NAFLD treatment.

LY6D is crucial for lipid accumulation and inflammation in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a serious metabolic disorder characterized by excess fat accumulation in the liver. Over the past decade, NAFLD prevalence and incidence have risen globally. There are currently no effective licensed drugs for its treatment. Thus, further study is required to identify new targets for NAFLD prevention and treatment. In this study, we fed C57BL6/J mice one of three diets, a standard chow diet, high-sucrose diet, or high-fat diet, and then characterized them. The mice fed a high-sucrose diet had more severely compacted macrovesicular and microvesicular lipid droplets than those in the other groups. Mouse liver transcriptome analysis identified lymphocyte antigen 6 family member D (Ly6d) as a key regulator of hepatic steatosis and the inflammatory response. Data from the Genotype-Tissue Expression project database showed that individuals with high liver Ly6d expression had more severe NAFLD histology than those with low liver Ly6d expression. In AML12 mouse hepatocytes, Ly6d overexpression increased lipid accumulation, while Ly6d knockdown decreased lipid accumulation. Inhibition of Ly6d ameliorated hepatic steatosis in a diet-induced NAFLD mouse model. Western blot analysis showed that Ly6d phosphorylated and activated ATP citrate lyase, which is a key enzyme in de novo lipogenesis. In addition, RNA- and ATAC-sequencing analyses revealed that Ly6d drives NAFLD progression by causing genetic and epigenetic changes. In conclusion, Ly6d is responsible for the regulation of lipid metabolism, and inhibiting Ly6d can prevent diet-induced steatosis in the liver. These findings highlight Ly6d as a novel therapeutic target for NAFLD.

Protein Arginine Methyltransferase 1 Ablation in Motor Neurons Causes Mitochondrial Dysfunction Leading to Age-related Motor Neuron Degeneration with Muscle Loss.

Neuromuscular dysfunction is tightly associated with muscle wasting that occurs with age or due to degenerative diseases. However, the molecular mechanisms underlying neuromuscular dysfunction are currently unclear. Recent studies have proposed important roles of Protein arginine methyltransferase 1 (Prmt1) in muscle stem cell function and muscle maintenance. In the current study, we set out to determine the role of Prmt1 in neuromuscular function by generating mice with motor neuron-specific ablation of Prmt1 (mnKO) using Hb9-Cre. mnKO exhibited age-related motor neuron degeneration and neuromuscular dysfunction leading to premature muscle loss and lethality. Prmt1 deficiency also impaired motor function recovery and muscle reinnervation after sciatic nerve injury. The transcriptome analysis of aged mnKO lumbar spinal cords revealed alterations in genes related to inflammation, cell death, oxidative stress, and mitochondria. Consistently, mnKO lumbar spinal cords of sciatic nerve injury model or aged mice exhibited elevated cellular stress response in motor neurons. Furthermore, Prmt1 inhibition in motor neurons elicited mitochondrial dysfunction. Our findings demonstrate that Prmt1 ablation in motor neurons causes age-related motor neuron degeneration attributing to muscle loss. Thus, Prmt1 is a potential target for the prevention or intervention of sarcopenia and neuromuscular dysfunction related to aging.

Frankincense ameliorates endometriosis via inducing apoptosis and reducing adhesion.

Background: Frankincense, a resin derived from trees of the Boswellia genus, has been used as an incense and a type of herbal medicine for treating inflammatory diseases such arthritis, chronic bowel illness, and asthma. While endometriosis is a well-known inflammatory gynecological illness caused by the ectopic attachment and development of uterine tissue over the menstrual cycle, the impact of frankincense on this illness is poorly understood. The purpose of this study was to explore the effects of frankincense on endometriosis. Methods: We used a network pharmacological assessment, in vitro and in vivo investigations with a human endometriotic cell line as well as a syngeneic uterine transfer mouse model. High-performance liquid chromatographic analysis was used to compare water-extracted frankincense (Fr) to its reference compounds and validate the sample. Results: A network pharmacological analysis suggested a positive effect of Fr on endometriosis. Fr relieved endometriosis by reducing ectopic endometrial adherence and development, according to both in vivo and in vitro models. We suggested that the ER stress/p53-apoptosis and chemokine-migration/adhesion pathways underlie Fr's anti-endometriotic action using RNA sequencing and bioinformatic analysis. Conclusion: This study revealed the potential effect of Fr on endometriosis using an experimental investigation. Fr may have the potential to be an effective and safe treatment for endometriosis.

The impact of cancer cachexia on gut microbiota composition and short-chain fatty acid metabolism in a murine model.

This study investigates the relationship between cancer cachexia and the gut microbiota, focusing on the influence of cancer on microbial composition. Lewis lung cancer cell allografts were used to induce cachexia in mice, and body and muscle weight changes were monitored. Fecal samples were collected for targeted metabolomic analysis for short chain fatty acids and microbiome analysis. The cachexia group exhibited lower alpha diversity and distinct beta diversity in gut microbiota, compared to the control group. Differential abundance analysis revealed higher Bifidobacterium and Romboutsia, but lower Streptococcus abundance in the cachexia group. Additionally, lower proportions of acetate and butyrate were observed in the cachexia group. The study observed that the impact of cancer cachexia on gut microbiota and their generated metabolites was significant, indicating a host-to-gut microbiota axis. [BMB Reports 2023; 56(7): 404-409].

Oral administration of ginseng berry concentrate improves lactate metabolism and increases endurance performance in mice.

In the present study, to determine the efficacy of oral supplementation of ginseng berry extracts in augmenting exercise performance and exercise-associated metabolism, male mice were given orally 200 and 400 mg/kg of body weight (BW) of GBC for nine weeks. Although there are no differences in pre-exercise blood lactate levels among (1) the control group that received neither exercise nor GBC, (2) the group that performed only twice-weekly endurance exercise, and (3) and (4) the groups that combined twice-weekly endurance exercise with either 200 or 400 mg/kg GBC, statistically significant reductions in post-exercise blood lactate levels were observed in the groups that combined twice-weekly endurance exercise with oral administration of either 200 or 400 mg/kg GBC. Histological analysis showed no muscle hypertrophy, but transcriptome analysis revealed changes in gene sets related to lactate metabolism and mitochondrial function. GBC intake increased nicotinamide adenine dinucleotide levels in the gastrocnemius, possibly enhancing the mitochondrial electron transport system and lactate metabolism. Further molecular mechanisms are needed to confirm this hypothesis. [BMB Reports 2023; 56(6): 353-358].

Loss of pex5 sensitizes zebrafish to fasting due to deregulated mitochondria, mTOR, and autophagy.

Animal models have been utilized to understand the pathogenesis of Zellweger spectrum disorders (ZSDs); however, the link between clinical manifestations and molecular pathways has not yet been clearly established. We generated peroxin 5 homozygous mutant zebrafish (pex5-/-) to gain insight into the molecular pathogenesis of peroxisome dysfunction. pex5-/- display hallmarks of ZSD in humans and die within one month after birth. Fasting rapidly depletes lipids and glycogen in pex5-/- livers and expedites their mortality. Mechanistically, deregulated mitochondria and mechanistic target of rapamycin (mTOR) signaling act together to induce metabolic alterations that deplete hepatic nutrients and accumulate damaged mitochondria. Accordingly, chemical interventions blocking either the mitochondrial function or mTOR complex 1 (mTORC1) or a combination of both improve the metabolic imbalance shown in the fasted pex5-/- livers and extend the survival of animals. In addition, the suppression of oxidative stress by N-acetyl L-cysteine (NAC) treatment rescued the apoptotic cell death and early mortality observed in pex5-/-. Furthermore, an autophagy activator effectively ameliorated the early mortality of fasted pex5-/-. These results suggest that fasting may be detrimental to patients with peroxisome dysfunction, and that modulating the mitochondria, mTORC1, autophagy activities, or oxidative stress may provide a therapeutic option to alleviate the symptoms of peroxisomal diseases associated with metabolic dysfunction.