Click Chemistry in Detecting Protein Modification.

Click chemistry, also known as "link chemistry," is an important molecular connection method that can achieve simple and efficient connections between specific small molecular groups at the molecular level. Click chemistry offers several advantages, including high efficiency, good selectivity, mild conditions, and few side reactions. These features make it a valuable tool for in-depth analysis of various protein posttranslational modifications (PTMs) caused by changes in cell metabolism during viral infection. This chapter considers the palmitoylation, carbonylation, and alkylation of STING and presents detailed information and experimental procedures for measuring PTMs using click chemistry.

Exploring antithrombotic mechanisms and effective constituents of Lagopsis supina using an integrated strategy based on network pharmacology, molecular docking, metabolomics, and experimental verification in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Thrombosis is a common cause of morbidity and mortality worldwide. Lagopsis supina (Stephan ex Willd.) Ikonn.-Gal. ex Knorring is an ancient Chinese herbal medicine used for treating thrombotic diseases. Nevertheless, the antithrombotic mechanisms and effective constituents of this plant have not been clarified. AIM OF THE STUDY: This work aimed to elucidate the pharmacodynamics and mechanism of L. supina against thrombosis. MATERIALS AND METHODS: Systematic network pharmacology was used to explore candidate effective constituents and hub targets of L. supina against thrombosis. Subsequently, the binding affinities of major constituents with core targets were verified by molecular docking analysis. Afterward, the therapeutic effect and mechanism were evaluated in an arteriovenous bypass thrombosis rat model. In addition, the serum metabolomics analysis was conducted using ultra-high performance liquid chromatography coupled with Q-Exactive mass spectrometry. RESULTS: A total of 124 intersected targets of L. supina against thrombosis were predicted. Among them, 24 hub targets were obtained and their mainly associated with inflammation, angiogenesis, and thrombosis approaches. Furthermore, 9 candidate effective constituents, including (22E,24R)-5α,8α-epidioxyergosta-6,22-dien-3ß-ol, aurantiamide, (22E,24R)-5α,8α-epidioxyergosta-6,9 (11),22-trien-3ß-ol, lagopsinA, lagopsin C, 15-epi-lagopsin C, lagopsin D, 15-epi-lagopsin D, and lagopsin G in L. supina and 6 potential core targets (TLR-4, TNF-α, HIF-1α, VEGF-A, VEGFR-2, and CLEC1B) were acquired. Then, these 9 constituents demonstrated strong binding affinities with the 6 targets, with their lowest binding energies were all less than -5.0 kcal/mol. The antithrombotic effect and potential mechanisms of L. supina were verified, showing a positively associated with the inhibition of inflammation (TNF-α, IL-1ß, IL-6, IL-8, and IL-10) and coagulation cascade (TT, APTT, PT, FIB, AT-III), promotion of angiogenesis (VEGF), suppression of platelet activation (TXB2, 6-keto-PGF1α, and TXB2/6-keto-PGF1α), and prevention of fibrinolysis (t-PA, u-PA, PAI-1, PAI-1/t-PA, PAI-1/u-PA, and PLG). Finally, 14 endogenous differential metabolites from serum samples of rats were intervened by L. supina based on untargeted metabolomics analysis, which were closely related to amino acid metabolism, inflammatory and angiogenic pathways. CONCLUSION: Our integrated strategy based on network pharmacology, molecular docking, metabolomics, and in vivo experiments revealed for the first time that L. supina exerts a significant antithrombotic effect through the inhibition of inflammation and coagulation cascade, promotion of angiogenesis, and suppression of platelet activation. This paper provides novel insight into the potential of L. supina as a candidate agent to treat thrombosis.

Astroglial membrane camouflaged Ptbp1 siRNA delivery hinders glutamate homeostasis via SDH/Nrf2 pathway.

Polypyrimidine tract-binding protein 1 (PTBP1) regulates numerous alternative splicing events during tumor progression and neurogenesis. Previously, PTBP1 downregulation was reported to convert astrocytes into functional neurons; however, how PTBP1 regulates astrocytic physiology remains unclear. In this study, we revealed that PTBP1 modulated glutamate uptake via ATP1a2, a member of Na+/K+-ATPases, and glutamate transporters in astrocytes. Ptbp1 knockdown altered mitochondrial function and energy metabolism, which involved PTBP1 regulating mitochondrial redox homeostasis via the succinate dehydrogenase (SDH)/Nrf2 pathway. The malfunction of glutamate transporters following Ptbp1 knockdown resulted in enhanced excitatory synaptic transmission in the cortex. Notably, we developed a biomimetic cationic triblock polypeptide system, i.e., polyethylene glycol44-polylysine30-polyleucine10 (PEG44-PLL30-PLLeu10) with astrocytic membrane coating to deliver Ptbp1 siRNA in vitro and in vivo, which approach allowed Ptbp1 siRNA to efficiently cross the blood-brain barrier and target astrocytes in the brain. Collectively, our findings suggest a framework whereby PTBP1 serves as a modulator in glutamate transport machinery, and indicate that biomimetic methodology is a promising route for in vivo siRNA delivery.

Polyribonucleotide nucleotidyltransferase 1 participates in metabolic-associated fatty liver disease pathogenesis by affecting lipid metabolism and mitochondrial homeostasis.

OBJECTIVE: Metabolic-associated fatty liver disease (MAFLD) represents one of the most prevalent chronic liver conditions worldwide, but its precise pathogenesis remains unclear. This research endeavors to elucidate the involvement and molecular mechanisms of polyribonucleotide nucleotidyltransferase 1 (PNPT1) in the progression of MAFLD. METHODS: The study employed western blot and qRT-PCR to evaluate PNPT1 levels in liver specimens from individuals diagnosed with MAFLD and in mouse models subjected to a high-fat diet. Cellular studies investigated the effects of PNPT1 on lipid metabolism, apoptosis, and mitochondrial stability in hepatocytes. Immunofluorescence was utilized to track the subcellular movement of PNPT1 under high lipid conditions. RNA immunoprecipitation and functional assays were conducted to identify interactions between PNPT1 and Mcl-1 mRNA. The role of PPARα as an upstream transcriptional regulator of PNPT1 was investigated. Recombinant adenoviral vectors were utilized to modulate PNPT1 expression in vivo. RESULTS: PNPT1 was found to be markedly reduced in liver tissues from MAFLD patients and HFD mice. In vitro, PNPT1 directly regulated hepatic lipid metabolism, apoptosis, and mitochondrial stability. Under conditions of elevated lipids, PNPT1 relocated from mitochondria to cytoplasm, modifying its physiological functions. RNA immunoprecipitation revealed that the KH and S1 domains of PNPT1 bind to and degrade Mcl-1 mRNA, which in turn affects mitochondrial permeability. The transcriptional regulator PPARα was identified as a significant influencer of PNPT1, impacting both its expression and subsequent cellular functions. Alterations in PNPT1 expression were directly correlated with the progression of MAFLD in mice. CONCLUSIONS: The study confirms the pivotal function of PNPT1 in the development of MAFLD through its interactions with Mcl-1 and its regulatory effects on lipid metabolism and mitochondrial stability. These insights highlight the intricate association between PNPT1 and MAFLD, shedding light on its molecular pathways and presenting a potential new therapeutic avenue for MAFLD management.

The synthesis of novel unnatural amino acid by intramolecular aza-Michael addition reaction as multitarget enzyme inhibitors.

Synthesis of novel unnatural amino acids (UAAs) from 4-oxo-4-phenylbut-2-enoic acid derivatives with intramolecular aza-Michael addition reaction in the presence of chlorosulfonyl isocyanate (CSI) was reported in soft conditions without any metal catalyst. Acids and base as a catalyst, and solvents effects were investigated for the synthesis of novel UAAs. This novel method provides inexpensive, practicable, and efficient approach to generate UAAs. The use of UAAs has attracted great interest in the development of therapeutic agents and drug discovery to improve their properties. In this context, in addition to the synthesis of new UAAs, their inhibition effects on important metabolic enzymes of acetylcholinesterase (AChE) and carbonic anhydrases I and II (hCA I and II) enzymes were investigated. The compound 2g showed the best inhibition for CA I and AChE enzymes, while compound 2i exhibited the best inhibition profile against CA II isoenzyme. The inhibition values of these compounds were found as 1.85 ± 0.64 for AChE, 0.53 ± 0.07 for hCA I, 0.44 ± 0.15 µM for hCA II, respectively, and they showed a stronger inhibitory property than acetazolamide (standard inhibitor for hCA I and II) and tacrine (standard inhibitor for AChE) molecules. The activity of the studied molecule against different proteins that are hCA I (PDB ID: 2CAB), hCA II (PDB ID: 5AML), and AChE (PDB ID: 1OCE) was examined. Finally, the drug properties of the studied molecule were examined by performing absorption, distribution, metabolism, excretion, and toxicity analysis.

Integrative analysis of bulk and single-cell RNA sequencing reveals sphingolipid metabolism and immune landscape in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is characterized by its aggressive behavior and complex molecular heterogeneity, posing significant challenges for treatment and prognostication. This study offers a comprehensive analysis of ccRCC by leveraging both bulk and single-cell RNA sequencing data, with a specific aim to unravel the complexities of sphingolipid metabolism and the intricate dynamics within the tumor microenvironment (TME). By examining ccRCC samples sourced from public databases, our investigation delves deep into the genetic and transcriptomic landscape of this cancer type. Employing advanced analytical techniques, we have identified pivotal patterns in gene expression and cellular heterogeneity, with a special focus on the roles and interactions of various immune cells within the TME. Significantly, our research has unearthed insights into the dynamics of sphingolipid metabolism in ccRCC, shedding light on its potential implications for tumor progression and strategies for immune evasion. A novel aspect of this study is the development of a risk score model designed to enhance prognostic predictions for ccRCC patients, which is currently pending external validation to ascertain its clinical utility. Despite its contributions, the study is mindful of its limitations, including a reliance on observational data from public sources and a primary focus on RNA sequencing data, which may constrain the depth and generalizability of the findings. The study does not encompass critical aspects, such as protein expression, posttranslational modifications, and comprehensive metabolic profiles. Moreover, its retrospective design underscores the necessity for future prospective studies to solidify these preliminary conclusions. Our findings illuminate the intricate interplay between genetic alterations, sphingolipid metabolism, and immune responses in ccRCC. This research not only enhances our understanding of the molecular foundations of ccRCC but also paves the way for the development of targeted therapies and personalized treatment modalities. The study underlines the importance of cautious interpretation of results and champions ongoing research using diverse methodologies to thoroughly comprehend and effectively combat this formidable cancer type.

Maternal dietary deficiencies in folic acid or choline reduce primary neuron viability after exposure to hypoxia through increased levels of apoptosis.

Objective: Ischemic stroke is the leading cause of death and disability globally. By addressing modifiable risk factors, particularly nutrition, the prevalence of stroke and its dire consequences can be mitigated. One-carbon (1C) metabolism is a critical biosynthetic process that is involved in neural tube closure, DNA synthesis, plasticity, and cellular proliferation. Folates and choline are two active components of 1C metabolism. We have previously demonstrated that maternal dietary deficiencies during pregnancy and lactation in folic acid or choline result in worse stroke outcomes in offspring. However, there is insufficient data to understand the neuronal mechanisms involved.Methods: Using C57Bl/6J female mice maintained on control, folic acid (0.3 mg/kg) or choline (choline bitrate 300 mg/kg) deficient diets we collected embryonic primary neurons from offspring and exposed them to hypoxic conditions for 6 hours. To determine whether increased levels of either folic acid or choline can rescue reduced neuronal viability, we supplemented cell media with folic acid and choline prior to and after exposure to hypoxia.Results: Our results suggest that maternal dietary deficiencies in either folic acid or choline during pregnancy negatively impacts offspring neuronal viability after hypoxia. Furthermore, increasing levels of folic acid (250 mg/ml) or choline chloride (250 mg/ml) prior to and after hypoxia have a beneficial impact on neuronal viability.Conclusion: The findings contribute to our understanding of the intricate interplay between maternal dietary factors, 1C metabolism, and the outcome of offspring to hypoxic events, emphasizing the potential for nutritional interventions in mitigating adverse outcomes.

Metabolic homeostasis in fungal infections from the perspective of pathogens, immune cells, and whole-body systems.

SUMMARYThe ability to overcome metabolic stress is a major determinant of outcomes during infections. Pathogens face nutrient and oxygen deprivation in host niches and during their encounter with immune cells. Immune cells require metabolic adaptations for producing antimicrobial compounds and mounting antifungal inflammation. Infection also triggers systemic changes in organ metabolism and energy expenditure that range from an enhanced metabolism to produce energy for a robust immune response to reduced metabolism as infection progresses, which coincides with immune and organ dysfunction. Competition for energy and nutrients between hosts and pathogens means that successful survival and recovery from an infection require a balance between elimination of the pathogen by the immune systems (resistance), and doing so with minimal damage to host tissues and organs (tolerance). Here, we discuss our current knowledge of pathogen, immune cell and systemic metabolism in fungal infections, and the impact of metabolic disorders, such as obesity and diabetes. We put forward the idea that, while our knowledge of the use of metabolic regulation for fungal proliferation and antifungal immune responses (i.e., resistance) has been growing over the years, we also need to study the metabolic mechanisms that control tolerance of fungal pathogens. A comprehensive understanding of how to balance resistance and tolerance by metabolic interventions may provide insights into therapeutic strategies that could be used adjunctly with antifungal drugs to improve patient outcomes.

Uncovering novel regulatory variants in carbohydrate metabolism: a comprehensive multi-omics study of glycemic traits in the Indian population.

Clinical biomarkers such as fasting glucose, HbA1c, and fasting insulin, which gauge glycemic status in the body, are highly influenced by diet. Indians are genetically predisposed to type 2 diabetes and their carbohydrate-centric diet further elevates the disease risk. Despite the combined influence of genetic and environmental risk factors, Indians have been inadequately explored in the studies of glycemic traits. Addressing this gap, we investigate the genetic architecture of glycemic traits at genome-wide level in 4927 Indians (without diabetes). Our analysis revealed numerous variants of sub-genome-wide significance, and their credibility was thoroughly assessed by integrating data from various levels. This identified key effector genes, ZNF470, DPP6, GXYLT2, PITPNM3, BEND7, and LORICRIN-PGLYRP3. While these genes were weakly linked with carbohydrate intake or glycemia earlier in other populations, our findings demonstrated a much stronger association in the Indian population. Associated genetic variants within these genes served as expression quantitative trait loci (eQTLs) in various gut tissues essential for digestion. Additionally, majority of these gut eQTLs functioned as methylation quantitative trait loci (meth-QTLs) observed in peripheral blood samples from 223 Indians, elucidating the underlying mechanism of their regulation of target gene expression. Specific co-localized eQTLs-meth-QTLs altered the binding affinity of transcription factors targeting crucial genes involved in glucose metabolism. Our study identifies previously unreported genetic variants that strongly influence the diet-glycemia relationship. These findings set the stage for future research into personalized lifestyle interventions integrating genetic insights with tailored dietary strategies to mitigate disease risk based on individual genetic profiles.

Health-related quality of life and caregiver burden of pediatric patients with inborn errors of metabolism in Japan using EQ-5D-Y, PedsQL, and J-ZBI.

PURPOSE: Inborn errors of metabolism (IEM) are known with poor long-term health concerns; however, the health-related quality of life (HRQoL) and the burden placed on families remain unclear. This study investigated the self- and proxy-reported HRQoL of pediatric patients with IEM with or without developmental disabilities and the burden placed on their caregivers. METHODS: Patients with IEM aged 8-15 years and their caregivers were asked to respond to the Pediatric Quality of Life Inventory (PedsQL), EuroQoL five-dimension questionnaire for younger populations (EQ-5D-Y), and Japanese version of the Zarit Caregiver Burden Interview (J-ZBI). We compared EQ-5D-Y scores with matched EQ-5D-Y population norms. Intraclass correlation coefficients (ICC) for self and proxy HRQoL scores of those without developmental disabilities were calculated. Correlation coefficients of HRQoL proxy responses with J-ZBI score were estimated. RESULTS: We included 66 patients with IEM (mean age, 11.5 years; males, 41.2%) in the study. The mean (± standard deviation) EQ-5D-Y scores without and with developmental disabilities were 0.957 (± 0.071) and 0.821 (± 0.175), respectively. The EQ-5D-Y scores significantly increased compared with the reference values (p < 0.01, effect size = 0.337). The ICC values were 0.331 and 0.477 for the EQ-5D-Y and PedsQL scores, respectively. HRQoL proxy scores had strong negative correlations with J-ZBI scores. CONCLUSION: The HRQoL of patients with IEM without developmental disabilities in our study was similar to that of the general Japanese population. The HRQoL of patients with IEM with developmental disabilities was low and associated with a tendency towards an increased burden of care.

Community structure and carbon metabolism functions of bacterioplankton in the Guangdong coastal zone.

Coastal ecosystems are an important region for biogeochemical cycling, are a hotspot of anthropogenic disturbance and play a crucial role in global carbon cycling through the metabolic activities of bacterioplankton. Bacterioplankton can be broadly classified into two lifestyles: free-living (FL) and particle-attached (PA). However, how coastal bacterioplankton the community structure, co-occurrence networks and carbon metabolic functions with different lifestyles are differentiated is still largely unknown. Understanding these processes is necessary to better determine the contributions of coastal bacterioplankton to carbon cycling. Here, the characteristics of community structure and carbon metabolism function of bacterioplankton with two lifestyles in the coastal areas of Guangdong Province were investigated using amplicon sequencing, metagenomic, and metatranscriptomic techniques. The results show that the main bacterioplankton responsible for carbon metabolism were the Pseudomonadota, Bacteroidota, and Actinomycetota. The microbial community structure, carbon metabolic function, and environmental preferences differ between different lifestyles. FL and PA bacteria exhibited higher carbon fixation and degradation potentials, respectively. A range of environmental factors, such as dissolved oxygen, pH, and temperature, were associated with the community structure and carbon metabolic functions of the bacterioplankton. Human activities, such as nutrient discharge, may affect the distribution of functional genes and enhance the carbon degradation functions of bacterioplankton. In conclusion, this study increased the understanding of the role of microorganisms in regulating carbon export in coastal ecosystems with intense human activity. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-024-00245-x.

Assessing the Effect of Exogenous Melatonin on Orthodontic Tooth Movement.

OBJECTIVE: To examine the effect of orthodontic tooth movement on experimental Wistar rats by synthesizing melatonin formulation for administration and conducting serological analysis of alkaline phosphatase (ALP) and melatonin, along with histological evaluation and immunohistochemistry analysis of ALP and interleukin-6 (IL-6) in both control and experimental groups. METHODOLOGY: Nine male Wistar rats were randomly divided into negative (n = 3), positive control (n = 3), and experimental groups (n = 3). Endogenous melatonin levels (pg/mL) were assessed, and an orthodontic force of 10 cN was applied to positive control and experimental groups using a ligature wire. The experimental group received a daily dose of 10 mg/kg melatonin via intraperitoneal injection. After eight weeks, blood samples and radiographs were collected, and mandible sections were prepared for histopathological and immunohistochemical evaluation. RESULTS: The radiographic evaluation shows minimal orthodontically induced tooth movement in comparison to the positive control group. In serological analysis, ALP was found to be increased in rats under the melatonin group. And, in the immunohistochemical evaluation, ALP was found to be increased in the melatonin group, whereas IL-6 was found to be decreased in the same (P = 0.027). CONCLUSIONS: The study elucidates that the administration of exogenous melatonin during orthodontic tooth movement in Wistar rats induces bone formation and inhibits resorption, eventually decelerating the process of orthodontic tooth movement. Our study emphasizes melatonin's dualistic role in stimulating bone production and suppressing resorption, offering potential therapeutic clinical implications in orthodontics.

Wilson's Disease in Childhood and the Challenges in Its Diagnosis: A Case Report.

Wilson's disease is a genetic neurometabolic disorder affecting copper metabolism in the body. It occurs due to mutations in the ATP7B gene. Here, we report a case of a 12-year-old boy, born out of a second-degree consanguineous marriage, who presented with complaints of jaundice for the past one year, poor scholastic performance, and behavioral abnormalities for the past one month. There was a history of multiple suicides in the maternal family, and liver disorder in the maternal uncle. Various examinations revealed jaundice, Kayser-Fleischer ring in eyes, and dystonia of the extremities with hepatosplenomegaly. Copper studies were inconclusive, and neuroimaging showed characteristic findings specific for Wilson's disease. The child was treated with a low-copper diet, vitamin K, oral zinc acetate, oral D-penicillamine, trihexyphenidyl, baclofen, clonazepam, and propranolol.

Exogenous salicylic acid treatment enhances the disease resistance of Panax vietnamensis by regulating secondary metabolite production.

Introduction: Salicylic acid (SA) is a phenolic compound widely found in plants. It plays a key role in exerting plant disease resistance. Panax vietnamensis Ha & Grushv., a valuable medicinal plant, contains high levels of phenolic compounds, which contribute significantly to the resilience of the plant against stress. However, the precise role of SA in regulating the synthesis of secondary metabolites in P.vietnamensis remains elusive. Methods: Two-year-old P. vietnamensis seedlings were treated with exogenous SA. We systematically assessed the changes in the physiological parameters of SA-treated P. vietnamensis leaves, employing transcriptome and metabolome analyses to elucidate the underlying mechanisms. Results: Our results revealed a significant improvement of the plant's antioxidant capacity at 6 h post-treatment. Furthermore, exogenous SA treatment promoted the biosynthesis of lignin and flavonoids such as rutin, coumarin, and cyanidin. In addition, it increased the levels of endogenous SA and jasmonic acid (JA), promoting the disease resistance of the plants. Thus, SA pretreatment enhanced the defense of P. vietnamensis against pathogens. Conclusions: Our study provided novel insights into the potential molecular mechanisms underlying SA-mediated biosynthesis of secondary metabolites. Furthermore, our results provided a theoretical foundation for optimizing the cultivation practices of P.vietnamensis and the application of SA as a plant immunomodulator.

Efficient nitrogen removal via simultaneous ammonium assimilation and heterotrophic denitrification of Paracoccus denitrificans R-1.

Although diverse microorganisms can remove ammonium and nitrate simultaneously, their metabolic mechanisms are not well understood. Paracoccus denitrificans R-1 showed the maximal NH4 + removal rate 9.94 mg L-1·h-1 and 2.91 mg L-1·h-1 under aerobic and anaerobic conditions, respectively. Analysis of the nitrogen balance calculation and isotope tracing experiment indicated that NH4 + was consumed through assimilation. The maximal NO3 - removal rate of strain R-1 was 18.05 and 19.76 mg L-1·h-1 under aerobic and anaerobic conditions, respectively. The stoichiometric consumption ratio of acetate to nitrate was 0.902 and NO3 - was reduced to N2 for strain R-1 through 15NO3 - isotopic tracing experiment, which indicated a respiratory process coupled with the oxidation of electron donors. Genomic analysis showed that strain R-1 contained genes for ammonium assimilation and denitrification, which effectively promoted each other. These findings provide insights into microbial nitrogen transformation and facilitate the simultaneous removal of NH4 + and NO3 - in a single reactor.

Mechanical regulation of lipid and sugar absorption by Piezo1 in enterocytes.

Obesity is primarily caused by excessive intake as well as absorption of sugar and lipid. Postprandial surge in distention pressure and intestinal motility accelerates the absorption of nutrients. The response of intestinal epithelial cells to mechanical stimulation is not fully understood. Piezo1, a mechanosensitive ion channel, is widely expressed throughout the digestive tract. However, its function in intestinal nutrient absorption is not yet clear. In our study, excessive lipid deposition was observed in the duodenum of obese patients, while duodenal Piezo1-CaMKK2-AMPKα was decreased when compared to normal-weight individuals. Under high-fat diet condition, the Piezo1 iKO mice exhibited abnormally elevated sugar and lipid absorption as well as severe lipid deposition in the duodenum and liver. These phenotypes were mainly caused by the inhibition of duodenal CaMKK2-AMPKα and the upregulation of SGLT1 and DGAT2. In contrast, Yoda1, a Piezo1 agonist, was found to reduce intestinal lipid absorption in diet induced obese mice. Overexpression of Piezo1, stretch and Yoda1 inhibited lipid accumulation and the expression of DGAT2 and SGLT1, whereas knockdown of Piezo1 stimulated lipid accumulation and DGAT2 in Caco-2 cells. Our study reveals a previously unexplored mechanical regulation of nutrient absorption in intestinal epithelial cells, which may shed new light on the therapy of obesity.

Phenylalanine deprivation inhibits multiple myeloma progression by perturbing endoplasmic reticulum homeostasis.

Amino acid metabolic remodeling is a hallmark of cancer, driving an increased nutritional demand for amino acids. Amino acids are pivotal for energetic regulation, biosynthetic support, and homeostatic maintenance to stimulate cancer progression. However, the role of phenylalanine in multiple myeloma (MM) remains unknown. Here, we demonstrate that phenylalanine levels in MM patients are decreased in plasma but elevated in bone marrow (BM) cells. After the treatment, phenylalanine levels increase in plasma and decrease in BM. This suggests that changes in phenylalanine have diagnostic value and that phenylalanine in the BM microenvironment is an essential source of nutrients for MM progression. The requirement for phenylalanine by MM cells exhibits a similar pattern. Inhibiting phenylalanine utilization suppresses MM cell growth and provides a synergistic effect with Bortezomib (BTZ) treatment in vitro and murine models. Mechanistically, phenylalanine deprivation induces excessive endoplasmic reticulum stress and leads to MM cell apoptosis through the ATF3-CHOP-DR5 pathway. Interference with ATF3 significantly affects phenylalanine deprivation therapy. In conclusion, we have identified phenylalanine metabolism as a characteristic feature of MM metabolic remodeling. Phenylalanine is necessary for MM proliferation, and its aberrant demand highlights the importance of low-phenylalanine diets as an adjuvant treatment for MM.

Exercise-Induced cytokines, diet, and inflammation and their role in adipose tissue metabolism.

Background: Obesity poses a significant global health challenge, necessitating effective prevention and treatment strategies. Exercise and diet are recognized as pivotal interventions in combating obesity. This study reviews the literature concerning the impact of exercise-induced cytokines, dietary factors, and inflammation on adipose tissue metabolism, shedding light on potential pathways for therapeutic intervention. Methodology: A comprehensive review of relevant literature was conducted to elucidate the role of exercise-induced cytokines, including interleukin-6 (IL-6), interleukin-15 (IL-15), brain-derived neurotrophic factor (BDNF), irisin, myostatin, fibroblast growth factor 21 (FGF21), follistatin (FST), and angiopoietin-like 4 (ANGPTL4), in adipose tissue metabolism. Various databases were systematically searched using predefined search terms to identify relevant studies. Articles selected for inclusion underwent thorough analysis to extract pertinent data on the mechanisms underlying the influence of these cytokines on adipose tissue metabolism. Results and Discussion: Exercise-induced cytokines exert profound effects on adipose tissue metabolism, influencing energy expenditure (EE), thermogenesis, fat loss, and adipogenesis. For instance, IL-6 activates AMP-activated protein kinase (AMPK), promoting fatty acid oxidation and reducing lipogenesis. IL-15 upregulates peroxisome proliferator-activated receptor delta (PPARδ), stimulating fatty acid catabolism and suppressing lipogenesis. BDNF enhances AMPK-dependent fat oxidation, while irisin induces the browning of white adipose tissue (WAT), augmenting thermogenesis. Moreover, myostatin, FGF21, FST, and ANGPTL4 each play distinct roles in modulating adipose tissue metabolism, impacting factors such as fatty acid oxidation, adipogenesis, and lipid uptake. The elucidation of these pathways offers valuable insights into the complex interplay between exercise, cytokines, and adipose tissue metabolism, thereby informing the development of targeted obesity management strategies. Conclusion: Understanding the mechanisms by which exercise-induced cytokines regulate adipose tissue metabolism is critical for devising effective obesity prevention and treatment modalities. Harnessing the therapeutic potential of exercise-induced cytokines, in conjunction with dietary interventions, holds promise for mitigating the global burden of obesity. Further research is warranted to delineate the precise mechanisms underlying the interactions between exercise, cytokines, and adipose tissue metabolism.

Mechanisms of mechanical force in periodontal homeostasis: a review.

Mechanical forces affect periodontal health through multiple mechanisms. Normally, mechanical forces can boost soft and hard tissue metabolism. However, excessive forces may damage the periodontium or result in irreversible inflammation, whereas absence of occlusion forces also leads to tissue atrophy and bone resorption. We systemically searched the PubMed and Web of Science databases and found certain mechanisms of mechanical forces on immune defence, extracellular matrix (ECM) metabolism, specific proteins, bone metabolism, characteristic periodontal ligament stem cells (PDLSCs) and non-coding RNAs (ncRNAs) as these factors contribute to periodontal homeostasis. The immune defence functions change under forces; genes, signalling pathways and proteinases are altered under forces to regulate ECM metabolism; several specific proteins are separately discussed due to their important functions in mechanotransduction and tissue metabolism. Functions of osteocytes, osteoblasts, and osteoclasts are activated to maintain bone homeostasis. Additionally, ncRNAs have the potential to influence gene expression and thereby, modify tissue metabolism. This review summarizes all these mechanisms of mechanical forces on periodontal homeostasis. Identifying the underlying causes, this review provides a new perspective of the mechanisms of force on periodontal health and guides for some new research directions of periodontal homeostasis.

Family-Based Interventions for Pediatric Obesity: A Comprehensive Systematic Review and Meta-Analysis of Their Effectiveness.

Genetics can influence obesity, and when it affects both parents and children, there is a high risk of developing cardiometabolic diseases. Studies have indicated that family-based treatment (FBT) is a cost-effective and successful option for achieving significant weight changes in both children and parents. While specialized clinics offer FBT, primary care settings, where most pediatric care takes place, may not have the necessary resources or expertise to provide intensive behavioral interventions for childhood obesity. Based on early findings, FBT could potentially have a positive impact on siblings as well, as when treated children and parents experience behavioral changes, it can also have a beneficial effect on their untreated siblings. Parents play a crucial role in shaping their children's behavior, and siblings often have a stronger influence on them than their parents or friends. For our meta-analysis, we utilized three graphical models created using RevMan 5.4, based on the selected articles. To develop our systematic review, we thoroughly analyzed a total of 10 articles. The subgroup analysis within these studies assessed the effectiveness of FBT for overweight children, revealing no significant differences between groups (p=0.77). This suggests that based on their BMI, FBT may not have a statistically significant impact on weight loss in overweight children. However, each study reviewed showed statistical significance (p<0.05). The findings of our meta-analysis underscore the need for more robust evidence and larger randomized controlled trials (RCTs) to enhance our understanding of FBT's benefits in pediatric obesity. This will be crucial for reducing the rising prevalence of obesity and maintaining lower incidence rates.