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Summary: The ribosome-associated protein quality control (RQC) pathway acts as a translational surveillance mechanism to maintain proteostasis. In mammalian cells, the cytoplasmic RQC pathway involves nuclear export mediator factor (NEMF)-dependent recruitment of the E3 ligase Listerin to ubiquitinate ribosome-stalled nascent polypeptides on the lysine residue for degradation. However, the quality control of ribosome-stalled nuclear-encoded mitochondrial nascent polypeptides remains elusive, as these peptides can be partially imported into mitochondria through translocons, restricting accessibility to the lysine by Listerin. Here, we identify a Listerin-independent organelle-specific mitochondrial RQC pathway that acts on NEMF-mediated carboxy-terminal poly-alanine modification. In the pathway, mitochondrial proteins carrying C-end poly-Ala tails are recognized by the cytosolic E3 ligase Pirh2 and the ClpXP protease in the mitochondria, which coordinately clear ribosome-stalled mitochondrial nascent polypeptides. Defects in this elimination pathway result in NEMF-mediated aggregates and mitochondrial integrity failure, thus providing a potential molecular mechanism of the RQC pathway in mitochondrial-associated human diseases.

Abstract. Background:. There is increasing concern among primary care practitioners about the use of opioids for chronic pain, including their adverse effects, but little attention has been given to how reports of side effects from prescription medication can contribute to outcomes among patients with chronic pain. The aim of this study was to investigate the impact of frequently reported side effects on mood, disability, and opioid misuse in patients with chronic pain prescribed opioids within primary care. Methods:. Two hundred (N = 200) patients with chronic pain taking opioids for pain were recruited into the study. All patients completed baseline measures and a monthly side effects checklist once a month for 6 months. Patients were divided evenly based on a median split of the number of endorsed side effects over 6 months. The subjects repeated the baseline measures at the end of the study period. Results:. Over time, reports of medication side effects tended to decrease, but differences in frequency of reported side effects from baseline to follow-up (6-month time) were not significant, and the order of the frequency of the reported side effects remained similar. Patients who reported significant medication-related adverse effects reported significantly greater activity interference, negative affect, and catastrophizing compared with those with fewer side effects (P < 0.01). In addition, those patients with pain who reported more side effects showed significantly higher scores on opioid misuse risk (P < 0.001). Discussion:. This study demonstrates the important role of monitoring medication-related side effects among patients with chronic pain who are prescribed opioid medication for pain within primary care.

BACKGROUND: Age contributes to body composition alteration, rises a common disorder in elderly known as sarcopenic obesity (SO), which is characterized by the combination of obesity (excess fat mass) and sarcopenia (reduced skeletal muscle mass) clinical form and function. CONTENT: The primary cause of SO is insulin resistance. Glucose transporter 4 (GLUT4) dysfunction results in impaired fatty acids oxidation. Decreased muscle mass results in lower mitochondria number and volume. Both will increase oxidative stress. Together with altered myokines in SO, oxidative stress was promoted and lead to higher M1 macrophages and failure in autophagy. The pro-inflammatory condition and dysbiosis links SO to a variety of cardiometabolic conditions, including non-alcoholic fatty liver disease, type 2 diabetes, and cardiovascular disease. The mortality, comorbidities, cardiometabolic diseases, and disability or impairment of SO is higher compare to obesity or sarcopenia alone. Some treatments have been developed for SO including adequate dietary intake, vitamin D and antioxidant supplementation, and exercises. SUMMARY: SO is more prevalent among the elderly and has a significant negative impact on their quality of life. Therefore, maintaining muscle mass and strength as well as preventing obesity should be the key goals of initiatives to support healthy aging. KEYWORDS: aging, body composition, obesity, sarcopenia, skeletal muscle, metabolic syndrome

BACKGROUND: Essential oils (EO) are complex volatile, naturally synthesized compounds from aromatic plants. It considers as healthy, effective, and safe since they were coming from nature. Gardenia jasminoides, Boswellia serrata, Commiphora myrrha, Foeniculum vulgarae, and Daucus carota are known to have antimicrobials, antioxidants, antiinflammation properties against respiratory tract infection. However, despite its natural content, a safety profile needs to be observed. Therefore, in this study, EO blend (EOB) made from the combination of these 5 plants was assessed for its efficacy and safety for respiratory tract infection in human. METHODS: A multicentre, randomized, open-label, phase II controlled trial involving 80 hospitalized adults with COVID-19 was conducted. One group of subjects only received standard of care (SoC), while the other group receive SoC and EOB orally for 10 days. RESULTS: There were significant decrease in interleukin (IL)-6 level (p=0.016) and interferon (IFN)-γ level (p=0.012), as well as better respiratory rate (p=0.024) for the group receiving SoC and EOB compared to the group receiving SoC only. However, there was no significant differences in aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine, and the corrected QT interval (QTc) prolongation value in both groups. All subjects with adverse effects were improved and recovered, and there were no serious adverse events found. CONCLUSION: The combination of G. jasminoides, B. serrata, C. myrrha, F. vulgarae, and D. carota EOB could improve the inflammatory and clinical status and safe to be used as adjuvant therapy for treating COVID-19 in adults. KEYWORDS: essential oils, COVID-19, inflammation, safety

The spiral bianshi curriculum, an improvement on bianshi teaching developed by Gu (2000) and in line with Marton's theory of variation (Marton & Booth, 1997), was tried out in a primary school in Hong Kong. This improved theoretical framework for the spiral bianshi curriculum comprises four types of bianshi problems--the inductive bianshi, the broadening bianshi, the deepening bianshi, and the applicative bianshi. Based on this framework, the research team developed a set of teaching materials on the three topics of division of fraction, speed, and volume. The materials were tried out in 21 Primary 6 classes (a total of 686 students) in a school. The effect was compared with a reference group using standard textbook materials in Hong Kong. A series of instruments, pre-tests, and post-tests were administered to gauge the effects on students' performance in solving routine and non-routine problems, as well as the affective outcomes including self-concept, attitude towards learning mathematics, approaches to learning, and conceptions of mathematics. The intervention effects of the experimental design were examined by hierarchical regression analysis. The research reveals that students using spiral bianshi teaching materials performed significantly better than their counterparts using standard textbook materials. However, no significant differences were identified among affective learning outcome variables despite the positive results on cognitive learning outcomes. The findings indicate that spiral bianshi curriculum has high potential in enhancing students' learning effectiveness. However, further studies are needed to map its strengths in detail.

BACKGROUND: Fibronectin type III domain-containing protein 5 (FNDC5), or also known as irisin, has been identified for two decades but almost completely disregarded for 10 years. It is present in skeletal muscle, heart, and brain, and in reaction to exercise can transform white adipose tissue into brown. Since then, irisin has gained a lot of attention for its potencies in treating metabolic disorders. In this review article, the potential future of irisin especially on metabolism and aging process will be discussed. CONTENT: Sedentary lifestyle is acknowledged as risk factor for type 2 diabetes mellitus, obesity, immune system issues, asthma, and neurological or heart illness. Irisin is secreted by muscle cells when exercising, produced after the proteolytic cleavage of FNDC5 protein. Irisin has positive impacts on maintaining physiological balance including reducing inflammation, keeping the bone homeostasis, as well as influencing metabolic processes and the neurological system function. Due to these many and advantageous characteristics, irisin could be a possible choice for preventing and managing disorders associated with modern society, and finding the agents to increase irisin can be beneficial. SUMMARY: Irisin offers a fresh potential basis for kinesitherapy and shows promise as a therapeutic target due to its various biological activities. Irisin pathway can be activated through dietary changes, the use of natural substances and drugs and can interact with this signalling pathway which involved peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and uncoupling protein mRNA 1 (UCP1) to resolve obesity and its metabolic comorbidities. KEYWORDS: irisin, FNDC5, exercise, inflammation, obesity, nervous system

BACKGROUND: World Health Organization has reported four million people die every year due to obesity comorbidity, and the prevalence of obesity is keep increasing, especially after COVID-19. Obesity has been defined as a chronic disease involving adipose tissue dysfunction which leads to metabolic diseases and psychosocial consequences. The review article will highlight some recent researches regarding the new conceptual framework that integrates both metabolic drives, as well as to summarize the numerous discussions about the current understanding of hypothalamic control of food intake and energy homeostasis. CONTENT: Obesity apparently is not simply regulated only by food and exercise. Hypothalamus takes part in controlling energy intake and expenditure via appetite regulation. Hedonic control in cortical and subcortical brain areas process cognitive, reward, information, and executive function. Managing metabolic adaptation, browning the white adipose tissue, and preserving lean mass can be another strategy to safely manage obesity. SUMMARY: Obesity need to be managed in a multimodal strategy including neurophysiology and physiology approach, together with environment support. Thus, a weight regain can be prevented. Commitment from both scientific and regulation point of view can shed a light to eradicate obesity. KEYWORDS: adipocyte, appetite, nutrition, obesity, physical activity, reward, satiety

BACKGROUND: Before WHO revoked the emergency use authorization for Chloroquine (CQ) and Hydroxychloroquine (HCQ) because of their side effects, it was suggested to use these two drugs for COVID-19 therapy. In addition, another derivate of quinine, namely Quinine Sulfate (QS), showed good in silico and in vitro antiviral activity against SARS-CoV-2. Prior the WHO revocation, this study was conducted to evaluate the efficacy of QS in mild-to-moderate COVID-19 patients. METHODS: This was an adaptive, controlled, multicenter, randomized, double-blind clinical trial involving mild-to-moderate COVID-19 patients in Indonesia. The participants were divided into 2 groups: the control group (standard COVID-19 treatment + placebo) and the treatment group (standard COVID-19 treatment + QS). The primary outcome was the efficacy of QS based on clinical status using a 7-point ordinal scale. The secondary outcomes were the efficacy of QS in terms of the incidence and duration of oxygen supplementation, incidence of mechanical ventilation, and length of stay. RESULTS: No significant difference in the efficacy parameters studied was found between the control group and the treatment group. The difference in the mean oxygen saturation was also measured and the results showed a significant difference where the treatment group had higher mean oxygen saturation than the control group (p=0.001). CONCLUSION: Although not significant, the treatment group showed better therapy outcomes compared to the control group. KEYWORDS: clinical trials, efficacy, quinine, chloroquine, hydroxychloroquine

Introduction: The national guidelines and the Standing Committee on Vaccination (STIKO) of the Robert Koch Institute (RKI) in Germany support preventive vaccinations for patients under immunomodulatory treatments. Material and methods: Retrospective analysis of data from patients with chronic inflammatory skin diseases from December 2021 to December 2022 with a focus on preventive vaccinations against influenza virus, varicella zoster virus, or SARS-CoV-2. Results: Patients with chronic inflammatory skin diseases were referred to our university outpatient’s clinic for recommendations of systemic therapy. Vaccinations against influenza virus, varicella zoster virus, or SARS-CoV-2 were documented in 7365 analyzed patient files. A total of 79.7% were completely vaccinated against SARS-CoV-2, 49.7% patients were vaccinated against the influenza virus, and only 9.2% were completely vaccinated against varicella zoster virus. Discussion: In our patients who came for counselling before or during systemic treatment, vaccination rates against SARS-CoV-2, varicella zoster virus, or influenza virus were low. Patients age 60 and above had higher rates than the average German population of the same age, but still no satisfying protection. Conclusions: We suggest informing patients about preventive vaccination before and during systemic immunomodulatory treatments and emphasize the need for active communication in this vulnerable patient group.

IntroductionIn recent years, diverse initiatives have been carried out to control the COVID-19 pandemic, ranging from measures restricting social activities to analyzing drugs and vaccines. Studies on herbal medicines are also increasingly conducted in various countries as an adjuvant therapy or supplement. Therefore, this systematic review aimed to investigate the efficacy of herbal medicines analyzed from various countries through clinical trials with the randomized controlled trial method. The outcomes of Length of Stay (LOS), Negative Conversion Time (NCT), and Negative Conversion Rate (NCR) were the main focus.MethodsAn extensive review of literature spanning from 2019 to 2023 was carried out using well-known databases including PubMed, Scopus, and Cochrane. The search included relevant keywords such as “randomized controlled trial,” “COVID-19,” and “herbal medicine.”ResultsA total of 8 articles were part of the inclusion criteria with outcomes of LOS, NCT, and NCR. In terms of LOS outcomes, all types of herbal medicines showed significant results, such as Persian Medicine Herbal (PM Herbal), Persian Barley Water (PBW), Jingyin Granules (JY granules), Reduning Injection, and Phyllanthus emblica (Amla). However, only JY granules showed significant results in NCR outcome, while JY granules and Reduning Injection showed significant results in reducing NCT.ConclusionThese findings enrich our understanding of the potential benefits of herbal medicines in influencing LOS, NCR and NCT parameters in COVID-19 patients. Herbal medicines worked to treat COVID-19 through antiviral, anti-inflammatory, and immunomodulatory mechanisms.

Background. Obesity is expected to hinder efferocytosis due to ADAM17-mediated cleavage of the MER tyrosine kinase receptor, producing soluble MER (sMER) that disrupts MERTK binding to cell death markers. However, the intracellular efferocytosis pathway in central obesity remains elusive, particularly the role of low-grade chronic inflammation in its initiation and identification of binding signals that disrupt efferocytosis. Objective. We investigate the efferocytosis signaling pathway in men with central obesity and its relationship with inflammation, cell death, and related processes. Methods. A cross-sectional study was conducted, and clinical data and blood samples were collected from 56 men with central obesity (obese group) and 29 nonobese individuals (control group). Clinical evaluations and predefined biochemical screening tests were performed. The efferocytosis signaling pathway was investigated by measuring phosphatidylserine (PS), ADAM17, TNF-alpha (TNF-α), and sMER. Results. Metabolic syndrome was detected in more than half of the participants in the obese group according to the predefined tests. Mean levels of PS, TNF-α, and sMER were higher in the obese group but not significantly different from those of the control group. Further analysis based on waist circumference (WC) ranges in the obese group revealed a significant increase in PS and sMER levels between the control group and the obese group with WC greater than 120 cm. ADAM17 levels were significantly higher in the obese group than in the control group. PS was positively correlated with WC and ADAM17. ADAM17 was positively correlated with TNF-α and sMER, indicating impaired efferocytosis. Conclusions. Central obesity appeared to cause a disturbance in efferocytosis that began with cell damage and death, along with an enlargement of the WC and an ongoing inflammatory response. Efferocytosis was disrupted by proinflammatory cytokine regulators, which induced the production of sMER and interfered with the efferocytosis process.

BACKGROUND: Many chronic disorders, including vascular diseases, metabolic syndrome, and neurological diseases, are known to share a common factor of excessive inflammation. It takes a lot of energy to heal damaged tissue, which is a complicated process. The outcome is often suboptimal, with some degree of fibrosis, depending on the tissue's ability to regenerate and the strength of the inflammatory response. We may get new insights into disease causation and therapeutic strategies by better understanding endogenous regulatory points within the inflammatory response. CONTENT: Despite of the benefit in raising an inflammatory response, it also have unfavourable effects. Unresolved inflammation can over accumulate collagenous connective tissue and induce fibrosis, promote tissue dysfunction, and finally organ failure. Currently, the resolution of inflammation was described in terms of contemporary molecules as a different mechanisms from anti-inflammatory, since in resolution, the pathogen and apoptotic cells crumbs will be cleared and the macrophages will set back the tissue homeostasis. An active transition in the mediators that predominate in exudates occurs in conjunction with the remission of inflammation. These groups of inborn pro-resolution named resolvins, maresins, and protectins work to reduce inflammation by triggering certain pathways that support homeostasis rather than by suppressing the immune system. SUMMARY: The resolution of inflammation, once believed to be a passive process, is now understood to entail active biochemical programs that allow inflamed tissues to regain equilibrium. In this review, we spotlight the resolution to inflammation as a strategy to prevent tissue fibrosis and hinder the organ damage. KEYWORDS: inflammation; resolution; fibrosis; wound healing; specialized pro-resolving mediators.

Abstract Cell death is a basic physiological process that occurs in all living organisms. A few key players in these mechanisms, as well as various forms of cell death programming, have been identified. Apoptotic cell phagocytosis, also known as apoptotic cell clearance, is a well-established process regulated by a number of molecular components, including ‘find-me’, ‘eat-me’ and engulfment signals. Efferocytosis, or the rapid phagocytic clearance of cell death, is a critical mechanism for tissue homeostasis. Despite having similar mechanism to phagocytic clearance of infections, efferocytosis differs from phagocytosis in that it induces a tissue-healing response and is immunologically inert. However, as field of cell death has rapid expanded, much attention has recently been drawn to the efferocytosis of additional necrotic-like cell types, such as necroptosis and pyroptosis. Unlike apoptosis, this method of cell suicide allows the release of immunogenic cellular material and causes inflammation. Regardless of the cause of cell death, the clearance of dead cells is a necessary function to avoid uncontrolled synthesis of pro-inflammatory molecules and inflammatory disorder. We compare and contrast apoptosis, necroptosis and pyroptosis, as well as the various molecular mechanisms of efferocytosis in each type of cell death, and investigate how these may have functional effects on different intracellular organelles and signalling networks. Understanding how efferocytic cells react to necroptotic and pyroptotic cell uptake can help us understand how to modulate these cell death processes for therapeutic purposes.

BACKGROUND: Immunotherapy, particularly the idea of immune checkpoint blockage is currently draw much attention in cancer treatment. It has been approved as an adjuvant, however, it cannot be a single cancer treatment. CONTENT: The discovery of the basic ligand-receptor interactions between immune and cancer cells inside the tumor microenvironment has led to the current interest in immunotherapy, specifically immune checkpoint inhibition. Different ligands produced by cancer cells interact with immune cells' surface receptors, activating inhibitory pathways, such programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1), that cause immune cells to become immunologically tolerant. On the other side, epigenetic modulators also play a critical role in enhancing the tumor microenvironment and regaining immunological recognition and immunogenicity. Some findings showed that such immune suppression can be reversed through various mechanisms involving antigens pathways, immune genetic, and epigenetic pathways. These findings have created a very encouraging foundation for research on the combination of epigenetic and immunotherapeutic drugs as cancer treatments. SUMMARY: The effectiveness of this suggested paradigm can only be demonstrated by clinical studies. Epigenetic treatment might replace immune checkpoint therapy as a powerful new cancer care technique that is generally well tolerated and should be proven with adequate clinical trials. KEYWORDS: epigenetics, immunotherapy, PTM, DNMT, HDAC, immune check point

BACKGROUND: Metastases are simply known as cancers spread to another part of the body, and often be responsible for the severity of cancer prognosis. Somehow, the complex mechanisms of metastases are not fully understood yet. CONTENT: The characteristic of cancer is akin to a never-healing wound. Cancer cells are plastic and dynamic as they build their niches and developed into metastases, even when they seem dormant. Therefore, cancer cells can survive the immune system. Recent research has shown the distinct biology of metastasis-initiating cell, which leads to tumor development in distant organs, immune surveillance evasion, and co-option of metastatic micro-environments. Effective cancer therapies must consider the regenerative states of metastatic malignancies and have careful observation of patient phenotypes. SUMMARY: This review aimed to provide an insight on genesis and characteristics of metastases, starting from its seeding and dormancy, until the advance phase. Thus, developing therapy for cancer metastases should not start as it grows, but even as earlier strategies since the primary tumor was detected. KEYWORDS: cancer metastasis, DTC, CTC, CSC, dormancy, pre-metastatic niche, plasticity

BACKGROUND: Metabolism impairment in obese condition usually initially triggered by inflammation and insulin signaling impairment. The involvement of metabolites, including lipids, amino acids, and ketone bodies, in altering insulin sensitivity has been revealed after massive data sets were provided by the studies regarding metabolomics and lipidomics. CONTENT: Metabolites were now understood to serve more than just the metabolism products, but also as active signaling molecules including in insulin and immunological actions. Different lipid metabolites can serve as signaling molecules to induce insulin resistance of sensitivity through a similar pathway, and impact on the inflammation status. Branched Chain Amino Acids (BCAA) and many amino acids have been correlated with mitochondrial dysfunction and insulin impairment. Ketogenic diet, supplementation and microbiota transplantation become the current strategies to set a preferable metabolites composition to modulate insulin sensitivity. SUMMARY: Thousands of metabolites can now be measured using technical and bioinformatics developments. Different types of amino acids, fatty acids, and bile acids are being studied in relation to altered metabolic states, particularly obesity and type 2 diabetes mellitus. A thorough knowledge of the metabolic changes that contribute to insulin resistance might lead to the discovery of new targets for enhancing insulin sensitivity and preventing and treating many metabolic disorders. KEYWORDS: metabolites, insulin resistance, lipids, amino acids, ketone bodies

BACKGROUND: Statins have been used for around three decades as the primary way to lower cholesterol and reduce the risk of atherosclerosis, but in some groups, statin resistance is common, and the danger of atherosclerosis is still high. CONTENT: Atherosclerosis was once believed to be caused by cholesterol and thrombotic material passively accumulating in the walls of arteries. However, current knowledge shows that the immune cells and inflammatory processes are essential in the formation, progression, and consequences of atherosclerotic lesions, characterized by a persistent inflammatory response, including thrombotic complications. Study of genetic, creating risk score for atherosclerosis, add more information to create more new therapies targeting low density lipoprotein cholesterol (LDL-C) receptor, and shows prospect. SUMMARY: Over time, atherosclerosis theories and treatment strategies have changed. While statins were widely used, they have now been supplanted by alternative options like the proprotein convertase subtilisin/kexin type 9 (PSCK9) inhibitor that manage atherosclerosis more effectively and comprehensive. KEYWORDS: atherosclerosis, cholesterol, inflammation, immune system, metabolism

BACKGROUND: Obesity incidence has risen dramatically during the last 50 years, reaching epidemic proportions. Obesity's growing prevalence, as well as its numerous metabolic and cardiovascular problems, poses a danger to human health and lifespan across the world. CONTENT: Numerous studies have shown that obesity causes inflammation, and suggest that inflammation may have a causal role in the development of insulin resistance, defective insulin secretion, and energy homeostasis disturbance. Obesity-induced inflammation is different from other inflammatory models because it includes tonic activation of the innate immune system, which has a long-term influence on metabolic balance. Inflammation can cause tissue damage by causing maladaptive responses such as fibrosis and necrosis. Obesity-induced inflammation is unique since it affects a variety of organs, including the adipose tissue, pancreas, liver, skeletal muscle, heart, and brain. These characteristics of obesity-induced inflammation make it difficult to decipher the underlying processes and how they affect metabolic systems. SUMMARY: The disruption of energy homeostasis caused by a positive energy balance is most likely the first trigger of metabolic inflammation, and the initial adaptive response aim to relieve the anabolic pressure caused by obesity. However, over time, this adaptive reaction becomes maladaptive, and the persistence of inflammation shows that the initial response has failed. The inflammation affects so many organ systems during obesity, and to develop novel treatment methods, a greater knowledge of the process was needed. KEYWORDS: obesity, inflammation, diabetes mellitus, non-alcoholic fatty liver disease, cardiovascular diseases, heart failure

BACKGROUND: Aging is an unavoidable part of life, defined by a gradual loss in tissue and organ function and an increasing chance of death. Current studies of aging connected the genetic and epigenetic changes to cause this process. CONTENT: When the aging-related epigenetic alterations is accumulated, it may result in irregulated gene expression, metabolic instability, stem cell senescence and exhaustion, and imbalance of tissue homeostasis, which all accelerate the aging process. Altered epigenetic gene regulatory mechanisms such as DNA methylation, histone modification and chromatin remodeling, and non-coding RNAs can induce aging process, thus manipulating these processes give a chance for the success of age-delaying interventions. SUMMARY: Given updated tools and technologies to investigate the epigenetic regulation affecting aging processes, new therapeutic strategies to delay this process can be developed to increase longevity and improve quality of life. KEYWORDS: aging, epigenetic, senescence, autophagy, mitochondria, metabolism, rejuvenation

BACKGROUND: Aging tissues lose their homeostatic and regenerative capacities, which has been linked to the degeneration of the stem cells such as the tissue-specific stem cells, the stem cell niches, and systemic cues that regulate stem cell activity. CONTENT: The maintenance of tissue homeostatic and regeneration dependent on its tissue-specific stem cells, that —long-lived cells with the ability to self-renew and differentiate into mature cells. Understanding the molecular mechanisms that governs stem cell survival, self-renewal, quiescence, proliferation, and commitment to specific differentiated cell lineages is critical for identifying the drivers and effectors of age-associated stem cell failure. Such understanding will be critical for the development of therapeutic approaches that can decrease, and possibly reverse and repair the age-related degenerative process in aging tissues. SUMMARY: The exact mechanisms and reasons of aging process were not fully elucidated until now. Stem cells is one of the keys for maintaining tissues heath and understanding how stem cell decline with age will give us opportunities to find strategy in increasing somatic stem cells regenerative capacity and delay the aging process. KEYWORDS: adult stem cell, aging, epigenetic, metabolism, quiescence, senescence

BACKGROUND: Mitochondria became a driving force in evolution due to their ability to manufacture adenosine triphosphate (ATP) through respiration. The functioning of mitochondria within eukaryotic cells has evolved dramatically as a result of evolution. Recent research has revealed mitochondria form plasticity to keep the cell's needs and function. CONTENT: Mitochondria have long been regarded as the cell's "powerhouse," providing energy for cell metabolism through oxidative phosphorylation (OXPHOS). A lot of physiological processes were known to be mediated by mitochondria including immunity and autophagy, cell death mechanism, and stem cell reprogramming. Mitochondria can change their shape to form a tubular network that is controlled by fission and fusion processes. Mitochondrial dynamics is the equilibrium between these two opposing processes that regulates mitochondrial number, size, and positioning within the cytoplasm. SUMMARY: All of these discoveries opened up new research avenues and revealed new targets for targeted medication development. Calorie restriction, and the mimetic agents were developed to increase mitochondria biogenesis to improve human lifespan. KEYWORDS: mitochondria, metabolism, homeostasis, stress response, aging, epigenetic

BACKGROUND: Millions of cells in multicellular organisms regenerate every day to replace aged and died cells. Effective cell clearance (efferocytosis) is critical for tissue homeostasis, as the human body recycles its cellular components. We summarize what is known about the mechanisms of efferocytosis and how it impacts the physiology of the organism, effects on inflammation and the adaptive immune response, as well as the consequences of defects in this critical homeostatic mechanism in this review. CONTENT: Cell death is the process by which the human body replaces aged or damaged cells with new ones. It can be triggered by genetically encoded machinery or regulated cell death, or by specific pharmacologic or genetic interventions, resulting in accidental cell death. Dying cells release signals that entice phagocytes to engulf them in a process known as efferocytosis. Efferocytosis is a multistep process involving the release of “find me” and “eat me” signals and destruction of death cells by phagocytes. Different types of cell death including apoptosis and necroptosis can express pro- or anti-inflammatory signals via macrophage activity modulation. SUMMARY: Failed or ineffective efferocytosis can result in disruption of tissue homeostasis, which can contribute to the development of chronic inflammatory diseases such as atherosclerosis, obesity, diabetes, and heart failure. Therefore, any therapeutic strategy that enhances efferocytosis will have a beneficial effect on the treatment of these metabolic disorders. KEYWORDS: apoptosis, necroptosis, phagocytosis, efferocytosis, macrophage.

High levels of M2 macrophage infiltration invariably contribute to poor cancer prognosis and can be manipulated by metabolic reprogramming in the tumor microenvironment. However, the metabolism-related genes (MRGs) affecting M2 macrophage infiltration and their clinical implications are not fully understood. In this study, we identified 173 MRGs associated with M2 macrophage infiltration in cases of gastric cancer (GC) using the TCGA and GEO databases. Twelve MRGs were eventually adopted as the prognostic signature to develop a risk model. In the high-risk group, the patients showed poorer survival outcomes than patients in the low-risk group. Additionally, the patients in the high-risk group were less sensitive to certain drugs, such as 5-Fluorouracil, Oxaliplatin, and Cisplatin. Risk scores were positively correlated with the infiltration of multiple immune cells, including CD8+ T cells and M2 macrophages. Furthermore, a difference was observed in the expression and distribution between the 12 signature genes in the tumor microenvironment through single-cell sequencing analysis. In vitro experiments proved that the M2 polarization of macrophages was suppressed by Sorcin-knockdown GC cells, thereby hindering the proliferation and migration of GC cells. These findings provide a valuable prognostic signature for evaluating clinical outcomes and corresponding treatment options and identifying potential targets for GC treatment.

Compared to the normal tissues, cancer cells tend to have higher proliferation rate and often lost their ability to undergo apoptosis. In addition, cancer cells can separate themselves from their original tissue thus causing metastasis in other part of body. While undergoing program cell death, disordered cellular programming can happen. The main causes of this cellular programming anomaly are epigenetic and genetic alterations, which have been known as two separate mechanisms in carcinogenetic. A recent outcome of whole exome sequencing of thousands of human cancers has been the unexpected discovery of many inactivating mutations in genes that control the epigenome. These mutations have the potential to disturb the DNA methylation patterns, histone modifications, and nucleosome positioning, hence, the causing gene expression alternation. Genetic alteration of the epigenome therefore contributes to cancer just as epigenetic process can cause point mutations and disable DNA repair functions. Epigenetic mechanisms changes could cause genetic mutations, and genetic mutations in epigenetic regulators could cause epigenome changes. Knowing that epigenome play a major role in the hierarchy of gene control mechanisms suggests that mutations might have impact on multiple pathways related to cancer phenotype. This pinpoint the fact that recently, the way the genes are organized and controlled are suggested to be a relevant factor for human carcinogenesis. Keywords: cancer genetic, cancer epigenetic, oncogens, tumor suppressor genes, driver mutation, passenger mutation

BACKGROUND: A lot of contemporary cancer research has concentrated on genetic influence. However, cancer also involves biochemical changes, such as metabolic adaptation to support the aberrant cell proliferation. CONTENT: The fast cell proliferation in cancer cells enforce a metabolic re-arrangement to promote their long-term survival. The increased glucose uptake and fermentation of glucose to lactate are common features of this altered metabolism known as “the Warburg effect”. These metabolic pathways regulation enable cancer cells to produce adenosine triphosphate (ATP) in an efficient way. Epigenetic and metabolic changes also both affect molecular rewiring in cancer cells and promote cancer development and progression. SUMMARY: Metabolic rewiring and epigenetic remodeling establishing a direct link between metabolism and nuclear transcription to promote the survival of tumor cells. A further understanding of how metabolic remodeling can result in epigenetic changes in tumors, affecting cancer cell differentiation, proliferation, and/or apoptosis, will lead to a new strategy for cancer therapy. KEYWORDS: cancer metabolism, epigenetics, metabolic reprogramming, molecular rewiring

Gallic acid, protocatechuic acid, catechol, and pyrogallol are only a few examples of industrially relevant aromatics. Today much attention is paid to the development of new microbial factories for the environmentally friendly biosynthesis of industrially relevant chemicals with renewable resources or organic pollutants as the starting material. The non–conventional yeast, Blastobotrys raffinosifermentans, possesses attractive properties for industrial bio-production processes such as thermo- and osmotolerance. An additional advantage is its broad substrate spectrum, with tannins at the forefront. The present study is dedicated to the characterization of catechol-1,2-dioxygenase (Acdo1p) and the analysis of its function in B. raffinosifermentans tannic acid catabolism. Acdo1p is a dimeric protein with higher affinity for catechol (KM = 0.004 ± 0.001 mM, kcat = 15.6 ± 0.4 s–1) than to pyrogallol (KM = 0.1 ± 0.02 mM, kcat = 10.6 ± 0.4 s–1). It is an intradiol dioxygenase and its reaction product with catechol as the substrate is cis,cis-muconic acid. B. raffinosifermentans G1212/YIC102-AYNI1-ACDO1-6H, which expresses the ACDO1 gene under the control of the strong nitrate-inducible AYNI1 promoter, achieved a maximum catechol-1,2-dioxygenase activity of 280.6 U/L and 26.9 U/g of dry cell weight in yeast grown in minimal medium with nitrate as the nitrogen source and 1.5% glucose as the carbon source. In the same medium with glucose as the carbon source, catechol-1,2-dioxygenase activity was not detected for the control strain G1212/YIC102 with ACDO1 expression under the regulation of its respective endogenous promoter. Gene expression analysis showed that ACDO1 is induced by gallic acid and protocatechuic acid. In contrast to the wild-type strain, the B. raffinosifermentans strain with a deletion of the ACDO1 gene was unable to grow on medium supplemented with gallic acid or protocatechuic acid as the sole carbon source. In summary, we propose that due to its substrate specificity, its thermal stability, and its ability to undergo long-term storage without significant loss of activity, B. raffinosifermentans catechol-1,2-dioxygenase (Acdo1p) is a promising enzyme candidate for industrial applications.

BACKGROUND: Metabolomics is a developed technology that comprehensively analyzes the metabolites in biological specimens. It appears to be a prospective method in the practice of precision medicine. CONTENT: Metabolomic technologies currently surpass beyond the traditional clinical chemistry techniques. Metabolomic is capable to perform a precise analysis for hundreds to thousands of metabolites, therefore provide a detailed characterization of metabolic phenotypes and metabolic derangements that underlie disease, to represent an individual’s overall health status, furthermore to discover new precise therapeutic targets, and discovery of biomarkers, either for diagnosis or therapy monitoring purpose. SUMMARY: Adequate data processing and quantification methods are still needed to be developed to boost integrated -omics as a powerful clinical practice platform. KEYWORDS: metabolomic, precision medicine, phenotyping, biomarker, nutritional pattern

BACKGROUND: Hormesis was initially defined as a phenomenon where a small dose of harmful agent exposure to living organisms gives beneficial effects. The dose and time of this ‘tress’ exposure has become the object of investigation across the broad range of biomedical studies. CONTENT: Hormesis characterized by the biphasic dose-effect or time-effect relationship for any substance. Some hormetic mechanisms performed biological plasticity, involve oxidative damage which instead induce antioxidant enzyme production in various cells. Early-life stress can increase resilience in later life and lack of stress can lead to vulnerability. Many stressors like dietary factors and natural environmental toxins can be occupied for healthy growth or homeostasis, which exemplifies how illness is the doorway to health. SUMMARY: Hormesis reconcile many paradoxical phenomena exert opposite effects of the same substance, either a xenobiotic or an endogenous substance, a hormone or a metabolite, a genetic manipulation or an epigenetic alteration, an experimental intervention or a natural event. Human bodies are highly adaptive. A resilient body would be resulted after the ‘training’. In this review, we will elucidate the hormesis’ definition, mechanisms and pathways, and also how hormesis impacts in human health and lifespan. KEYWORDS: biphasic, cell signaling, dose response, hormesis, preconditioning