Liver histology is associated with long-term clinical outcomes in patients with metabolic dysfunction-associated steatohepatitis.

BACKGROUND: Few studies have examined the risk of long-term clinical outcomes in patients with metabolic dysfunction-associated steatohepatitis in relation to liver histology. We aimed to study this using a real-world cohort. METHODS: Adults (N = 702) recorded on Vanderbilt University Medical Center's Synthetic Derivative database (1984-2021) with evidence of metabolic dysfunction-associated steatohepatitis on liver biopsy were followed from the first biopsy until the first clinical event or last database entry (median: 4.7 y). Risks of cirrhosis (N = 650), other noncirrhotic liver-related (N = 702) and cardiovascular-related outcomes (N = 660), and mortality due to liver, cardiovascular, or cancer events (N = 660) were determined as a function of baseline histology (fibrosis stage [F], lobular inflammation grade [LI], hepatocyte ballooning grade [HB], and steatosis score) adjusting for sex, age, diabetes, and weight-loss surgery. RESULTS: Cirrhosis risk was reduced for lower versus higher fibrosis stage (HR: F0-1 vs. F3: 0.22 [95% CI: 0.12-0.42]), LI1 versus LI2-3 (0.42 [0.19-0.97]), and HB1 versus HB2 (0.20 [0.08-0.50]). Lower fibrosis stage was associated with significantly lower risks of liver-related outcomes versus F4 cirrhosis (eg, F0-1: 0.12 [0.05-0.25]), whereas no differences were seen across baseline lobular inflammation, hepatocyte ballooning, and steatosis grades/scores. Lower versus higher lobular inflammation grade was associated with lower risks for liver-related outcomes in patients with weight-loss surgery. There was a trend for lower risks for cardiovascular-related and any long-term outcomes with lower versus higher fibrosis stage. CONCLUSIONS: Fibrosis stage and lobular inflammation and hepatocyte ballooning grades predict the risk of long-term outcomes, supporting the use of these histological features as potential surrogate markers of disease progression or clinical outcomes.

Myeloid Trem2 ameliorates the progression of metabolic dysfunction-associated steatotic liver disease by regulating macrophage pyroptosis and inflammation resolution.

BACKGROUND: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing year by year and has become one of the leading causes of end-stage liver disease worldwide. Triggering Receptor Expressed on Myeloid Cells 2 (Trem2) has been confirmed to play an essential role in the progression of MASLD, but its specific mechanism still needs to be clarified. This study aims to explore the role and mechanism of Trem2 in MASLD. METHODS: Human liver tissues were obtained from patients with MASLD and controls. Myeloid-specific knockout mice (Trem2mKO) and myeloid-specific overexpression mice (Trem2TdT) were fed a high-fat diet, either AMLN or CDAHFD, to establish the MASLD model. Relevant signaling molecules were assessed through lipidomics and RNA-seq analyses after that. RESULTS: Trem2 is upregulated in human MASLD/MASH-associated macrophages and is associated with hepatic steatosis and inflammation progression. Hepatic steatosis and inflammatory responses are exacerbated with the knockout of myeloid Trem2 in MASLD mice, while mice overexpressing Trem2 exhibit the opposite phenomenon. Mechanistically, Trem2mKO can aggravate macrophage pyroptosis through the PI3K/AKT signaling pathway and amplify the resulting inflammatory response. At the same time, Trem2 promotes the inflammation resolution phenotype transformation of macrophages through TGFß1, thereby promoting tissue repair. CONCLUSIONS: Myeloid Trem2 ameliorates the progression of Metabolic dysfunction-associated steatotic liver disease by regulating macrophage pyroptosis and inflammation resolution. We believe targeting myeloid Trem2 could represent a potential avenue for treating MASLD.

Sulforaphane reduces adipose tissue fibrosis via promoting M2 macrophages polarization in HFD fed-mice.

Adipose tissue fibrosis has been identified as a novel contributor to the pathomechanism of obesity associated metabolic disorders. Sulforaphane (SFN) has been shown to have an anti-obesity effect. However, the impact of SFN on adipose tissue fibrosis is still not well understood. In this study, obese mice induced by high-fat diets (HFD) were used to examine the effects of SFN on adipose tissue fibrosis. According to the current findings, SFN dramatically enhanced glucose tolerance and decreased body weight in diet-induced-obesity (DIO) mice. Additionally, SFN therapy significantly reduced extracellular matrix (ECM) deposition and altered the expression of genes related to fibrosis. Furthermore, SFN also reduced inflammation and promoted macrophages polarization towards to M2 phenotype in adipose tissue, which protected adipose tissue from fibrosis. Notably, SFN-mediated nuclear factor E2-related factor 2 (Nrf2) activation was crucial in decreasing adipose tissue fibrosis. These results implied that SFN had favorable benefits in adipose tissue fibrosis, which consequently ameliorates obesity-related metabolic problems. Our research provides new treatment strategies for obesity and associated metabolic disorders.

Noninvasive tests to identify liver fibrosis in metabolic dysfunction-associated steatotic liver disease are affected by race.

OBJECTIVE: The objective of this study was to assess the performance of noninvasive tests (NITs) across different racial and ethnic groups in a large multiethnic cohort. METHODS: Data were derived from the National Health and Nutrition Examination Survey (NHANES) 2017 through 2020. Participants without valid transient elastography measurements or with alternative etiologies of liver steatosis disease were excluded from the study. RESULTS: Among the 6359 adults included in the study, fatty liver index and nonalcoholic fatty liver disease liver fat scores performed well for the prediction of metabolic dysfunction-associated steatotic liver disease, without significant changes across racial and ethnic groups. However, significant differences were observed across racial and ethnic groups for the prediction of advanced fibrosis and cirrhosis. The fibrosis-4 (FIB-4) index, aspartate aminotransferase to platelet ratio index (APRI), and nonalcoholic fatty liver disease fibrosis score underperformed in non-Hispanic Black patients for the detection of cirrhosis. For the detection of advanced fibrosis, their performance was also numerically worse in non-Hispanic Black patients but only reached statistical significance for APRI. Using a cutoff point of 12 kPa for advanced fibrosis, both APRI and the FIB-4 index performed significantly worse in non-Hispanic Black patients. CONCLUSIONS: In a large, diverse national cohort, the performance of NITs was overall poor compared with transient elastography, and NITs showed differences across racial and ethnic groups. Given the widespread use of NITs, it is imperative that the scores are equitable across racial and ethnic groups.

N6-methyladenosine in myeloid cells: a novel regulatory factor for inflammation-related diseases.

N6-methyladenosine (m6A) is one of the most abundant epitranscriptomic modifications on eukaryotic mRNA. Evidence has highlighted that m6A is altered in response to inflammation-related factors and it is closely associated with various inflammation-related diseases. Multiple subpopulations of myeloid cells, such as macrophages, dendritic cells, and granulocytes, are crucial for the regulating of immune process in inflammation-related diseases. Recent studies have revealed that m6A plays an important regulatory role in the functional of multiple myeloid cells. In this review, we comprehensively summarize the function of m6A modification in myeloid cells from the perspective of myeloid cell production, activation, polarization, and migration. Furthermore, we discuss how m6A-mediated myeloid cell function affects the progression of inflammation-related diseases, including autoimmune diseases, chronic metabolic diseases, and malignant tumors. Finally, we discuss the challenges encountered in the study of m6A in myeloid cells, intended to provide a new direction for the study of the pathogenesis of inflammation-related diseases.

The regulatory role of PI3K in ageing-related diseases.

Ageing is a physiological/pathological process accompanied by the progressive damage of cell function, triggering various ageing-related disorders. Phosphatidylinositol 3-kinase (PI3K), which serves as one of the central regulators of ageing, is closely associated with cellular characteristics or molecular features, such as genome instability, telomere erosion, epigenetic alterations, and mitochondrial dysfunction. In this review, the PI3K signalling pathway was firstly thoroughly explained. The link between ageing pathogenesis and the PI3K signalling pathway was then summarized. Finally, the key regulatory roles of PI3K in ageing-related illnesses were investigated and stressed. In summary, we revealed that drug development and clinical application targeting PI3K is one of the focal points for delaying ageing and treating ageing-related diseases in the future.

The Role of CD38 in the Pathogenesis of Cardiorenal Metabolic Disease and Aging, an Approach from Basic Research.

Aging is a major risk factor for the leading causes of mortality, and the incidence of age-related diseases including cardiovascular disease, kidney disease and metabolic disease increases with age. NAD+ is a classic coenzyme that exists in all species, and that plays a crucial role in oxidation-reduction reactions. It is also involved in the regulation of many cellular functions including inflammation, oxidative stress and differentiation. NAD+ declines with aging in various organs, and the reduction in NAD+ is possibly involved in the development of age-related cellular dysfunction in cardiorenal metabolic organs through the accumulation of inflammation and oxidative stress. Levels of NAD+ are regulated by the balance between its synthesis and degradation. CD38 is the main NAD+-degrading enzyme, and CD38 is activated in response to inflammation with aging, which is associated with the reduction in NAD+ levels. In this review, focusing on CD38, we discuss the role of CD38 in aging and the pathogenesis of age-related diseases, including cardiorenal metabolic disease.

Recent update on application of dihydromyricetin in metabolic related diseases.

As a new type of natural flavonoids, dihydromyricetin (DMY) has attracted more and more attention. It has a series of pharmacological effects, such as anti-inflammatory, anti-tumor, anti-oxidation, antibacterial and so on, and it is almost no toxicity and with excellent safety. Therefore, even if the bioavailability is poor, it is often added to daily food, beverages and even medicines. In recent years, some researchers have found that DMY can treat some diseases by anti-oxidation, anti-inflammation, promoting cell death and regulate the activity of lipid and glucose metabolism. In addition, the mechanism of DMY on these diseases was also related to the signal pathway of AMPK, PI3K/Akt, PPAR and the participation of microRNAs. This review describes the mechanism of DMY in metabolic related diseases from three aspects: metabolic diseases, liver diseases, and cancers, hoping to provide some new ideas for clinical researches.

Extracellular matrix remodeling facilitates obesity-associated cancer progression.

Obesity, a global public health concern, is an important risk factor for metabolic diseases and several cancers. Fibro-inflammation in adipose tissues (ATs) is tightly associated with the pathologies of obesity; excessive or uncontrolled extracellular matrix (ECM) production in AT has a crucial role in this pathogenesis. The ECM is a critical and functional component of various tissues, providing a mechanical and chemical network of proteins that controls cell survival, development, and tissue repair. The ECM is tightly regulated and dynamically remodeled; this is an important factor for AT expansion and can result in modifications to the physical shape and biological function of AT. Here, we focus on ECM remodeling in AT and how it affects obesity-related cancer progression.

Cancer as a Metabolic Disorder.

Cancer has long been considered a genetic disease characterized by a myriad of mutations that drive cancer progression. Recent accumulating evidence indicates that the dysregulated metabolism in cancer cells is more than a hallmark of cancer but may be the underlying cause of the tumor. Most of the well-characterized oncogenes or tumor suppressor genes function to sustain the altered metabolic state in cancer. Here, we review evidence supporting the altered metabolic state in cancer including key alterations in glucose, glutamine, and fatty acid metabolism. Unlike genetic alterations that do not occur in all cancer types, metabolic alterations are more common among cancer subtypes and across cancers. Recognizing cancer as a metabolic disorder could unravel key diagnostic and treatments markers that can impact approaches used in cancer management.

A critical review of Astragalus polysaccharides: From therapeutic mechanisms to pharmaceutics.

As the important active ingredients of Astragali Radix (AR), Astragalus polysaccharides (APs) have therapeutic potential for multiple diseases including nervous system diseases, cardiovascular diseases, diabetes mellitus, and cancer. A large number of cell experiments combined with animal experiments have shed light on the therapeutic mechanisms and therapeutic effects of APs on a variety of diseases. However, the clinical application of APs is not widespread, except for the use of injected APs in the clinical adjuvant therapy of cancer. Due to the excessive molecular weight, bulky, low solubility and negatively charged characteristics, APs have low bioavailability which limits their clinical application. With the deepening of researches on the pharmaceutics of APs, the nanocrystals and moderate structural modification enormously boost the bioavailability, which may expand the application of APs. This review summarizes the studies in pharmacodynamic properties and pharmaceutics of APs, with the purpose of providing experimental researches and clinical application data for expanding the clinical development through expounding the therapeutic mechanisms and pharmaceutical researches of APs.

Pharmacological targeting of endoplasmic reticulum stress in disease.

The accumulation of misfolded proteins in the endoplasmic reticulum (ER) leads to ER stress, resulting in activation of the unfolded protein response (UPR) that aims to restore protein homeostasis. However, the UPR also plays an important pathological role in many diseases, including metabolic disorders, cancer and neurological disorders. Over the last decade, significant effort has been invested in targeting signalling proteins involved in the UPR and an array of drug-like molecules is now available. However, these molecules have limitations, the understanding of which is crucial for their development into therapies. Here, we critically review the existing ER stress and UPR-directed drug-like molecules, highlighting both their value and their limitations.

The role of FUNDC1 in mitophagy, mitochondrial dynamics and human diseases.

Mitochondria are the principal sites of energy metabolism and provide most of the energy needed for normal cellular function. They are dynamic organelles that constantly undergo fission, fusion and mitophagy to maintain their homeostasis and function. However, dysregulated mitochondrial dynamics and mitophagy leads to reduced ATP generation and mutation of their DNA, which ultimately leads to cell death. Increasing evidence has shown that the FUN14 domain-containing protein 1 (FUNDC1), a novel mitophagy receptor, participates in the process of mitochondrial dynamics and mitophagy and plays a critical role in various human diseases. Herein, we review the role of FUNDC1 in mitophagy and mitochondrial dynamics, thus providing a better understanding of the relationship between the two processes. Moreover, we summarize the treatments targeting FUNDC1, and suggest that FUNDC1 may represent a promising therapeutic target for the treatment of several human diseases such as cardiovascular diseases, metabolic syndrome, cancer and chronic obstructive pulmonary disease (COPD).

An emerging role of the 5' termini of mature tRNAs in human diseases: Current situation and prospects.

The fundamental biological roles of a class of small noncoding RNAs (sncRNAs), derived from mature tRNAs or pre-tRNAs, in human diseases have received increasing attention in recent years. These ncRNAs are called tRNA-derived fragments (tRFs) or tRNA-derived small RNAs (tsRNAs). tRFs mainly include tRF-1, tRF-5, tRF-3 and tRNA halves (tiRNAs or tRHs), which are produced by enzyme-specific cleavage of tRNAs. Here, we classify tRF-5 and 5' tiRNAs into the same category: 5'-tRFs and review the biological functions and regulatory mechanisms of 5'-tRFs in cancer and other diseases (metabolic diseases, neurodegenerative diseases, pathological stress injury and virus infection) to provide a new theoretical basis for the diagnosis and treatment of diseases.

[Considerations on pathological diagnosis of inherited metabolic liver disease].

A liver biopsy has an important suggestive role in the diagnosis of inherited metabolic liver disease (IMLD). This article introduces the IMLD pathological diagnosis considerations, five types of classification of liver biopsy based on the morphological characteristics (basic normal liver tissue morphology, steatosis, cholestatic disease, storage/deposition, and hepatitis), and a summary of the pathological characteristics of different injury patterns and common diseases in order to provide clues for the correct diagnosis.

Metabolic Disorders in Multiple Myeloma.

Multiple myeloma (MM) is the second most common hematological malignancy and is attributed to monoclonal proliferation of plasma cells in the bone marrow. Cancer cells including myeloma cells deregulate metabolic pathways to ensure proliferation, growth, survival and avoid immune surveillance, with glycolysis and glutaminolysis being the most identified procedures involved. These disorders are considered a hallmark of cancer and the alterations performed ensure that enough energy is available for rapid cell proliferation. An association between metabolic syndrome, inflammatory cytokinesand incidence of MM has been also described, while the use of metformin and statins has been identified as a positive prognostic factor for the disease course. In this review, we aim to present the metabolic disorders that occur in multiple myeloma, the potential defects on the immune system and the potential advantage of targeting the dysregulated pathways in order to enhance antitumor therapeutics.

Pathophysiological Molecular Mechanisms of Obesity: A Link between MAFLD and NASH with Cardiovascular Diseases.

Obesity is now a worldwide epidemic ensuing an increase in comorbidities' prevalence, such as insulin resistance, type 2 diabetes (T2D), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic steatohepatitis (NASH), hypertension, cardiovascular disease (CVD), autoimmune diseases, and some cancers, CVD being one of the main causes of death in the world. Several studies provide evidence for an association between MAFLD and atherosclerosis and cardio-metabolic disorders, including CVDs such as coronary heart disease and stroke. Therefore, the combination of MAFLD/NASH is associated with vascular risk and CVD progression, but the underlying mechanisms linking MAFLD/NASH and CVD are still under investigation. Several underlying mechanisms may probably be involved, including hepatic/systemic insulin resistance, atherogenic dyslipidemia, hypertension, as well as pro-atherogenic, pro-coagulant, and pro-inflammatory mediators released from the steatotic/inflamed liver. MAFLD is strongly associated with insulin resistance, which is involved in its pathogenesis and progression to NASH. Insulin resistance is a major cardiovascular risk factor in subjects without diabetes. However, T2D has been considered the most common link between MAFLD/NASH and CVD. This review summarizes the evidence linking obesity with MAFLD, NASH, and CVD, considering the pathophysiological molecular mechanisms involved in these diseases. We also discuss the association of MAFLD and NASH with the development and progression of CVD, including structural and functional cardiac alterations, and pharmacological strategies to treat MAFLD/NASH and cardiovascular prevention.

MANF: A Novel Endoplasmic Reticulum Stress Response Protein-The Role in Neurological and Metabolic Disorders.

The mesencephalic astrocyte-derived neurotrophic factor (MANF), also named as arginine-rich protein (ARP) or arginine-rich mutated in early-stage tumors (ARMET), is a novel evolutionary conserved protein related to unfolded protein response. Growing evidence suggests that MANF critically involves in many ER stress-related diseases with a protective effect. Here, we review the function of MANF based on its structure in neurological and metabolic disorders and summarize its potential applications in disease diagnosis and therapies.

Successful Diagnoses and Remarkable Metabolic Disorders in Patients With Solitary Hypothalamic Mass: A Case Series Report.

Background: Solitary intracranial hypothalamic mass occurs rarely. The etiological diagnosis of solitary hypothalamus lesion is challenging and often unachievable. Although previous studies indicated that lesions affecting the hypothalamus often cause significant metabolic disorders, few reports about the metabolic disturbances of patients with solitary hypothalamic mass have been reported. Method: Twenty-five patients with solitary hypothalamus lesions who had been evaluated and treated in Huashan Hospital from January 2010 to December 2020 were retrospectively enrolled. The clinical manifestations, radiological features, endocrine and metabolic disorders, and pathology were analyzed. Results: The male to female ratio was 5/20. The median age of onset was 22 (19, 35) years old. The most common initial symptom was polydipsia/polyuria (19/25, 76.0%) and amenorrhea (9/20, 45.0%). A high prevalence of hypopituitarism of different axes was found, with almost all no less than 80%. Central hypogonadism (21/22, 95.5%) and central diabetes insipidus (19/21, 90.5%) were the top two pituitary dysfunctions. Conclusive diagnoses were achieved by intracranial surgical biopsy/resection or stereotactic biopsy in 16 cases and by examining extracranial lesions in 3 cases. The pathological results were various, and the most common diagnoses were Langerhans cell histiocytosis (7/19) and hypothalamitis (5/19). The mean timespan from onset to diagnosis in the 19 cases was 34 ± 26 months. Metabolic evaluations revealed remarkable metabolic disorders, including hyperlipidemia (13/16, 81.3%), hyperglycemia (10/16, 62.5%), hyperuricemia (12/20, 60%), overweight/obesity (13/20, 65.0%), and hepatic adipose infiltration (10/13, 76.6%). Conclusion: Either surgical or stereotactic biopsy will be a reliable and relatively safe procedure to help to confirm the pathological diagnosis of solitary hypothalamic mass. Metabolic disorders were severe in patients with solitary hypothalamic mass. The management of such cases should cover both the treatment of the primary disease, as well as the endocrine and metabolic disorders.

The impact of obesity on adipocyte-derived extracellular vesicles.

Recently, the emerging roles of adipocyte-derived extracellular vesicles (EVs) linking obesity and its comorbidities have been recognized. In obese subjects, adipocytes are having hypertrophic growth and are under stressed. The dysfunction adipocytes dysregulate the assembly of the biological components in the EVs including exosomes. This article critically reviews the current findings on the impact of obesity on the exosomal cargo contents that induce the pathophysiological changes. Besides, this review also summarizes the understanding on how obesity affects the biogenesis of adipocyte-derived exosomes and the exosome secretion. Furthermore, the differences of the exosomal contents in different adipose depots, and the impact of obesity on the exosomes that are derived from the stromal vascular fraction such as the adipose tissue macrophages and adipocyte-derived stem cells will also be discussed. The current development and potential application of exosome-based therapy will be summarized. This review provides crucial information for the design of novel exosome-based therapy for the treatment of obesity and its comorbidities.