Search Results (15,800)

2,4-Dichlorophenoxyacetic acid (2,4-D), originally developed as a synthetic auxinic herbicide, is the most widely used chemical inducer of somatic embryogenesis (SE) in plants. Despite extensive use of 2,4-D in plant regeneration, the systems-level regulatory mechanisms connecting hormonal signaling, metabolic reprogramming, translational control, and embryogenic competence remain poorly resolved. Here, we hypothesize that TOR signaling functions as an integrative molecular hub coordinating transcriptional, metabolic, and developmental reprogramming during somatic embryogenesis induction. To investigate the molecular regulatory landscape associated with 2,4-D-induced SE, we performed a systems-level analysis integrating publicly available transcriptomic data from Arabidopsis thaliana with high-confidence protein–protein interaction (PPI) network analyses using STRING v12.0 (confidence score ≥ 0.900). Using a previously published transcriptomic dataset, we identified 1927 upregulated genes associated with SE induction, which were organized into 34 functional modules related to transcriptional regulation, translation metabolism, hormone signaling and cellular homeostasis. Within this interactome, TARGET OF RAPAMYCIN (TOR) kinase emerged as an integrative regulatory hub associated with multiple pathways involved in embryogenic reprogramming. Network analyses revealed three major TOR-associated regulatory axes: (1) the TOR–FKBP12–RPS6A axis, associated with ribosome biogenesis and translational regulation; (2) the TOR–CBP20 axis, connected with transcriptional reprogramming; SE master regulators (LEC1, LEC2, and FUS3); and lipid, sterol, brassinosteroid (BR), and auxin-associated pathways; and (3) the TOR–TAP46 axis, linked with one-carbon metabolism, nucleotide biosynthesis, DNA replication and repair, and genome-stability pathways. Additionally, the network contained 411 embryo-lethal (EMBL) genes distributed across multiple regulatory modules, reinforcing the biological relevance of the identified interactome and highlighting the importance of coordinated developmental, metabolic, and transcriptional regulation during embryogenesis induction. These findings support a systems-level TOR-associated regulatory framework involved in the integration of transcriptional, translational, metabolic, hormonal, and genome-maintenance pathways during embryogenesis. This interactome model provides a foundation for functional studies aimed at dissecting the molecular mechanisms underlying SE and identifying candidate targets to improve regeneration and biotechnological application and crop genetic engineering. Collectively, this study proposes a mechanistic framework in which TOR signaling integrates developmental, metabolic, translational, and genome-stability pathways to orchestrate embryogenic competence, providing candidate molecular targets for improving plant regeneration and genome engineering platforms. Full article

Royal jelly (RJ) is a highly valued bee-derived functional food and natural health product, in which 10-hydroxy-2-decenoic acid (10-HDA) represents the most characteristic lipid component. As a unique fatty acid found exclusively in RJ, 10-HDA serves not only as a key marker for product authenticity, freshness, and quality evaluation but also as a major contributor to the biological activities of RJ, including immunomodulatory, metabolic regulatory, antimicrobial, anti-inflammatory, antitumor, and dermatological effects. Given its nutritional and quality-related importance, and because most previous reviews have focused primarily on the biological activities or compositional characteristics of 10-HDA, current knowledge regarding its biosynthesis, secretion, and regulatory mechanisms in worker mandibular glands has not yet been systematically organized and summarized. Understanding these processes is essential for explaining the biological origin of 10-HDA accumulation in RJ and for developing strategies to improve 10-HDA yield, royal jelly quality, and production standardization. This review summarizes current knowledge on the physicochemical properties and health-related functions of 10-HDA and further integrates recent advances in its endogenous biosynthesis and regulatory mechanisms. Particular emphasis is placed on the proposed three-step biosynthetic pathway, beginning with stearic acid and proceeding through cytochrome P450-mediated ω-hydroxylation, successive β-oxidation, and terminal dehydrogenation. We also discuss how 10-HDA production is shaped by worker developmental stage, glandular maturation, genetic background, dietary nutrients, botanical origin, endocrine signals, and apicultural management practices. By linking the biological origin of 10-HDA with its functional properties and quality-determining role in RJ, this review provides an integrated framework for understanding the formation of 10-HDA-rich royal jelly. By linking the biological origin, functional properties, and quality-determining role of 10-HDA in RJ, this review provides an integrated framework for understanding 10-HDA-rich royal jelly. It also identifies key gaps in biosynthetic validation, secretion mechanisms, and regulatory networks, offering guidance for RJ quality standardization, production optimization, and functional food development. Full article

Background: Alcoholic liver disease (ALD) represents a major global health burden, encompassing a spectrum of hepatic abnormalities ranging from steatosis to cirrhosis and hepatocellular carcinoma. Laennec, a human placenta-derived hydrolysate, was evaluated for its therapeutic effects on alcohol-induced fatty liver in an experimental animal model. Methods: Animals were pretreated with alcohol for 2 weeks, followed by the co-administration of alcohol and Laennec for 4 weeks. The study included four groups: normal control, alcohol-only, and low- and high-dose Laennec-treated groups. Results: Alcohol administration significantly elevated the serum ALT levels (3.17-fold vs. control), indicating hepatocellular injury, whereas Laennec treatment reduced the ALT levels in a dose-dependent manner. The AST levels increased in the alcohol-only group, although the change was not statistically significant; however, the AST levels decreased in the low-dose Laennec-treated groups. The AST/ALT ratio showed significantly dose-dependent recovery in the high-dose group. Laennec treatment attenuated hepatic lipid accumulation and inflammation, with the most pronounced effects observed in the high-dose group. Regarding alcohol-metabolizing enzymes, Laennec exhibited an inhibitory effect on alcohol-induced ADH activity, with no significant effect on ALDH. CYP2E1 activity was suppressed in a dose-dependent manner following Laennec administration. No significant changes were observed in the GPx activity. Additionally, high-dose Laennec significantly restored the catalase and STAT3 (Ser727) phosphorylation levels. Histopathological analysis (H&E staining) demonstrated marked reductions in lipid droplet accumulation and inflammatory cell infiltration in Laennec-treated groups compared to the alcohol-only group. Conclusion: These findings suggest that Laennec exerts hepatoprotective effects against alcohol-induced liver injury and steatosis, as evidenced by improvements in biochemical markers, enzyme activity, and histological features. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide and is driven by complex metabolic and inflammatory disturbances. Extra virgin olive oil (EVOO), a hallmark of the Mediterranean diet, contains numerous bioactive compounds that may exert beneficial effects on liver and cardiometabolic health. This preliminary study investigated the interactions of selected EVOO-derived compounds, with molecular targets implicated in MASLD using an integrated in silico approach. Methods: Phenolic compounds, secoiridoids, fatty acids, sterols, squalene, and vitamin E were evaluated. Physicochemical properties, drug-likeness, and pharmacokinetic profiles were predicted using ADMETlab 3.0. Molecular docking analyses were performed against liver X receptors (LXRα and LXRβ), peroxisome proliferator-activated receptors (PPARα and PPARγ), hydroxymethylglutaryl-CoA reductase, cyclooxygenase-1, and cyclooxygenase-2. Binding modes were further examined by three-dimensional interaction analyses. Results: The investigated compounds displayed heterogeneous physicochemical and pharmacokinetic profiles. Oleuropein, oleacein, and oleocanthal demonstrated the most consistent binding patterns across targets involved in lipid metabolism, inflammation, and cardiometabolic regulation. In contrast, highly lipophilic compounds, including squalene, β-sitosterol, and vitamin E, frequently achieved high docking scores but formed fewer biologically relevant interactions. Conclusions: EVOO phenolics, particularly oleuropein, oleacein, and oleocanthal, emerged as promising multi-target modulators of MASLD-related pathways, supporting the potential role of EVOO in MASLD prevention and management. Full article

Early-life dietary transition is a critical window for gut microbiota assembly and intestinal maturation in squabs. This study compared the overall artificial-feeding system using a lactic acid bacteria-fermented diet (AF) with a parent-feeding system (PF) during 18–25 days of age. Because AF differed from PF in both diet exposure and feeding ecology, including manual feeding, absence of parental feeding and crop milk, altered feeding rhythm, and potential loss of parental microbial transmission, the objective was to characterize associations between the two systems rather than to isolate the effect of fermentation alone. Squabs were assigned to AF or PF for 7 days. Microbial communities in the duodenum, jejunum, ileum, and rectum were profiled by 16S rRNA sequencing, and body size traits, organ indices, jejunal morphology, muscle histology, serum biochemical indicators, and muscle composition were assessed. The AF system, characterized by lower pH, a higher acid value, and detectable lactic acid bacteria in the feed, was associated with higher alpha diversity in multiple segments and distinct beta-diversity profiles relative to PF. Across intestinal regions, lactobacilli-related genera were enriched, with Limosilactobacillus consistently identified as the most discriminant genus and, together with Lactobacillus, occupying central positions in exploratory co-occurrence networks. AF was also associated with a greater jejunal villus height and villus height-to-crypt depth ratio, larger muscle fiber dimensions, higher intramuscular fat content with increased levels of selected polyunsaturated fatty acids, altered lipid-related serum indicators, and higher organ indices, including the bursa of Fabricius. PICRUSt2 further suggested differences in predicted functional potential related to carbohydrate, amino acid, lipid, and cofactor/vitamin metabolism, although these outputs represent inference from 16S data rather than directly measured functions. Collectively, the AF system was associated with a lactobacilli-centered, tract-wide microbial signature and coordinated intestinal, muscular, and lipid-related phenotypes in squabs, but the findings should not be interpreted as evidence for fermentation alone. Full article

Neurodegeneration with brain iron accumulation (NBIA) comprises a group of rare genetic movement disorders characterized by progressive neurological deterioration, dystonia, parkinsonism, spasticity, and abnormal iron deposition in the basal ganglia. Although iron accumulation is the shared neuroradiological hallmark, most NBIA genes do not directly regulate iron metabolism. Instead, major NBIA forms arise from disruption of distinct but converging cellular pathways, including coenzyme A (CoA) biosynthesis, lipid metabolism, mitochondrial function, and autophagy. This narrative review aims to examine the pathogenic mechanisms of major NBIA disorders, namely pantothenate kinase-associated neurodegeneration (PKAN), COASY protein-associated neurodegeneration (CoPAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MPAN), and beta-propeller protein-associated neurodegeneration (BPAN), and how these insights are guiding therapeutic development. Preclinical strategies aimed at restoring CoA metabolism, improving mitochondrial function, limiting lipid peroxidation, modulating autophagy, or correcting the underlying genetic defect have shown encouraging results, although none have yet reached robust clinical validation. Clinical translation remains limited by disease rarity, clinical heterogeneity, absence of validated biomarkers, and preclinical models that only partially recapitulate human pathology. Advancing the field will depend on earlier molecular diagnosis, biomarkers capable of tracking disease stage, and trial designs suited to ultra-rare populations. NBIA thus offers a paradigm for how mechanistic classification of a genetically defined disease group can redirect therapeutic strategy away from a shared radiological feature and toward pathway-specific intervention. Full article

Age-associated metabolic dysfunction is commonly defined by abnormalities in adiposity, glucose regulation, lipid metabolism, and blood pressure. Although clinically useful, these criteria do not fully capture the biological heterogeneity that explains why older adults with similar metabolic profiles may follow divergent trajectories toward type 2 diabetes, cardiovascular disease, metabolic dysfunction-associated steatotic liver disease, frailty or multimorbidity. This narrative Review summarizes clinical, translational, and mechanistic evidence on the biological processes that shape metabolic aging, with particular emphasis on inflammaging, immunosenescence, cellular senescence, oxidative stress, mitochondrial dysfunction, adipose tissue dysfunction, endothelial injury, and inflammation-related microRNAs. We first discuss how chronic low-grade inflammation and immune remodeling alter the interpretation of conventional metabolic syndrome components in older adults. We then review redox imbalance and mitochondrial stress as amplifiers of insulin resistance, lipid injury, vascular dysfunction, and tissue remodeling. The review also examines inflammation-related microRNAs, including circulating and extracellular-vesicle-associated miRNAs, as post-transcriptional regulators that may connect inflammatory, metabolic, and redox pathways. Finally, we discuss how conventional metabolic markers may be integrated with inflammatory mediators, oxidative-stress indicators, adipokines, endothelial and senescence-related markers, and miRNA profiles to improve biological interpretation of metabolic risk. Within this context, we present the Inflammaging–Redox–InflammamiR Axis as a conceptual framework for organizing these overlapping mechanisms rather than as an established diagnostic or causal model. The proposed biomarker tiers and candidate risk phenotypes are author-derived, hypothesis-generating constructs intended to guide future longitudinal and interventional research. Clinical translation will require standardized assays, longitudinal validation, external replication, and intervention studies. Full article

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease with limited treatment options. Here, we demonstrate that fucoxanthin (FUCO), a natural marine carotenoid, attenuates free fatty acid (FFA)-induced hepatocellular steatosis and inflammatory responses in vitro by targeting the EGR2-CD36 axis (EGR2, early growth response protein 2; CD36, cluster of differentiation 36). In FFA-induced hepatocyte models (HepG2, Hep3B, and AML12), FUCO significantly reduced lipid accumulation and inflammatory markers without cytotoxicity. Mechanistic studies revealed that FUCO specifically inhibited fatty acid uptake and transport by downregulating CD36, while triglyceride (TG) degradation remained unaffected. RNA sequencing identified EGR2 as a master regulator induced by FFA and suppressed by FUCO. Functional validation showed that EGR2 overexpression completely blocked FUCO’s lipid-lowering effects and restored CD36 expression, confirming that FUCO acts through EGR2-dependent CD36 inhibition. Bioinformatic analysis further supported EGR2-mediated regulation of CD36 via tumor necrosis factor (TNF) and sterol regulatory element-binding factor (SREBF) pathways. Collectively, our findings establish EGR2 as a critical molecular target for FUCO and provide mechanistic insights that may support its further evaluation in preclinical models for MASH therapy. Full article

Glutathione peroxidase 4 (GPX4) is canonically viewed as the primary suppressor of ferroptosis, yet its role in the tumor microenvironment (TME) extends far beyond antioxidant catalysis to encompass immuno-metabolic regulation. In this review, we synthesize recent advances in enzymology, immunology, and cancer metabolism to propose a “lipid peroxidation threshold” framework, wherein GPX4 sets cell-type-specific thresholds that determine susceptibility to ferroptosis across tumor cells, CD8⁺ T cells, dendritic cells (DCs), and myeloid populations. We discuss how these thresholds are dynamically adjusted by post-translational modifications, nutrient competition and intercellular feedback loops, resulting in significant spatial heterogeneity between the tumor core and the tumor invasive front. There is a current selectivity paradox in GPX4 inhibitors, as well as resistance through nuclear factor erythroid 2-related factor 2 (Nrf2) and ferroptosis suppressor protein 1 (FSP1) that restricts the efficacy of GPX4 inhibitors as monotherapy. We focus on rational combination approaches: GPX4 modulation with immune checkpoint blockade (ICB), chemotherapy, and targeting myeloid-derived suppressor cells (MDSCs); and the pressing need for predictive biomarkers and single-cell spatial profiling. We conclude that successful clinical translation requires moving beyond indiscriminate GPX4 inhibition toward precision “threshold engineering” that selectively lowers tumor lipid peroxidation thresholds while sparing immune cells. Full article

Cardiometabolic residual risk in type 2 diabetes mellitus (T2D) persists despite major advances in glucose-lowering therapy, lipid management, blood pressure control, weight reduction, and organ-protective strategies. This residual burden should not be interpreted solely as the consequence of incomplete achievement of conventional therapeutic targets, but rather as the clinical expression of persistent molecular activity involving multiple interconnected organs and pathways. Insulin resistance, metaflammation, oxidative stress, mitochondrial dysfunction, lipotoxicity, endothelial impairment, hepatic metabolic dysregulation, renal inflammation, fibrotic remodeling, and metabolic memory interact within a dynamic network linking adipose tissue, liver, kidney, immune cells, and vasculature. In this review, we discuss the biochemical and molecular drivers of cardiometabolic residual risk in T2D, with particular emphasis on impaired insulin receptor substrate/PI3K/Akt signaling, stress-kinase activation, NLRP3 inflammasome priming and assembly, MASLD-related lipotoxicity and fibrogenesis, podocyte and tubular injury, endothelial nitric oxide synthase uncoupling, AGE-RAGE signaling, and thrombo-inflammatory vascular injury. These pathways explain why biological vulnerability may persist even when conventional clinical parameters appear adequately controlled. We also examine the role of translational biomarkers and simple clinical indices, including TyG-derived indices, adiposity markers, hepatic steatosis and fibrosis scores, albuminuria, eGFR, and lipid-related markers, as accessible windows into active biological pathways. Finally, we review how contemporary therapeutic strategies may modulate selected components of this residual-risk network. A pathway-centered interpretation of T2D may support more precise residual-risk phenotyping and help move cardiometabolic care beyond isolated target control toward mechanism-based prevention. This review further links these mechanisms to the contemporary cardiovascular–kidney–metabolic (CKM) framework, as defined by the 2026 AHA/ACC/ADA/ASN CKM Guideline, and disaggregates the underlying molecular network into organ-specific pathway cascades that make the causal relationships between metabolic, inflammatory, hepatic, renal, and vascular injury more explicit. Full article

Background: Prostaglandin E₂ (PGE₂) is a key lipid mediator involved in inflammation and bone homeostasis. Its systemic production is reliably reflected by 24 h urinary excretion of PGE₂ (U-PGE₂) and its major metabolite (U-PGEM). However, the physiological association between systemic PGE₂ production, calcium-phosphorus homeostasis and bone turnover markers remains unclear. This study aims to elucidate these relationships in a general Chinese adult population. Methods: In this multicenter, cross-sectional study, 737 Chinese adults underwent standardized 24 h urine collection. Multivariable linear regression was used to assess independent associations with bone metabolism markers. Restricted cubic spline models were further employed to examine nonlinear relationships. Results: The median 24 h U-PGE₂ and U-PGEM excretion levels were 133.87 and 246.76 pg/mmol creatinine, respectively, with no significant sex differences (both p > 0.05). Multivariable regression analyses revealed that both 24 h U-PGE₂ and U-PGEM were independently and positively associated with advancing age. Notably, both 24 h U-PGE₂ and U-PGEM maintained a significant inverse association with serum calcium (Overall p < 0.05). Restricted cubic spline analyses further demonstrated a significant non-linear association between both 24 h U-PGE₂ and U-PGEM and total procollagen type 1 N-propeptide (P1NP; both Overall p < 0.05). This relationship was characterized by a steep decline in U-PGE₂ and U-PGEM excretion at lower P1NP concentrations, which subsequently plateaued at higher concentrations (Overall p < 0.05). Additionally, U-PGEM exhibited a significant inverse linear association with intact parathyroid hormone (PTH; Overall p < 0.05). Conclusions: This study provided valuable insights into the clinical determinants of 24 h U-PGE₂ and U-PGEM in Chinese adults and their independent associations with calcium-phosphorus homeostasis and bone turnover markers. Full article

Phytobiotics are promising dietary tools to improve metabolic stability and physiological resilience against chemical stressors in aquaculture. This study evaluated nrf2-linked antioxidant and metabolic modulation by dietary Origanum vulgare essential oil (OEO) in Nile tilapia (Oreochromis niloticus) under malathion-induced organophosphate stress. Fish, with an initial weight of 5.76 ± 0.56 g, were distributed in three tanks per treatment, with 15 fish per tank, and fed diets containing 0 (control), 0.75, 1.50, 2.25 and 3.00 g kg⁻¹ OEO for eight weeks, followed by exposure to malathion (7.04 mg L⁻¹) for 96 h. OEO enhanced (p < 0.05) growth performance, feed utilisation, and survival after exposure, with the greatest productive and survival outcomes at 3.00 g kg⁻¹. Fish that received the supplement also had lower (p < 0.05) lipid peroxidation, better antioxidant enzyme activity and a more favourable modulation of nrf2, gpx and keap1 expression, together with biochemical and histological patterns that were consistent with a better condition of the liver and kidney. The heatmap and PCA supported a treatment-related separation, with 2.25 and 3.00 g kg⁻¹ OEO showing the most favourable integrated physiological profiles. Dietary OEO was associated with antioxidant, metabolic and tissue-level resilience linked to modulation of nrf2-related transcriptional responses. Full article

Obesity is a major global health problem and is closely associated with a broad range of metabolic disorders, including metabolic syndrome (MetS), dyslipidemia, hypertension, atherosclerosis, type 2 diabetes mellitus, and cardiovascular disease. The gut microbiota plays a central role in maintaining intestinal epithelial integrity, regulating glucose and lipid metabolism, and modulating immune function. Through the gut–brain axis, it also contributes to appetite regulation and energy homeostasis by influencing the release of anorexigenic hormones. Dysbiosis, including alterations in the relative abundance of major bacterial phyla such as Firmicutes and Bacteroidetes, has been associated with increased intestinal permeability, metabolic endotoxemia, and chronic low-grade inflammation, all of which may contribute to the development of obesity and insulin resistance. Diets rich in plant-derived fiber can beneficially shape gut microbiota composition. Bacterial fermentation of dietary fiber produces short-chain fatty acids (SCFAs), including butyrate, acetate, and propionate, which contribute to intestinal barrier integrity, inflammatory regulation, immune regulation, and metabolic homeostasis. Overall, the interaction between gut microbiota, diet, and host metabolic pathways represents a promising field for therapeutic and nutritional interventions aimed at preventing and managing MetS and metabolic diseases. Full article

The nutritional management of pregnant yaks is critical yet remains understudied, particularly under housed conditions. This study investigated the effects of concentrate supplementation at varying nutritional levels on growth performance, blood metabolism, and rumen microbiota in housed pregnant yaks during the warm season. Eighteen mid-gestation yaks were allocated to low- (LP), medium- (MP), and high-nutrition (HP) groups and fed for 110 days. Growth performance, serum metabolites, hormones, and rumen microbiota composition were assessed. No significant differences were observed in final body weight, average daily gain, or dry matter intake among the groups (p > 0.05). However, the serum malondialdehyde concentration was significantly higher in the MP group (3.03 nmol/mL) than in the LP group (1.30 nmol/mL) (p < 0.05). Concentrations of glucose and lipid metabolites tended to increase with higher nutritional levels, whereas circulating levels of growth-related hormones (GH, INS, IGF-1, and IGF-2) showed a declining trend (p > 0.05). Rumen alpha diversity was numerically highest in the MP group. Specific taxa (norank_o_Clostridia_UCG-014) were enriched in the MP and LP groups (p < 0.05). The microbial composition in the MP group was positively correlated with blood TG, TC, and HDL-C (p < 0.05). In conclusion, within the constraints of the present experimental design, medium- or low-nutrition concentrate supplementation maintained growth performance and modulated the rumen microbiota associated with lipid metabolism. However, the elevated MDA in the MP group warrants caution, and the observed trends should be interpreted as preliminary and require validation in future studies with larger sample sizes. Full article

Background/Objectives: Nicotinamide mononucleotide (NMN), a precursor of nicotinamide adenine dinucleotide (NAD⁺), is used as a dietary supplement, but its safety and metabolic effects in adults remain unclear. This review assessed the short-term safety and tolerability of oral NMN or NMN-related supplementation and examined metabolic and vascular outcomes. Methods: PubMed, Embase, Scopus, Web of Science, CNKI, and Wanfang were searched from inception to 13 May 2026. Eligible studies were parallel randomized controlled trials comparing oral NMN or NMN-related preparations with placebo, blank control, lifestyle control, or the same background intervention without NMN. Safety outcomes included adverse events, serious adverse events, withdrawals due to adverse events, system-specific adverse events, alanine aminotransferase, and aspartate aminotransferase. Random-effects models were used, with GRADE for evidence certainty. Results: Fifteen trials were included, with 10 contributing to safety analyses. NMN doses ranged from 250–2000 mg/day, and durations ranged from 14 days to 24 weeks. NMN did not increase overall, serious, withdrawal-related, or system-specific adverse events, nor did it significantly elevate ALT or AST. No significant effects were observed on body weight, BMI, fasting glucose, HbA1c, lipid profiles, or systolic blood pressure. Diastolic blood pressure decreased slightly, while HOMA-IR showed a non-significant downward trend. Conclusions: Short-term oral NMN or NMN-related supplementation showed favorable tolerability, with no clear increase in adverse events or hepatic biochemical abnormalities. Broad metabolic benefits were not evident, but changes in diastolic blood pressure and HOMA-IR suggest preliminary vascular-metabolic signals, especially in older adults or people with early metabolic risk. Larger and longer trials should confirm efficacy and long-term safety. This review was registered in PROSPERO (CRD420261382497). Full article