How mesenchymal stem cells transform into adipocytes: Overview of the current understanding of adipogenic differentiation.

Mesenchymal stem cells (MSCs) are stem/progenitor cells capable of self-renewal and differentiation into osteoblasts, chondrocytes and adipocytes. The transformation of multipotent MSCs to adipocytes mainly involves two subsequent steps from MSCs to preadipocytes and further preadipocytes into adipocytes, in which the process MSCs are precisely controlled to commit to the adipogenic lineage and then mature into adipocytes. Previous studies have shown that the master transcription factors C/enhancer-binding protein alpha and peroxisome proliferation activator receptor gamma play vital roles in adipogenesis. However, the mechanism underlying the adipogenic differentiation of MSCs is not fully understood. Here, the current knowledge of adipogenic differentiation in MSCs is reviewed, focusing on signaling pathways, noncoding RNAs and epigenetic effects on DNA methylation and acetylation during MSC differentiation. Finally, the relationship between maladipogenic differentiation and diseases is briefly discussed. We hope that this review can broaden and deepen our understanding of how MSCs turn into adipocytes.

Mice harboring the T316N variant in the GABAAR γ2 subunit exhibit sleep-related hypermotor epilepsy phenotypes and hypersynchronization in the thalamocortical pathway.

OBJECTIVE: Sleep-related hypermotor epilepsy (SHE) is a focal epilepsy syndrome characterized by seizures that predominantly occur during sleep. The pathogenesis of these seizures remains unclear. We previously detected rare variants in GABRG2, which encodes the γ2 subunit of γ-aminobutyric acid type A receptor (GABAAR), in patients with SHE and demonstrated that these variants impaired GABAAR function in vitro. However, the mechanisms by which GABRG2 variants contribute to seizure attacks during sleep remain unclear. METHODS: In this study, we designed a knock-in (KI) mouse expressing the mouse Gabrg2 T316N variant, corresponding to human GABRG2 T317N variant, using CRISPR/Cas9. Continuous video-electroencephalogram monitoring and in vivo multichannel electrophysiological recordings were performed to explore seizure susceptibility to pentylenetetrazol (PTZ), alterations in the sleep-wake cycle, spontaneous seizure patterns, and synchronized activity in the motor thalamic nuclei (MoTN) and secondary motor cortex (M2). Circadian variations in the expression of total, membrane-bound, and synaptic GABAAR subunits were also investigated. RESULTS: No obvious changes in gross morphology were detected in Gabrg2T316N/+ mice compared to their wild-type (Gabrg2+/+) littermates. Gabrg2T316N/+ mice share key phenotypes with patients, including sleep fragmentation and spontaneous seizures during sleep. Gabrg2T316N/+ mice showed increased susceptibility to PTZ-induced seizures and higher mortality after seizures. Synchronization of the local field potentials between the MoTN and M2 was abnormally enhanced in Gabrg2T316N/+ mice during light phase, when sleep dominates, accompanied by increased local activities in the MoTN and M2. Interestingly, in Gabrg2+/+ mice, GABAAR γ2 subunits showed a circadian increase on the neuronal membrane and synaptosomes in the transition from dark phase to light phase, which was absent in Gabrg2T316N/+ mice. CONCLUSION: We generated a new SHE mouse model and provided in vivo evidence that rare variants of GABRG2 contribute to seizure attacks during sleep in SHE.

Nitrogen-rich Ce-N compounds under high pressure.

Four high-pressure N-rich compounds (Pmn21-CeN7, Amm2-CeN9, P1̄-CeN10, and P1̄-II-CeN10) are proposed using first-principles calculations. Novel polymeric units (a heart shaped layered structure, chain-like N8 rings, and two new banded structures) in four cerium nitrides are reported for the first time in this study. The analyses of electronic structures and bonding properties show that the charge transfer between Ce and N atoms promotes the formation of the Ce-N ionic bond and N-N covalent bond, which play an important role in stabilizing the nitrogen skeleton. Four new phases possess high energy densities (3.24-3.86 kJ g-1), indicating that they are favorable high-energy density materials. Moreover, P1̄-CeN10 possesses ultra-incompressibility along the [1 0 0] direction. Finally, infrared and Raman spectra are analyzed to provide guidance for experimental synthesis.

Prognostic value of systemic immune-inflammation index and monocyte-to-HDL-cholesterol ratio in early cardio-cerebral complications in elderly patients with acute severe carbon monoxide poisoning.

To investigate how effectively systemic immune-inflammation index (SII) and Monocyte-to-HDL-cholesterol ratio (MHR) predict the development of early cardio-cerebral complications in elderly patients who have experienced acute severe carbon monoxide poisoning (ASCMP). A retrospective analysis was conducted on 77 elderly patients with ASCMP admitted to the emergency department of Harrison International Peace Hospital from November 2020 to March 2022. The prevalence of early-onset complications among the 77 individuals was 38.96%. Binary Logistics regression analysis showed that SII and MHR were independent influencing factors of early cardio-cerebral complications in elderly patients with ASCMP. The complication group had a longer length of stay, a greater mortality rate, and a higher incidence of delayed encephalopathy after acute carbon monoxide poisoning (p < .05) than the non-complication group. The area under the curve (AUC) of SII and MHR in predicting early cardio-cerebral complications in elderly patients with ASCMP were 0.724 and 0.796, respectively, with 80.0% and 63.3% sensitivity, and 61.7% and 87.2% specificity. The incidence of early cardio-cerebral complications in elderly patients who had ASCMP is high and the prognosis is poor. SII and MHR can be utilized as independent predictors of early cardio-cerebral complications in elderly patients with ASCMP, allowing doctors to diagnose and treat cardio-cerebral complications earlier and improve prognosis.

RGD-p21Ras-scFv expressed prokaryotically on a pilot scale inhibits ras-driven colorectal cancer growth by blocking p21Ras-GTP.

BACKGROUND: Ras gene mutation and/or overexpression are drivers in the progression of cancers, including colorectal cancer. Blocking the Ras signaling has become a significant strategy for cancer therapy. Previously, we constructed a recombinant scFv, RGD-p21Ras-scFv by linking RGD membrane-penetrating peptide gene with the anti-p21Ras scFv gene. Here, we expressed prokaryotically RGD-p21Ras-scFv on a pilot scale, then investigated the anti-tumor effect and the mechanism of blocking Ras signaling. METHODS: The E. coli bacteria which could highly express RGD-p21Ras-scFv was screened and grown in 100 L fermentation tank to produce RGD-p21Ras-scFv on optimized induced expression conditions. The scFv was purified from E. coli bacteria using His Ni-NTA column. ELISA was adopted to test the immunoreactivity of RGD-p21Ras-scFv against p21Ras proteins, and the IC50 of RGD-p21Ras-scFv was analyzed by CCK-8. Immunofluorescence colocalization and pull-down assays were used to determine the localization and binding between RGD-p21Ras-scFv and p21Ras. The interaction forces between RGD-p21Ras-scFv and p21Ras after binding were analyzed by molecular docking, and the stability after binding was determined by molecular dynamics simulations. p21Ras-GTP interaction was detected by Ras pull-down. Changes in the MEK-ERK /PI3K-AKT signaling paths downstream of Ras were detected by WB assays. The anti-tumor activity of RGD-p21Ras-scFv was investigated by nude mouse xenograft models. RESULTS: The technique of RGD-p21Ras-scFv expression on a pilot scale was established. The wet weight of the harvested bacteria was 31.064 g/L, and 31.6 mg RGD-p21Ras-scFv was obtained from 1 L of bacterial medium. The purity of the recombinant antibody was above 85%, we found that the prepared on a pilot scale RGD-p21Ras-scFv could penetrate the cell membrane of colon cancer cells and bind to p21Ras, then led to reduce of p21Ras-GTP (active p21Ras). The phosphorylation of downstream effectors MEK-ERK /PI3K-AKT was downregulated. In vivo antitumor activity assays showed that the RGD-p21Ras-scFv inhibited the proliferation of colorectal cancer cell lines. CONCLUSION: RGD-p21Ras-scFv prokaryotic expressed on pilot-scale could inhibited Ras-driven colorectal cancer growth by partially blocking p21Ras-GTP and might be able to be a hidden therapeutic antibody for treating RAS-driven tumors.

A New Strategy for Obesity Treatment: Revealing the Frontiers of Anti-obesity Medications.

Obesity dramatically increases the risk of type 2 diabetes, fatty liver, hypertension, cardiovascular disease, and cancer, causing both declines in quality of life and life expectancy, which is a serious worldwide epidemic. At present, more and more patients with obesity are choosing drug therapy. However, given the high failure rate, high cost, and long design and testing process for discovering and developing new anti-obesity drugs, drug repurposing could be an innovative method and opportunity to broaden and improve pharmacological tools in this context. Because different diseases share molecular pathways and targets in the cells, anti-obesity drugs discovered in other fields are a viable option for treating obesity. Recently, some drugs initially developed for other diseases, such as treating diabetes, tumors, depression, alcoholism, erectile dysfunction, and Parkinson's disease, have been found to exert potential anti-obesity effects, which provides another treatment prospect. In this review, we will discuss the potential benefits and barriers associated with these drugs being used as obesity medications by focusing on their mechanisms of action when treating obesity. This could be a viable strategy for treating obesity as a significant advance in human health.

Impact of innovative immunization strategy on PCV13 vaccination coverage among children under 5 years in Weifang city, China: A retrospective study.

BACKGROUND: Pneumococcal Diseases (PDs) remains a serious public health problem around the world and in China. Pneumococcal vaccination is the most cost-effective measure to prevent PDs. In 2021, the government of Weifang City, Shandong Province, China introduced a free dose of domestic 13-valent Pneumococcal Conjugate Vaccine (PCV 13) to vaccinate registered children aged 6 months-2 years. This study aimed to evaluate the vaccination rate of PCV13 in children aged under 5 years before and after the vaccination program to provide evidences for further improving the prevention and control strategy for PDs. METHODS: We collected data from the children's vaccination information management system in Weifang City and analyzed the PCV13 vaccination coverage and characteristics in all vaccination clinics of Weifang City for children aged under 5 years. We compared the differences in vaccination rates by gender, birth year, manufacturer, and county before and after innovative immunization strategy. RESULTS: Among the included 593,784 children aged under 5 years, the PCV13 vaccination rate in Weifang was generally low before the innovative immunization strategy. Urban children had a higher PCV13 coverage than rural children (P < 0.001), and parents tended to vaccinate their children with imported PCV13.The full vaccination rate for domestic and imported PCV13 was 0.67 % and 1.70 %, respectively. After the vaccination program, the PCV13 coverage of children increased significantly in all counties within Weifang City (P < 0.001), especially for children above 12 months of age. Most parents preferred to vaccinate their children with domestic PCV13, and the full vaccination rate of domestic and imported PCV13 was 6.59 % and 0.16 %, respectively. CONCLUSIONS: The vaccination rate of PCV13 in children is still much lower than the global average, posting a severe health challenge that needs to be addressed thoroughly. To improve the prevention and control strategy for PDs, it is recommended to continue to explore other relevant incentives based on the innovative immunization strategy. Furthermore, it is also recommended that China should incorporate PCV13 into the National Immunization Programs (NIP) as soon as possible.

Influence of Gut Microbiota and its Metabolites on Progression of Metabolic Associated Fatty Liver Disease.

Metabolic associated fatty liver disease (MAFLD) has become a prevalent chronic liver disease worldwide because of lifestyle and dietary changes. Gut microbiota and its metabolites have been shown to play a critical role in the pathogenesis of MAFLD. Understanding of the function of gut microbiota and its metabolites in MAFLD may help to elucidate pathological mechanisms, identify diagnostic markers, and develop drugs or probiotics for the treatment of MAFLD. Here we review the pathogenesis of MAFLD by gut microbiota and its metabolites and discuss the feasibility of treating MAFLD from the perspective of gut microbes.

Novel predictors for livebirth delivery rate in patients with idiopathic non-obstructive azoospermia based on the clinical prediction model.

Objective: To build a prediction model for live birth delivery per intracytoplasmic sperm injection (ICSI) in iNOA patients by obtaining sperm by microdissection testicular sperm extraction (mTESE). Methods: A retrospective cohort study of 377 couples with iNOA male partners treated with 519 mTESE-ICSI cycles was conducted from September 2013 to July 2021 at the Reproductive Medical Centre of Peking University Third Hospital. Following exclusions, 377 couples with iNOA male partners treated with 482 mTESE-ICSIs were included. A prediction model for live birth delivery per ICSI cycle was built by multivariable logistic regression and selected by 10-fold cross-validation. Discrimination was evaluated by c-statistics and calibration was evaluated by the calibration slope. Results: The live birth delivery rate per mTESE-ICSI cycle was 39.21% (189/482) in these couples. The model identified that the presence of motile sperm during mTESE, bigger testes, higher endometrial thickness on the day of human chorionic gonadotrophin (hCG) administration (ET-hCG), and higher quality embryos are associated with higher live birth delivery success rates. The results of the model were exported based on 10-fold cross-validation. In addition, the area under the mean ROC curve was 0.71 ± 0.05 after 10-fold cross-validation, indicating that the prediction model had certain prediction precision. A calibration plot with an estimated intercept of -1.653 (95% CI: -13.403 to 10.096) and a slope of 1.043 (95% CI: 0.777 to 1.308) indicated that the model was well-calibrated. Conclusion: Our prediction model will provide valuable information about the chances of live birth delivery in couples with iNOA male partners who have a plan for mTESE-ICSI treatment. Therefore, it can improve and personalize counseling for the medical treatment of these patients.

Skeletal muscles and gut microbiota-derived metabolites: novel modulators of adipocyte thermogenesis.

Obesity occurs when overall energy intake surpasses energy expenditure. White adipose tissue is an energy storage site, whereas brown and beige adipose tissues catabolize stored energy to generate heat, which protects against obesity and obesity-associated metabolic disorders. Metabolites are substrates in metabolic reactions that act as signaling molecules, mediating communication between metabolic sites (i.e., adipose tissue, skeletal muscle, and gut microbiota). Although the effects of metabolites from peripheral organs on adipose tissue have been extensively studied, their role in regulating adipocyte thermogenesis requires further investigation. Skeletal muscles and intestinal microorganisms are important metabolic sites in the body, and their metabolites play an important role in obesity. In this review, we consolidated the latest research on skeletal muscles and gut microbiota-derived metabolites that potentially promote adipocyte thermogenesis. Skeletal muscles can release lactate, kynurenic acid, inosine, and ß-aminoisobutyric acid, whereas the gut secretes bile acids, butyrate, succinate, cinnabarinic acid, urolithin A, and asparagine. These metabolites function as signaling molecules by interacting with membrane receptors or controlling intracellular enzyme activity. The mechanisms underlying the reciprocal exchange of metabolites between the adipose tissue and other metabolic organs will be a focal point in future studies on obesity. Furthermore, understanding how metabolites regulate adipocyte thermogenesis will provide a basis for establishing new therapeutic targets for obesity.

A Campylobacteriosis Outbreak Caused by One Asymptomatic Food Handler Carrier.

In August 2021, three students with diarrhea from the same school visited a local hospital in the S district of Beijing. An epidemic investigation showed that there were more students with diarrhea in the same school and they had one meal together. Campylobacter jejuni was isolated from both patients with diarrhea and asymptomatic food handlers; however, the latter also carried Campylobacter coli. Phylogenomic analysis showed that there was a campylobacteriosis outbreak among the students, and the asymptomatic food handler may have been the source of the infection. Routine inspection and surveillance for Campylobacter is needed for the food producing staff, particularly those cooking in the cafeteria in schools or other public food services.

Association between negative parent-related family interactions and child social anxiety: A cross-cultural systematic review and meta-analysis.

This meta-analysis systematically evaluates the strength and direction of the association between negative parent-related family interactions and child social anxiety, and identifies several influencing moderators. Two investigators independently searched international (PsycINFO, PubMed, and Web of Science) and Chinese (CNKI, WanFang, and VIP) databases from their inception dates until March 5, 2023, for suitable articles. Of the 5771 identified records, 85 studies were selected based on inclusion of at least one of the following three dimensions of negative family interactions: insecure attachment (n = 27), parent-related family conflicts (n = 19), or negative parenting styles (n = 46). Meta-analyses showed that all three dimensions were significantly associated with child social anxiety (insecure attachment: r = 0.271, p < 0.0001; parent-related family conflicts: r = 0.226, p < 0.0001; negative parenting styles: r = 0.186, p < 0.0001). For all three dimensions, this association was stronger in children from East Asian culture than in those from European or American culture. In addition, age group, information source, and publication year also significantly moderated this association. Our findings will help guide further research and provide recommendations for the development of effective interventions for reducing social anxiety.

The intratumor mycobiome promotes lung cancer progression via myeloid-derived suppressor cells.

Although polymorphic microbiomes have emerged as hallmarks of cancer, far less is known about the role of the intratumor mycobiome as living microorganisms in cancer progression. Here, using fungi-enriched DNA extraction and deep shotgun metagenomic sequencing, we have identified enriched tumor-resident Aspergillus sydowii in patients with lung adenocarcinoma (LUAD). By three different syngeneic lung cancer mice models, we find that A. sydowii promotes lung tumor progression via IL-1ß-mediated expansion and activation of MDSCs, resulting in suppressed activity of cytotoxic T lymphocyte cells and accumulation of PD-1+ CD8+ T cells. This is mediated by IL-1ß secretion via ß-glucan/Dectin-1/CARD9 pathway. Analysis of human samples confirms that enriched A. sydowii is associated with immunosuppression and poor patient outcome. Our findings suggest that intratumor mycobiome, albeit at low biomass, promotes lung cancer progression and could be targeted at the strain level to improve patients with LUAD outcome.

Vinblastine resets tumor-associated macrophages toward M1 phenotype and promotes antitumor immune response.

BACKGROUND: Massive tumor-associated macrophage (TAM) infiltration is observed in many tumors, which usually display the immune-suppressive M2-like phenotype but can also be converted to an M1-like antitumor phenotype due to their high degree of plasticity. The macrophage polarization state is associated with changes in cell shape, macrophage morphology is associated with activation status. M1 macrophages appeared large and rounded, while M2 macrophages were stretched and elongated cells. Manipulating cell morphology has been shown to affect the polarization state of macrophages. The shape of the cell is largely dependent on cytoskeletal proteins, especially, microtubules. As a microtubule-targetting drug, vinblastine (VBL) has been used in chemotherapy. However, no study to date has explored the effect of VBL on TAM shape changes and its role in tumor immune response. METHOD: We used fluorescent staining of the cytoskeleton and quantitative analysis to reveal the morphological differences between M0, M1, M2, TAM and VBL-treated TAM. Flow cytometry was used to confirm the polarization states of these macrophages using a cell surface marker-based classification. In vivo antibody depletion experiments in tumor mouse models were performed to test whether macrophages and CD8+ T cell populations were required for the antitumor effect of VBL. VBL and anti-PD-1 combination therapy was then investigated in comparison with monotherapy. RNA-seq of TAM of treated and untreated with VBL was performed to explore the changes in pathway activities. siRNA mediated knockdown experiments were performed to verify the target pathway that was affected by VBL treatment. RESULTS: Here, we showed that VBL, an antineoplastic agent that destabilizes microtubule, drove macrophage polarization into the M1-like phenotype both in vitro and in tumor models. The antitumor effect of VBL was attenuated in the absence of macrophages or CD8+ T cells. Mechanistically, VBL induces the activation of NF-κB and Cyba-dependent reactive oxygen species generation, thus polarizing TAMs to the M1 phenotype. In parallel, VBL promotes the nuclear translocation of transcription factor EB, inducing lysosome biogenesis and a dramatic increase in phagocytic activity in macrophages. CONCLUSIONS: This study explored whether manipulating cellular morphology affects macrophage polarization and consequently induces an antitumor response. Our data reveal a previously unrecognized antitumor mechanism of VBL and suggest a drug repurposing strategy combining VBL with immune checkpoint inhibitors to improve malignant tumor immunotherapy.

Correlation between connexin 43 expression in circulating tumor cells and biological characteristics of breast cancer.

Background: Connexin 43 (Cx43) has been closely linked to the occurrence and progression of breast cancer. Distant metastasis of breast cancer is aided by the epithelial-mesenchymal transition of circulating tumor cells (CTCs). However, the impact of Cx43 expression on CTCs and the extent of its role in the disease remain unclear. Methods: We determined CTCs in 156 patients, who had breast cancer with a disease course of two or more years. We also measured the expression of Cx43 in the CTCs. The CTCs were detected in the blood of 139 of these patients. These 139 patients were divided into two groups: the Cx43 group and the non-Cx43 group based on their Cx43 expression. Results: Overall, Cx43 expression was found in 83 of the 139 patients (59.7%, 83/139 cases). The two groups significantly differed in terms of the number of mixed biphenotypic type CTCs and the total number of CTCs (P < 0.05). There were significant correlations between Cx43 expression and Ki67 expression, tumor size, lymph node metastasis, and TNM stage (P < 0.05 for all). The data suggested that patients with Cx43 expression had a higher risk of distant metastasis and had later-stage disease. The difference in Cx43 expression between patients with and without epidermal growth factor receptor 2 (Her2) overexpression was statistically significant (P < 0.05). The difference in disease-free survival (DFS) between the two groups was statistically significant (P = 0.03), and the Cx43 group had a shorter duration of DFS. Univariate Cox regression analysis revealed that Cx43 expression, Her2 expression, and tumor size were significantly correlated with DFS (P = 0.03, 0.0023, and 0.01, respectively). Conclusion: Cx43 expression in the CTCs of patients with breast cancer is a cancer-promoting factor.

Machine learning analysis reveals aberrant dynamic changes in amplitude of low-frequency fluctuations among patients with retinal detachment.

Background: There is increasing evidence that patients with retinal detachment (RD) have aberrant brain activity. However, neuroimaging investigations remain focused on static changes in brain activity among RD patients. There is limited knowledge regarding the characteristics of dynamic brain activity in RD patients. Aim: This study evaluated changes in dynamic brain activity among RD patients, using a dynamic amplitude of low-frequency fluctuation (dALFF), k-means clustering method and support vector machine (SVM) classification approach. Methods: We investigated inter-group disparities of dALFF indices under three different time window sizes using resting-state functional magnetic resonance imaging (rs-fMRI) data from 23 RD patients and 24 demographically matched healthy controls (HCs). The k-means clustering method was performed to analyze specific dALFF states and related temporal properties. Additionally, we selected altered dALFF values under three distinct conditions as classification features for distinguishing RD patients from HCs using an SVM classifier. Results: RD patients exhibited dynamic changes in local intrinsic indicators of brain activity. Compared with HCs, RD patients displayed increased dALFF in the bilateral middle frontal gyrus, left putamen (Putamen_L), left superior occipital gyrus (Occipital_Sup_L), left middle occipital gyrus (Occipital_Mid_L), right calcarine (Calcarine_R), right middle temporal gyrus (Temporal_Mid_R), and right inferior frontal gyrus (Frontal_Inf_Tri_R). Additionally, RD patients showed significantly decreased dALFF values in the right superior parietal gyrus (Parietal_Sup_R) and right paracentral lobule (Paracentral_Lobule_R) [two-tailed, voxel-level p < 0.05, Gaussian random field (GRF) correction, cluster-level p < 0.05]. For dALFF, we derived 3 or 4 states of ALFF that occurred repeatedly. There were differences in state distribution and state properties between RD and HC groups. The number of transitions between the dALFF states was higher in the RD group than in the HC group. Based on dALFF values in various brain regions, the overall accuracies of SVM classification were 97.87, 100, and 93.62% under three different time windows; area under the curve values were 0.99, 1.00, and 0.95, respectively. No correlation was found between hamilton anxiety (HAMA) scores and regional dALFF. Conclusion: Our findings offer important insights concerning the neuropathology that underlies RD and provide robust evidence that dALFF, a local indicator of brain activity, may be useful for clinical diagnosis.

New insight of obesity-associated NAFLD: Dysregulated "crosstalk" between multi-organ and the liver?

Obesity plays a crucial role in the development of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanism for the pathogenesis of obesity-associated NAFLD remains largely obscure. Although the "multiple hit" theory provides a more accurate explanation of NAFLD pathogenesis, it still cannot fully explain precisely how obesity causes NAFLD. The liver is the key integrator of the body's energy needs, receiving input from multiple metabolically active organs. Thus, recent studies have advocated the "multiple crosstalk" hypothesis, highlighting that obesity-related hepatic steatosis may be the result of dysregulated "crosstalk" among multiple extra-hepatic organs and the liver in obesity. A wide variety of circulating endocrine hormones work together to orchestrate this "crosstalk". Of note, with deepening understanding of the endocrine system, the perception of hormones has gradually risen from the narrow sense (i.e. traditional hormones) to the broad sense of hormones as organokines and exosomes. In this review, we focus on the perspective of organic endocrine hormones (organokines) and molecular endocrine hormones (exosomes), summarizing systematically how the two types of new hormones mediate the dialogue between extra-hepatic organs and liver in the pathogenesis of obesity-related NAFLD.