3D hepatic organoid production from human pluripotent stem cells.

Hepatic organoids might provide a golden opportunity for realizing precision medicine in various hepatic diseases. Previously described hepatic organoid protocols from pluripotent stem cells rely on complicated multiple differentiation steps consisting of both 2D and 3D differentiation procedures. Therefore, the spontaneous formation of hepatic organoids from 2D monolayer culture is associated with a low-throughput production, which might hinder the standardization of hepatic organoid production and hamper the translation of this technology to the clinical or industrial setting. Here we describe the stepwise and fully 3D production of hepatic organoids from human pluripotent stem cells. We optimized every differentiation step by screening for optimal concentrations and timing of differentiation signals in each differentiation step. Hepatic organoids are stably expandable without losing their hepatic functionality. Moreover, upon treatment of drugs with known hepatotoxicity, we found hepatic organoids are more sensitive to drug-induced hepatotoxicity compared with 2D hepatocytes differentiated from PSCs, making them highly suitable for in vitro toxicity screening of drug candidates. The standardized fully 3D protocol described in the current study for producing functional hepatic organoids might serve as a novel platform for the industrial and clinical translation of hepatic organoid technology.

Mangiferin improves early porcine embryonic development by reducing oxidative stress.

Mangiferin (MGN) is primarily found in the fruits, leaves, and bark of plants of the Anacardiaceae family, including mangoes. MGN exhibits various pharmacological effects, such as protection of the liver and gallbladder, anti-lipid peroxidation, and cancer prevention. This study aimed to investigate the effects of MGN supplementation during in vitro culture (IVC) on the antioxidant capacity of early porcine embryos and the underlying mechanisms involved. Porcine parthenotes in the IVC medium were exposed to different concentrations of MGN (0, 0.01, 0.1, and 1 µM). The addition of 0.1 µM MGN significantly increased the blastocyst formation rate of porcine embryos while reducing the apoptotic index and autophagy. Furthermore, the expression of antioxidation-related (SOD2, GPX1, NRF2, UCHL1), cell pluripotency (SOX2, NANOG), and mitochondria-related (TFAM, PGC1α) genes was upregulated. In contrast, the expression of apoptosis-related (CAS3, BAX) and autophagy-related (LC3B, ATG5) genes decreased after MGN supplementation. These findings suggest that MGN improves early porcine embryonic development by reducing oxidative stress-related genes.

Enhancing antioxidant levels and mitochondrial function in porcine oocyte maturation and embryonic development through notoginsenoside R1 supplementation.

This study examines the impact of Notoginsenoside R1 (NGR1), a compound from Panax notoginseng, on the maturation of porcine oocytes and their embryonic development, focusing on its effects on antioxidant levels and mitochondrial function. This study demonstrates that supplementing in vitro maturation (IVM) medium with NGR1 significantly enhances several biochemical parameters. These include elevated levels of glutathione (GSH), nuclear factor erythrocyte 2-related factor 2 (NRF2) and mRNA expression of catalase (CAT) and GPX. Concurrently, we observed a decrease in reactive oxygen species (ROS) levels and an increase in JC-1 immunofluorescence, mitochondrial distribution, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) and nuclear NRF2 mRNA levels. Additionally, there was an increase in ATP production and lipid droplets (LDs) immunofluorescence. These biochemical improvements correlate with enhanced embryonic outcomes, including a higher blastocyst rate, increased total cell count, enhanced proliferative capacity and elevated octamer-binding transcription factor 4 (Oct4) and superoxide dismutase 2 (Sod2) gene expression. Furthermore, NGR1 supplementation resulted in decreased apoptosis, reduced caspase 3 (Cas3) and BCL2-Associated X (Bax) mRNA levels and decreased glucose-regulated protein 78 kD (GRP78) immunofluorescence in porcine oocytes undergoing in vitro maturation. These findings suggest that NGR1 plays a crucial role in promoting porcine oocyte maturation and subsequent embryonic development by providing antioxidant levels and mitochondrial protection.

Hypoxic bone marrow mesenchymal stromal cells-derived exosomal miR-182-5p promotes liver regeneration via FOXO1-mediated macrophage polarization.

Mesenchymal stromal cells (MSCs) are attractive candidates for treating hepatic disorders given their potential to enhance liver regeneration and function. The paracrine paradigm may be involved in the mechanism of MSC-based therapy, and exosomes (Exo) play an important role in this paracrine activity. Hypoxia significantly improves the effectiveness of MSC transplantation. However, whether hypoxia preconditioned MSCs (Hp-MSCs) can enhance liver regeneration, and whether this enhancement is mediated by Exo, are unknown. In this study, mouse bone marrow-derived MSCs (BM-MSCs) and secreted Exo were injected through the tail vein. We report that Hp-MSCs promote liver regeneration after partial hepatectomy in mice through their secreted exosomes. Interestingly, MSC-Exo were concentrated in liver 6 h after administration and mainly taken up by macrophages, but not hepatocytes. Compared with normoxic MSC-Exo (N-Exo), hypoxic MSC-Exo (Hp-Exo) enhanced M2 macrophage polarization both in vivo and in vitro. Microarray analysis revealed significant enrichment of microRNA (miR)-182-5p in Hp-Exo compared with that in N-Exo. In addition, miR-182-5p knockdown partially abolished the beneficial effect of Hp-Exo. Finally, Hp-MSC-derived exosomal miR-182-5p inhibited theprotein expression of forkhead box transcription factor 1 (FOXO1) in macrophages, which inhibited toll-like receptor 4 (TLR4) expression and subsequently induced an anti-inflammatory response. These results highlight the therapeutic potential of Hp-Exo in liver regeneration and suggest that miR-182-5p from Hp-Exo facilitates macrophage polarization during liver regeneration by modulating the FOXO1/TLR4 signaling pathway.

Detection of Haemophilus influenzae by loop-mediated isothermal amplification coupled with nanoparticle-based lateral flow biosensor assay.

BACKGROUND: Haemophilus influenzae was the most aggressive pathogen and formed a major cause of bacterial meningitis and pneumonia in young children and infants, which need medical emergency requiring immediate diagnosis and treatment. However, From isolation to identification of H. influenzae, the traditional diagnose strategy was time-consuming and expensive. Therefore, the establishment of a convenient, highly sensitive, and stable detection system is urgent and critical. RESULTS: In this study, we used a combined method to detect H. influenzae. Six specific primers were designed on the basis of outer membrane protein P6 gene sequence of H. influenzae. The reaction condition such as the optimum temperature was 65℃, and the optimum reaction time was 30 min, respectively. Through the loop-mediated isothermal amplification (LAMP) in combination with nanoparticle-based lateral flow biosensor (LFB), the sensitivity of LAMP-LFB showed 100 fg was the lowest genomic DNA templates concentration in the pure cultures. Meanwhile, the specificity of H. influenzae-LAMP-LFB assay showed the exclusive positive results, which were detected in H. influenzae templates. In 55 clinical sputum samples, 22 samples were positive with LAMP-LFB method, which was in accordance with the traditional culture and Polymerase Chain Reaction (PCR) method. The accuracy in diagnosing H. influenzae with LAMP-LFB could reach 100%, compared to culture and PCR method, indicating the LAMP-LFB had more advantages in target pathogen detection. CONCLUSIONS: Taken together, LAMP-LFB could be used as an effective diagnostic approach for H. influenzae in the conditions of basic and clinical labs, which would allow clinicians to make better informed decisions regarding patient treatment without delay.

A novel self-nanomicellizing system of empagliflozin for oral treatment of acute pancreatitis: An experimental study.

Acute pancreatitis (AP) is a severe inflammatory disorder hampered by a lack of effective drugs in its clinical practice. Empagliflozin (EMP) exhibits potential effects against AP but is limited by poor water-solubility and low bioavailability. Herein, a novel self-nanomicellizing formulation of EMP with phytochemical rebaudioside A (RA) as the nanocarrier (RA-EMP) was fabricated to address these issues. RA-EMP powder could be simply prepared and exhibited excellent storage stability, dramatically improved EMP's apparent solubility, and instantly self-assembled into micelles with high EMP encapsulation efficiency in water. In vivo experimental studies showed that RA-EMP exhibited significantly enhanced oral bioavailability of EMP and dramatically improved therapeutic efficacy against AP. The mechanisms through suppressing the effects of oxidative stress and proinflammatory cytokines were involved in this therapeutic effect. The results demonstrated that RA-EMP could serve as a promising way to enhance the oral bioavailability and strengthen the potential therapeutic efficacy of EMP against AP.

Association between social support and life satisfaction among people with substance use disorder: the mediating role of resilience.

The purpose of this cross-sectional study was to assess the correlation between social support and life satisfaction among individuals with substance use disorder and investigate the mediating effect of resilience between these variables. A total of 513 individuals with substance use disorder aged 19-65 years were recruited from two compulsory detoxification units in Nanjing, China. Participants were requested to independently complete the Satisfaction with Life Scale, the Multidimensional Scale of Perceived Social Support, and the Connor-Davidson Resilience Scale. A correlation matrix was used to analyze various characteristics. The relationship among social support, resilience, and life satisfaction was evaluated with hierarchical regression analysis and the bootstrap method, based on a structural equation model. Social support was significantly associated with life satisfaction in individuals with substance use disorder. Moreover, resilience played an intermediary role between social support and life satisfaction in individuals with substance use disorder. Our results confirm resilience partially mediates the association between social support and life satisfaction. These findings provide a clearer understanding regarding the impact of resilience and social support on life satisfaction in individuals with substance use disorder.

Revisiting the Stokes-Einstein relation for glass-forming melts.

Molecular dynamics simulations of Ni36Zr64, Cu65Zr35 and Ni80Al20 were carried out over a broad range of temperature (900-3000 K) to investigate the Stokes-Einstein (SE) relation for glass-forming melts. Our results reproduce experimental structural and transport properties. Results show that the breakdown temperature of the SE relation (TSE) equals the dynamical crossover temperature (TA) and both are roughly twice the glass-transition temperature (Tg) for the three glass-forming melts (TSE = TA ≈ 2.0Tg). The product of the individual component self-diffusion coefficient and viscosity Dαη can be roughly regarded as a constant at the transition zone (a small temperature range around TSE) in which the temperature behaviors of self-diffusion coefficient and viscosity switch from high-temperature Arrhenius to a low-temperature VFT behavior. Below TSE, the decoupling of component diffusion coefficients was found. In particular, the decoupling of component diffusion coefficients can be ascribed to the decoupling of the partial pair structural correlation of components, which can be clearly reflected by the intersection of the high-temperature and low-temperature behaviors of the ratio between the partial pair correlation entropy of components (Sß2/Sα2). Furthermore, the ratio between the partial pair correlation entropy of components may be used to predict the validity of the SE relation, in the absence of both transport coefficients and atomic coordinates.

Poverty increases the risk of incident cognitive impairment among older adults: a longitudinal study in China.

Objectives: With a longitudinal design, we aimed to investigate the relationship between poverty and the risk of incident cognitive impairment in China.Methods: We used three waves of the Chinese Longitudinal Healthy Longevity Survey (2008-2014). Cognitive impairment was assessed using the Chinese version of the Mini Mental State Examination. Poverty was measured according to the latest national poverty line settled at an annual per-capita income of 2300 yuan (approximately equivalent to 1.25 dollar/day) in 2011 in China. A marginal structural model was utilized to explore the association between poverty and the risk of incident cognitive impairment. The subgroup analyses were also conducted in this study.Results: The cumulative incidence of cognitive impairment over 6 years was 30.69% (1936/6309). Poverty increased 34% risk of incident cognitive impairment in the elderly (odds ratio = 1.34, 95% confidence interval (CI): 1.15-1.56) after controlling behavioral factors and health status covariates. Participants who were male (OR = 1.38, 95% CI: 1.08-1.76), lived in urban areas (OR = 1.55, 95% CI: 1.22-1.98), and were married (OR = 1.72, 95% CI: 1.28-2.32) had higher poverty risks on incident cognitive impairment in subgroup analyses.Conclusions: Our results provide empirical support for the ongoing discussion about how economic hardship impacts of cognitive functioning, and highlight the negative health risks that economically disadvantaged individuals may experience.

Neural stem cell secretome and its role in the treatment of neurodegenerative disorders.

Neurological diseases in the central nervous system are mostly characterized by the failure of endogenous repair to restore tissue damage and salvage lost function. Currently, studies have shown that neural stem cell transplantation provides a good therapeutic effect on neurological diseases. For this reason, neural stem cell transplantation has been explored as a cell replacement therapy. Although transplanted cells can replace cells lost during or post central nervous system injury, many studies have shown that this mechanism is insufficient as most of these newly formed cells fail to integrate and eventually die. Although it was initially thought that neural stem cell could only replace lost cells, recent experiments have shown that transplanted neural stem cell can also play bystander roles such as neuroprotection and immune regulation, promote tissue repair by preventing tissue damage, interfere with pathogenic processes, or by rescuing endogenous nerve cells. However, compelling evidence has raised concerns about this bystander effect, which can be caused by several biologically active molecules (collectively known as the secretome) produced by neural stem cells. These results also raise the possibility of the neural stem cell secretome as a potential candidate for neural stem cell transplantation therapies based on the bystander effect. A better understanding of the molecules and mechanisms of this effect is of critical importance for neural stem cell-based therapies. This review aims to discuss the function and application of neural stem cell secretome in the treatment of neurodegenerative disorders.

Loneliness and depression among Chinese drug users: Mediating effect of resilience and moderating effect of gender.

This study aims to explore potential correlations between gender, loneliness, resilience, and depression simultaneously among Chinese drug users; and especially to investigate the mediating effect of resilience and the moderating effect of gender on the correlation between loneliness and depression. Participants of this study included 513 drug users (399 men and 114 women) who were under treatment in two compulsory drug treatment institutions in one Eastern Chinese city. All participants completed the UCLA (University of California, Los Angeles) loneliness scale, the Zung self-rating depression scale, and the Connor-Davidson resilience scale. A correlation matrix was constructed to analyze correlations between these three characteristics. Path analyses were performed in the PROCESS for SPSS in order to test the mediating effect of resilience on the association between loneliness and depression; while a series of hierarchical multiple regressions were conducted in SPSS 22.0 to test the moderating effect of gender on the association between loneliness and depression. Compared to male drug users, female ones reported higher average scores on loneliness and depression, which indicated that female drug users suffered severer loneliness and depression. Resilience partially mediates the link between loneliness and depression and gender acts as a moderator for the relationship between loneliness and depression.

Study on PM2.5 pollution and the mortality due to lung cancer in China based on geographic weighted regression model.

BACKGROUND: PM2.5 has become a major component of air pollution in China and has led to a series of health problems. The mortality rate caused by lung cancer has reached the point where it cannot be ignored in China. Air pollution is becoming more and more serious in China, which is increasingly affecting people's lives and health. METHODS: Considering the variations in the geographical environment in China, this paper studied the relationship between PM2.5 concentration and lung cancer mortality based on the geographical weighted regression model in 31 provinces in 2004 and 2008, autonomous regions and municipalities of China. RESULTS: The results indicated there was a significant positive correlation between PM2.5 concentration and lung cancer mortality (r = 0.0052, P = 0.036). Additionally, the longer the time of exposure to PM2.5 is, the higher morbidity is. CONCLUSION: It is suggested that the Chinese government should launch some environmental policy, especially in those areas with severe PM2.5 pollutions, and keep the citizens away from exposure to PM2.5 pollution in the long term.

Laser cooling of MgCl and MgBr in theoretical approach.

Ab initio calculations for three low-lying electronic states (X(2)Σ(+), A(2)Π, and 2(2)Π) of MgCl and MgBr molecules, including spin-orbit coupling, are performed using multi-reference configuration interaction plus Davidson correction method. The calculations involve all-electronic basis sets and Douglas-Kroll scalar relativistic correction. Spectroscopic parameters well agree with available theoretical and experimental data. Highly diagonally distributed Franck-Condon factors f00 for A(2)Π3/2,1/2 (υ' = 0) → X(2)Σ(+) 1/2 (υ″ = 0) are determined for both MgCl and MgBr molecules. Suitable radiative lifetimes τ of A(2)Π3/2,1/2 (υ' = 0) states for rapid laser cooling are also obtained. The proposed laser drives A(2)Π3/2 (υ' = 0) → X(2)Σ(+) 1/2 (υ″ = 0) transition by using three wavelengths (main pump laser λ00; two repumping lasers λ10 and λ21). These results indicate the probability of laser cooling MgCl and MgBr molecules.

Transport coefficients and entropy-scaling law in liquid iron up to Earth-core pressures.

Molecular dynamics simulations were applied to study the structural and transport properties, including the pair distribution function, the structure factor, the pair correlation entropy, self-diffusion coefficient, and viscosity, of liquid iron under high temperature and high pressure conditions. Our calculated results reproduced experimentally determined structure factors of liquid iron, and the calculated self-diffusion coefficients and viscosity agree well with previous simulation results. We show that there is a moderate increase of self-diffusion coefficients and viscosity along the melting curve up to the Earth-core pressure. Furthermore, the temperature dependencies of the pair correlation entropy, self-diffusion, and viscosity under high pressure condition have been investigated. Our results suggest that the temperature dependence of the pair correlation entropy is well described by T(-1) scaling, while the Arrhenius law well describes the temperature dependencies of self-diffusion coefficients and viscosity under high pressure. In particular, we find that the entropy-scaling laws, proposed by Rosenfeld [Phys. Rev. A 15, 2545 (1977)] and Dzugutov [Nature (London) 381, 137 (1996)] for self-diffusion coefficients and viscosity in liquid metals under ambient pressure, still hold well for liquid iron under high temperature and high pressure conditions. Using the entropy-scaling laws, we can obtain transport properties from structural properties under high pressure and high temperature conditions. The results provide a useful ingredient in understanding transport properties of planet's cores.

Nanovaccines: An effective therapeutic approach for cancer therapy.

Cancer vaccines hold considerable promise for the immunotherapy of solid tumors. Nanomedicine offers several strategies for enhancing vaccine effectiveness. In particular, molecular or (sub) cellular vaccines can be delivered to the target lymphoid tissues and cells by nanocarriers and nanoplatforms to increase the potency and durability of antitumor immunity and minimize negative side effects. Nanovaccines use nanoparticles (NPs) as carriers and/or adjuvants, offering the advantages of optimal nanoscale size, high stability, ample antigen loading, high immunogenicity, tunable antigen presentation, increased retention in lymph nodes, and immunity promotion. To induce antitumor immunity, cancer vaccines rely on tumor antigens, which are administered in the form of entire cells, peptides, nucleic acids, extracellular vesicles (EVs), or cell membrane-encapsulated NPs. Ideal cancer vaccines stimulate both humoral and cellular immunity while overcoming tumor-induced immune suppression. Herein, we review the key properties of nanovaccines for cancer immunotherapy and highlight the recent advances in their development based on the structure and composition of various (including synthetic and semi (biogenic) nanocarriers. Moreover, we discuss tumor cell-derived vaccines (including those based on whole-tumor-cell components, EVs, cell membrane-encapsulated NPs, and hybrid membrane-coated NPs), nanovaccine action mechanisms, and the challenges of immunocancer therapy and their translation to clinical applications.

Apigenin delays postovulatory oocyte aging by reducing oxidative stress through SIRT1 upregulation.

After ovulation, senescent oocytes inevitably experience reduced quality and defects in embryonic development. Apigenin (API) is a flavonoid with a wide range of pharmacological effects. Therefore, this study examined the protective effects of API on the quality of porcine oocytes during in-vitro ageing and the underlying mechanisms. The results showed that API treatment could reduce the activation rate after aging for 48 h. In addition, API significantly reduced reactive oxygen species, abnormal distribution of mitochondria, early apoptosis in ageing oocytes, increased glutathione, and mitochondrial adenosine triphosphate levels in ageing oocytes. Importantly, API increased the embryonic development rate in aged oocytes. We also examined molecular changes, finding decreased sirtuin 1 expression in in-vitro postovulatory oocytes, but API reversed this effect. Our results suggest that API attenuates the deterioration of oocyte quality during in-vitro ageing, possibly by reducing oxidative stress through the upregulation of sirtuin 1.

Application of a Magnetic Platform in α6 Integrin-Positive iPSC-TM Purification.

The emergence of induced pluripotent stem cell (iPSC) technology has provided a new approach to regenerating decellularized trabecular meshwork (TM) in glaucoma. We have previously generated iPSC-derived TM (iPSC-TM) using a medium conditioned by TM cells and verified its function in tissue regeneration. Because of the heterogeneity of iPSCs and the isolated TM cells, iPSC-TM cells appear to be heterogeneous, which impedes our understanding of how the decellularized TM may be regenerated. Herein, we developed a protocol based on a magnetic-activated cell sorting (MACS) system or an immunopanning (IP) method for sorting integrin subunit alpha 6 (ITGA6)-positive iPSC-TM, an example of the iPSC-TM subpopulation. We first analyzed the purification efficiency of these two approaches by flow cytometry. In addition, we also determined cell viability by analyzing the morphologies of the purified cells. To conclude, the MACS-based purification could yield a higher ratio of ITGA6-positive iPSC-TM and maintain a relatively higher cell viability than the IP-based method, allowing for the preparation of any iPSC-TM subpopulation of interest and facilitating a better understanding of the regenerative mechanism of iPSC-based therapy.

Efficacy and Safety of Mesenchymal Stromal Cells Therapy for COVID-19 Infection: A Systematic Review and Meta-analysis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an infectious respiratory disease prevalent worldwide with a high mortality rate, and there is currently no specific medicine to treat patients. OBJECTIVE: We aimed to assess the safety and efficacy of stem cell therapy for COVID-19 by providing references for subsequent clinical treatments and trials. METHOD: We systematically searched PubMed, Embase, Cochrane, and Web of Science, using the following keywords: "stem cell" or "stromal cell" and "COVID-19." Controlled clinical trials published in English until 24th August 2021 were included. We followed the PRISMA guidelines and used Cochrane Collaboration's tool for assessing the risk of bias. We analysed the data using a fixed-effect model. RESULTS: We identified 1779 studies, out of which eight were eligible and included in this study. Eight relevant studies consisted of 156 patients treated with stem cells and 144 controls (300 individuals in total). There were no SAEs associated with stem cell therapy in all six studies, and no significant differences in AEs (p = 0.09, I2 = 40%, OR = 0.53, 95% CI: 0.26 to 1.09) between the experimental group and control group were observed. Moreover, the meta-analysis found that stem cell therapy effectively reduced the high mortality rate of COVID-19 (14/156 vs. 43/144; p<0.0001, I2 = 0%, OR=0.18, 95% CI: 0.08 to 0.41). CONCLUSION: This study suggests that MSCs therapy for COVID-19 has shown some promising results in safety and efficacy. It effectively reduces the high mortality rate of COVID-19 and does not increase the incidence of adverse events.

TNF-α/IL-1ß-licensed hADSCs alleviate cholestatic liver injury and fibrosis in mice via COX-2/PGE2 pathway.

BACKGROUND: Adipose tissue-derived stem cell (ADSC) transplantation has been shown to be effective for the management of severe liver disorders. Preactivation of ADSCs enhanced their therapeutic efficacy. However, these effects have not yet been examined in relation to cholestatic liver injury. METHODS: In the present study, a cholestatic liver injury model was established by bile duct ligation (BDL) in male C57BL/6 mice. Human ADSCs (hADSCs) with or without tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1ß) pretreatment were administrated into the mice via tail vein injections. The efficacy of hADSCs on BDL-induced liver injury was assessed by histological staining, real-time quantitative PCR (RT-qPCR), Western blot, and enzyme-linked immune sorbent assay (ELISA). In vitro, the effects of hADSC conditioned medium on the activation of hepatic stellate cells (HSCs) were investigated. Small interfering RNA (siRNA) was used to knock down cyclooxygenase-2 (COX-2) in hADSCs. RESULTS: TNF-α/IL-1ß preconditioning could downregulate immunogenic gene expression and enhance the engraftment efficiency of hADSCs. Compared to control hADSCs (C-hADSCs), TNF-α/IL-1ß-pretreated hADSCs (P-hADSCs) significantly alleviated BDL-induced liver injury, as demonstrated by reduced hepatic cell death, attenuated infiltration of Ly6G + neutrophils, and decreased expression of pro-inflammatory cytokines TNF-α, IL-1ß, C-X-C motif chemokine ligand 1 (CXCL1), and C-X-C motif chemokine ligand 2 (CXCL2). Moreover, P-hADSCs significantly delayed the development of BDL-induced liver fibrosis. In vitro, conditioned medium from P-hADSCs significantly inhibited HSC activation compared to that from C-hADSCs. Mechanistically, TNF-α/IL-1ß upregulated COX-2 expression and increased prostaglandin E2 (PGE2) secretion. The blockage of COX-2 by siRNA transfection reversed the benefits of P-hADSCs for PGE2 production, HSC activation, and liver fibrosis progression. CONCLUSION: In conclusion, our results suggest that TNF-α/IL-1ß pretreatment enhances the efficacy of hADSCs in mice with cholestatic liver injury, partially through the COX-2/PGE2 pathway.

Customized liver organoids as an advanced in vitro modeling and drug discovery platform for non-alcoholic fatty liver diseases.

Non-alcoholic fatty liver disease (NAFLD) and its progressive form non-alcoholic steatohepatitis (NASH) have presented a major and common health concern worldwide due to their increasing prevalence and progressive development of severe pathological conditions such as cirrhosis and liver cancer. Although a large number of drug candidates for the treatment of NASH have entered clinical trial testing, all have not been released to market due to their limited efficacy, and there remains no approved treatment for NASH available to this day. Recently, organoid technology that produces 3D multicellular aggregates with a liver tissue-like cytoarchitecture and improved functionality has been suggested as a novel platform for modeling the human-specific complex pathophysiology of NAFLD and NASH. In this review, we describe the cellular crosstalk between each cellular compartment in the liver during the pathogenesis of NAFLD and NASH. We also summarize the current state of liver organoid technology, describing the cellular diversity that could be recapitulated in liver organoids and proposing a future direction for liver organoid technology as an in vitro platform for disease modeling and drug discovery for NAFLD and NASH.