Global trends in diabetic eye disease research from 2012 to 2021.

JOURNAL/nrgr/04.03/01300535-202410000-00032/figure1/v/2024-02-06T055622Z/r/image-tiff Diabetic eye disease refers to a group of eye complications that occur in diabetic patients and include diabetic retinopathy, diabetic macular edema, diabetic cataracts, and diabetic glaucoma. However, the global epidemiology of these conditions has not been well characterized. In this study, we collected information on diabetic eye disease-related research grants from seven representative countries--the United States, China, Japan, the United Kingdom, Spain, Germany, and France--by searching for all global diabetic eye disease journal articles in the Web of Science and PubMed databases, all global registered clinical trials in the ClinicalTrials database, and new drugs approved by the United States, China, Japan, and EU agencies from 2012 to 2021. During this time period, diabetic retinopathy accounted for the vast majority (89.53%) of the 2288 government research grants that were funded to investigate diabetic eye disease, followed by diabetic macular edema (9.27%). The United States granted the most research funding for diabetic eye disease out of the seven countries assessed. The research objectives of grants focusing on diabetic retinopathy and diabetic macular edema differed by country. Additionally, the United States was dominant in terms of research output, publishing 17.53% of global papers about diabetic eye disease and receiving 22.58% of total citations. The United States and the United Kingdom led international collaborations in research into diabetic eye disease. Of the 415 clinical trials that we identified, diabetic macular edema was the major disease that was targeted for drug development (58.19%). Approximately half of the trials (49.13%) pertained to angiogenesis. However, few drugs were approved for ophthalmic (40 out of 1830; 2.19%) and diabetic eye disease (3 out of 1830; 0.02%) applications. Our findings show that basic and translational research related to diabetic eye disease in the past decade has not been highly active, and has yielded few new treatment methods and newly approved drugs.

Invigorating human MSCs for transplantation therapy via Nrf2/DKK1 co-stimulation in an acute-on-chronic liver failure mouse model.

Background: Since boosting stem cell resilience in stressful environments is critical for the therapeutic efficacy of stem cell-based transplantations in liver disease, this study aimed to establish the efficacy of a transient plasmid-based preconditioning strategy for boosting the capability of mesenchymal stromal cells (MSCs) for anti-inflammation/antioxidant defenses and paracrine actions in recipient hepatocytes. Methods: Human adipose mesenchymal stem cells (hADMSCs) were subjected to transfer, either with or without the nuclear factor erythroid 2-related factor 2 (Nrf2)/Dickkopf1 (DKK1) genes, followed by exposure to TNF-α/H2O2. Mouse models were subjected to acute chronic liver failure (ACLF) and subsequently injected with either transfected or untransfected MSCs. These hADMSCs and ACLF mouse models were used to investigate the interaction between Nrf2/DKK1 and the hepatocyte receptor cytoskeleton-associated protein 4 (CKAP4). Results: Activation of Nrf2 and DKK1 enhanced the anti-stress capacity of MSCs in vitro. In a murine model of ACLF, transient co-overexpression of Nrf2 and DKK1 via plasmid transfection improved MSC resilience against inflammatory and oxidative assaults, boosted MSC transplantation efficacy, and promoted recipient liver regeneration due to a shift from the activation of the anti-regenerative IFN-γ/STAT1 pathway to the pro-regenerative IL-6/STAT3 pathway in the liver. Importantly, the therapeutic benefits of MSC transplantation were nullified when the receptor CKAP4, which interacts with DKK1, was specifically removed from recipient hepatocytes. However, the removal of the another receptor low-density lipoprotein receptor-related protein 6 (LRP6) had no impact on the effectiveness of MSC transplantation. Moreover, in long-term observations, no tumorigenicity was detected in mice following transplantation of transiently preconditioned MSCs. Conclusions: Co-stimulation with Nrf2/DKK1 safely improved the efficacy of human MSC-based therapies in murine models of ACLF through CKAP4-dependent paracrine mechanisms.

ROS/RNS as molecular signatures of chronic liver diseases.

The liver can succumb to oxidant damage during the development of chronic liver diseases. Despite their physiological relevance to hepatic homeostasis, excessive reactive oxygen/nitrogen species (ROS/RNS) production under pathological conditions is detrimental to all liver constituents. Chronic oxidative stress coupled to unresolved inflammation sets in motion the activation of profibrogenic hepatic stellate cells (HSCs) and later pathogenesis of liver fibrosis, cirrhosis, and liver cancer. The liver antioxidant and repair systems, along with autophagic and ferroptotic machineries, are implicated in the onset and trajectory of disease development. In this review, we discuss the ROS/RNS-related mechanisms underlying liver fibrosis of distinct etiologies and highlight preclinical and clinical trials of antifibrotic therapies premised on remediating oxidative/nitrosative stress in hepatocytes or targeting HSC activation.

Hepatic COX1 loss leads to impaired autophagic flux and exacerbates nonalcoholic steatohepatitis.

The mechanisms underlying autophagic defects in nonalcoholic steatohepatitis (NASH) remain largely unknown. We aimed to elucidate the roles of hepatic cyclooxygenase 1 (COX1) in autophagy and the pathogenesis of diet-induced steatohepatitis in mice. Human nonalcoholic fatty liver disease (NAFLD) liver samples were used to examine the protein expression of COX1 and the level of autophagy. Cox1Δhepa mice and their wildtype littermates were generated and fed with 3 different NASH models. We found that hepatic COX1 expression was increased in patients with NASH and diet-induced NASH mice models accompanied by impaired autophagy. COX1 was required for basal autophagy in hepatocytes and liver specific COX1 deletion exacerbated steatohepatitis by inhibiting autophagy. Mechanistically, COX1 directly interacted with WD repeat domain, phosphoinositide interacting 2 (WIPI2), which was crucial for autophagosome maturation. Adeno-associated virus (AAV)-mediated rescue of WIPI2 reversed the impaired autophagic flux and improved NASH phenotypes in Cox1Δhepa mice, indicating that COX1 deletion-mediated steatohepatitis was partially dependent on WIPI2-mediated autophagy. In conclusion, we demonstrated a novel role of COX1 in hepatic autophagy that protected against NASH by interacting with WIPI2. Targeting the COX1-WIPI2 axis may be a novel therapeutic strategy for NASH.

Melatonin alleviates alcoholic liver disease via EGFR-BRG1-TERT axis regulation.

Chronic alcohol consumption causes liver steatosis, cell death, and inflammation. Melatonin (MLT) is reported to alleviate alcoholic liver disease (ALD)-induced injury. However, its direct regulating targets in hepatocytes are not fully understood. In the current study, a cell-based screening model and a chronic ethanol-fed mice ALD model were used to test the protective mechanisms of MLT. MLT ameliorated ethanol-induced hepatocyte injury in both cell and animal models (optimal doses of 10 µmol/L and 5 mg/kg, respectively), including lowered liver steatosis, cell death, and inflammation. RNA-seq analysis and loss-of-function studies in AML-12 cells revealed that telomerase reverse transcriptase (TERT) was a key downstream effector of MLT. Biophysical assay found that epidermal growth factor receptor (EGFR) on the hepatocyte surface was a direct binding and regulating target of MLT. Liver specific knock-down of Tert or Egfr in the ALD mice model impaired MLT-mediated liver protection, partly through the regulation of nuclear brahma-related gene-1 (BRG1). Long-term administration (90 days) of MLT in healthy mice did not cause evident adverse effect. In conclusion, MLT is an efficacious and safe agent for ALD alleviation. Its direct regulating target in hepatocytes is EGFR and downstream BRG1-TERT axis. MLT might be used as a complimentary agent for alcoholics.

The Hepatoprotective and Hepatotoxic Roles of Sex and Sex-Related Hormones.

Most liver diseases, including acute liver injury, drug-induced liver injury, viral hepatitis, metabolic liver diseases, and end-stage liver diseases, are strongly linked with hormonal influences. Thus, delineating the clinical manifestation and underlying mechanisms of the "sexual dimorphism" is critical for providing hints for the prevention, management, and treatment of those diseases. Whether the sex hormones (androgen, estrogen, and progesterone) and sex-related hormones (gonadotrophin-releasing hormone, luteinizing hormone, follicle-stimulating hormone, and prolactin) play protective or toxic roles in the liver depends on the biological sex, disease stage, precipitating factor, and even the psychiatric status. Lifestyle factors, such as obesity, alcohol drinking, and smoking, also drastically affect the involving mechanisms of those hormones in liver diseases. Hormones deliver their hepatic regulatory signals primarily via classical and non-classical receptors in different liver cell types. Exogenous sex/sex-related hormone therapy may serve as a novel strategy for metabolic liver disease, cirrhosis, and liver cancer. However, the undesired hormone-induced liver injury should be carefully studied in pre-clinical models and monitored in clinical applications. This issue is particularly important for menopause females with hormone replacement therapy (HRT) and transgender populations who want to receive gender-affirming hormone therapy (GAHT). In conclusion, basic and clinical studies are warranted to depict the detailed hepatoprotective and hepatotoxic mechanisms of sex/sex-related hormones in liver disease. Prolactin holds a promising perspective in treating metabolic and advanced liver diseases.

Sex bias in alcohol research: A 20-year comparative study.

We aimed to assess the sex-inclusive and sex-based analysis bias in alcohol research for the past 20 years. Data were abstracted from 2988 original research articles published from 2000 through 2019 in 51 representative journals across 9 biomedical disciplines. An analysis in 5-year intervals revealed that the percentage of studies using participants of both sexes was significantly higher between 2015 and 2019 than between 2000 and 2014. When stratified, clinical studies showed a higher percentage of both-sex studies compared to basic studies using animals. The reasons for the use of single-sex cohorts mainly included insufficient participant numbers and misconceptions surrounding the hormonal variability of females. Implementation of the NIH SABV policy promoted the ratio of NIH-funded papers with sex-based analyses. In conclusion, sex bias in alcohol-related biomedical studies has improved over the past 20 years, particularly after the implementation of the SABV policy. Although clinical studies increasingly included sex-based analysis, basic studies were biased towards the use of males.