Angiotensin-converting enzyme 2 alleviates liver fibrosis through the renin-angiotensin system.

The present letter to the editor is related to the study titled 'Angiotensin-converting enzyme 2 improves liver fibrosis in mice by regulating autophagy of hepatic stellate cells'. Angiotensin-converting enzyme 2 can alleviate liver fibrosis by regulating autophagy of hepatic stellate cells and affecting the renin-angiotensin system.

Proinflammatory phenotype of B10 and B10pro cells elicited by TNF-α in rheumatoid arthritis.

OBJECTIVES: B10 and B10pro cells suppress immune responses via secreting interleukin (IL)-10. However, their regulators and underlying mechanisms, especially in human autoimmune diseases, are elusive. This study aimed to address these questions in rheumatoid arthritis (RA), one of the most common highly disabling autoimmune diseases. METHODS: The frequencies and functions of B10 and B10pro cells in healthy individuals and patients with RA were first analysed. The effects of proinflammatory cytokines, particularly tumour necrosis factor (TNF)-α on the quantity, stability and pathogenic phenotype of these cells, were then assessed in patients with RA before and after anti-TNF therapy. The underlying mechanisms were further investigated by scRNA-seq database reanalysis, transcriptome sequencing, TNF-α-/- and B cell-specific SHIP-1-/- mouse disease model studies. RESULTS: TNF-α was a key determinant for B10 cells. TNF-α elicited the proinflammatory feature of B10 and B10pro cells by downregulating IL-10, and upregulating interferon-γ and IL-17A. In patients with RA, B10 and B10pro cells were impaired with exacerbated proinflammatory phenotype, while anti-TNF therapy potently restored their frequencies and immunosuppressive functions, consistent with the increased B10 cells in TNF-α-/- mice. Mechanistically, TNF-α diminished B10 and B10pro cells by inhibiting their glycolysis and proliferation. TNF-α also regulated the phosphatidylinositol phosphate signalling of B10 and B10pro cells and dampened the expression of SHIP-1, a dominant phosphatidylinositol phosphatase regulator of these cells. CONCLUSIONS: TNF-α provoked the proinflammatory phenotype of B10 and B10pro cells by disturbing SHIP-1 in RA, contributing to the disease development. Reinstating the immunosuppressive property of B10 and B10pro cells might represent novel therapeutic approaches for RA.

Robust scoring of selective drug responses for patient-tailored therapy selection.

Most patients with advanced malignancies are treated with severely toxic, first-line chemotherapies. Personalized treatment strategies have led to improved patient outcomes and could replace one-size-fits-all therapies, yet they need to be tailored by testing of a range of targeted drugs in primary patient cells. Most functional precision medicine studies use simple drug-response metrics, which cannot quantify the selective effects of drugs (i.e., the differential responses of cancer cells and normal cells). We developed a computational method for selective drug-sensitivity scoring (DSS), which enables normalization of the individual patient's responses against normal cell responses. The selective response scoring uses the inhibition of noncancerous cells as a proxy for potential drug toxicity, which can in turn be used to identify effective and safer treatment options. Here, we explain how to apply the selective DSS calculation for guiding precision medicine in patients with leukemia treated across three cancer centers in Europe and the USA; the generic methods are also widely applicable to other malignancies that are amenable to drug testing. The open-source and extendable R-codes provide a robust means to tailor personalized treatment strategies on the basis of increasingly available ex vivo drug-testing data from patients in real-world and clinical trial settings. We also make available drug-response profiles to 527 anticancer compounds tested in 10 healthy bone marrow samples as reference data for selective scoring and de-prioritization of drugs that show broadly toxic effects. The procedure takes <60 min and requires basic skills in R.

Chronic exposure to nanocellulose altered depression-related behaviors in mice on a western diet: The role of immune modulation and the gut microbiome.

AIMS: To determine if cellulose nanofibrils (CNF) have potential applications as food additives. MATERIALS AND METHODS: Male C57BL/6 mice on a Western diet were exposed to CNF for one month at a dose of 30 mg/kg by gavage. Male NOD mice, a model for type 1 diabetes (T1D), were used in a six-month study. KEY FINDINGS: Sequencing analysis of 16S rRNA genes suggested significant changes in gut microbiome of male C57BL/6 mice exposed to CNF. Analysis of functional metagenomics indicated that many of the functional contents that might be altered following CNF ingestion were associated with lipid and carbohydrate processing. Further studies in NOD mice suggested that there were some decreases in the blood glucose levels during the insulin tolerance test and glucose tolerance test following CNF treatment. However, these small decreases were not considered biologically meaningful as there were no significant changes in either the area under the curve or the first-order rate constant for glucose disappearance. Moreover, serum concentrations of cytokines/chemokines including IL-3, IL-12(p70) and the keratinocyte chemoattractant were increased following chronic exposure to CNF. In addition, behavioral studies suggested that the percentage of immobility time during the tail-suspension test was significantly increased following six months of exposure to CNF in NOD mice, signifying an increase in depression-related behavior. SIGNIFICANCE: Collectively, long-term CNF consumption was associated with changes in the ecology of the gut microbiome, immune homeostasis, and possibly energy metabolism and mental health in male NOD mice on a Western diet.

Repurposed Fenoprofen Targeting SaeR Attenuates Staphylococcus aureus Virulence in Implant-Associated Infections.

Implant-associated infections (IAIs) caused by S. aureus can result in serious challenges after orthopedic surgery. Due to biofilm formation and antibiotic resistance, this refractory infection is highly prevalent, and finding drugs to attenuate bacterial virulence is becoming a rational alternative strategy. In S. aureus, the SaeRS two-component system (TCS) plays a key role in the production of over 20 virulence factors and the pathogenesis of the bacterium. Here, by conducting a structure-based virtual screening against SaeR, we identified that fenoprofen, a USA Food and Drug Administration (FDA)-approved nonsteroid anti-inflammatory drug (NSAID), had excellent inhibitory potency against the response regulator SaeR protein. We showed that fenoprofen attenuated the virulence of S. aureus without drug resistance. In addition, it was helpful in relieving osteolysis and restoring the walking ability of mice in vitro and in implant-associated infection models. More importantly, fenoprofen treatment suppressed biofilm formation and changed the biofilm structure, which caused S. aureus to form loose and porous biofilms that were more vulnerable to infiltration and elimination by leukocytes. Our results reveal that fenoprofen is a potent antivirulence agent with potential value in clinical applications and that SaeR is a drug target against S. aureus implant-associated infections.

Can financial development improve environmental quality? New findings from spatial measures of Chinese urban panel data.

China's economy has achieved remarkable success, while it has also paid a high environmental cost. Environmental pollution not only causes great economic losses, but also severely restricts the development of society. Both theory and practice demonstrate that financial development plays a significant role in environmental governance, but the internal mechanism of its impacts has remained to be explored. It is vital to investigate the influence mechanism of financial development on the environmental quality in order to accomplish sustainable economic development through finance and enhance environmental quality concurrently. This paper, using mediating model, spatial Durbin and spatial error model, constructs a theoretical framework financial development on environmental quality from two dimensions, i.e., Financial Interrelations Ratio (FIR) and Financial Efficiency (FE), based on panel data of 234 cities in China from 2010 to 2019. And the results are as follows: (1) the improvement of Financial Interrelations Ratio (FIR) and Financial Efficiency (FE) had not yet reached the level of environmental pollution improvement; (2) in terms of mechanism, the rise of the level of financial development promoted economic growth, but inhibited the optimization of industrial structure, which increased industrial pollution emissions and deteriorates environmental quality; (3) urban environment had significant spatial dependence; (4) the impact of financial development on environmental quality in eastern region has been transformed into an improvement effect, while it still shows a deteriorating effect in central and western regions. Some policy recommendations related to the use of financial development to improve environmental quality are proposed at last, which will help to promote ecological protection and high quality synergistic economic development in China.

Advancing drug development in pediatric oncology, a focus on cancer biology and targeted therapies: iMATRIX platform.

With the development of novel treatment therapies as well as evolving and innovative approaches to conduct clinical trials, the landscape of pediatric oncology drug development has dramatically changed in recent years. Despite this change, approvals for new drugs and labeling updates to ensure availability of proper treatment for pediatric patients with cancer remain slow. The context of drug development in pediatric tumors has also changed with regulatory initiatives in the US and Europe, creating a great need for faster development of novel drugs. Today, conventional study designs have been replaced or complemented by novel clinical trial designs, such as master protocols and platform trials, to optimize cancer drug development and enable faster regulatory approval. The iMATRIX platform is a mechanism-of-action (MOA)-based phase 1/2 trial framework for concurrently studying multiple molecules across a range of relevant pediatric tumor types, taking into account the biology of each pediatric tumor type. Six studies have been conducted, ongoing, or planned on the iMATRIX platform - investigating atezolizumab, cobimetinib, entrectinib, idasanutlin, alectinib, and glofitamab. A brief overview of study designs and characteristics are shared in this article, along with learnings from them.

Six weeks effect of different nanocellulose on blood lipid level and small intestinal morphology in mice.

AIMS: Cellulose nanofibrils (CNF, or NFC), cellulose nanocrystals (CNC, or NCC), and Tempo (2,2,6,6-tetramethylpiperidine-1-oxyl radical) oxidized CNF (Tempo-CNF) were compared for the short-term effect on mice fed with a high-fat and high-sugar (Western diet, WD) to investigate their effect when combined with a sub-optimal diet. SCOPE: Thirty C57B/C female mice (10 weeks old; 5-6 mice/group) were given water, cellulose, or three types of nanocellulose once daily in a dose of 30 mg/kg body weight by oral gavage. After six weeks, weight changes, fecal output, glucose homeostasis, and gut permeability showed no significant among groups. Serum analysis including triglycerides, cholesterol and total bile acids and small intestinal morphology including villus length, villus width, crypt depth, goblet cell count and goblet cell density were no difference for all groups. Only CNC group had higher excretion of bile acids in the feces. CONCLUSIONS: These results suggest that current treated dose using three types of nanocellulose had no detrimental effects on blood lipid level and small intestinal morphology.

Multi-omics profiling visualizes dynamics of cardiac development and functions.

Cardiogenesis is a tightly regulated dynamic process through a continuum of differentiation and proliferation events. Key factors and pathways governing this process remain incompletely understood. Here, we investigate mice hearts from embryonic day 10.5 to postnatal week 8 and dissect developmental changes in phosphoproteome-, proteome-, metabolome-, and transcriptome-encompassing cardiogenesis and cardiac maturation. We identify mitogen-activated protein kinases as core kinases involved in transcriptional regulation by mediating the phosphorylation of chromatin remodeling proteins during early cardiogenesis. We construct the reciprocal regulatory network of transcription factors (TFs) and identify a series of TFs controlling early cardiogenesis involved in cycling-dependent proliferation. After birth, we identify cardiac resident macrophages with high arachidonic acid metabolism activities likely involved in the clearance of injured apoptotic cardiomyocytes. Together, our comprehensive multi-omics data offer a panoramic view of cardiac development and maturation that provides a resource for further in-depth functional exploration.

Systematic review of computational methods for drug combination prediction.

Synergistic effects between drugs are rare and highly context-dependent and patient-specific. Hence, there is a need to develop novel approaches to stratify patients for optimal therapy regimens, especially in the context of personalized design of combinatorial treatments. Computational methods enable systematic in-silico screening of combination effects, and can thereby prioritize most potent combinations for further testing, among the massive number of potential combinations. To help researchers to choose a prediction method that best fits for various real-world applications, we carried out a systematic literature review of 117 computational methods developed to date for drug combination prediction, and classified the methods in terms of their combination prediction tasks and input data requirements. Most current methods focus on prediction or classification of combination synergy, and only a few methods consider the efficacy and potential toxicity of the combinations, which are the key determinants of therapeutic success of drug treatments. Furthermore, there is a need to further develop methods that enable dose-specific predictions of combination effects across multiple doses, which is important for clinical translation of the predictions, as well as model-based identification of biomarkers predictive of heterogeneous drug combination responses. Even if most of the computational methods reviewed focus on anticancer applications, many of the modelling approaches are also applicable to antiviral and other diseases or indications.

Dietary advanced glycation end-products elicit toxicological effects by disrupting gut microbiome and immune homeostasis.

The aging immune system is characterized by a low-grade chronic systemic inflammatory state ("inflammaging") marked by elevated serum levels of inflammatory molecules such as interleukin (IL)-6 and C-reactive protein (CRP). These inflammatory markers were also reported to be strong predictors for the development/severity of Type 2 diabetes, obesity, and COVID-19. The levels of these markers have been positively associated with those of advanced glycation end-products (AGEs) generated via non-enzymatic glycation and oxidation of proteins and lipids during normal aging and metabolism. Based on the above observations, it is clinically important to elucidate how dietary AGEs modulate inflammation and might thus increase the risk for aging-exacerbated diseases. The present narrative review discusses the potential pro-inflammatory properties of dietary AGEs with a focus on the inflammatory mediators CRP, IL-6 and ferritin, and their relations to aging in general and Type 2 diabetes in particular. In addition, underlying mechanisms - including those related to gut microbiota and the receptors for AGEs, and the roles AGEs might play in affecting physiologies of the healthy elderly, obese individuals, and diabetics are discussed in regard to any greater susceptibility to COVID-19.

The direct health care cost to Medicare of Down syndrome dementia as compared with Alzheimer's disease among 2015 Californian beneficiaries.

BACKGROUND: Aging individuals with Down syndrome (DS) are at increased risk of dementia due to trisomy of chromosome 21 on which the amyloid precursor protein gene is located and with increased life expectancy. Yet, little is known about the costs associated with DS dementia and how this compares to Alzheimer's disease (AD). OBJECTIVE: To better understand direct healthcare costs and care consumption in DS dementia, we compared the total cost of care to US Medicare and the drivers of these medical expenditures in individuals with DS with and without dementia, and in those with AD without DS. METHODS: The effect of dementia in DS on costs and care utilization was estimated with 2015 California Medicare fee-for-service data (parts A and B). Among 3,001,977 Californian Medicare beneficiaries, 353 individuals had DS with dementia (age 45-89 years). We compared their number of chronic comorbidity conditions among 27 and their care and Medicare costs to those of age- and sex-matched individuals with DS without dementia and those with AD without DS. RESULTS: Medicare annual cost per beneficiary was a mean of 43.5% and 82.2% higher with DS dementia (mean $35,011) than DS without dementia (mean $24,401) and AD without dementia (mean $19,212), related to greater utilization of inpatient services. DS dementia was associated with increased level of multimorbidity (mean of 3.4 conditions in addition to dementia vs. 2.7 and 2.2 conditions for DS without dementia and AD, respectively), with more emergency room visits (88% vs. 76.5% and 54.4%) and with more primary care physician visits (91.2% vs. 87.3% and 81.3%). CONCLUSION: DS adults with dementia have higher health care costs than DS adults without dementia and adults with AD. Understanding costs and complex health care needs in DS dementia could facilitate management of adult and geriatric care resources for these high-need high-cost individuals.

DrugSpaceX: a large screenable and synthetically tractable database extending drug space.

One of the most prominent topics in drug discovery is efficient exploration of the vast drug-like chemical space to find synthesizable and novel chemical structures with desired biological properties. To address this challenge, we created the DrugSpaceX (https://drugspacex.simm.ac.cn/) database based on expert-defined transformations of approved drug molecules. The current version of DrugSpaceX contains >100 million transformed chemical products for virtual screening, with outstanding characteristics in terms of structural novelty, diversity and large three-dimensional chemical space coverage. To illustrate its practical application in drug discovery, we used a case study of discoidin domain receptor 1 (DDR1), a kinase target implicated in fibrosis and other diseases, to show DrugSpaceX performing a quick search of initial hit compounds. Additionally, for ligand identification and optimization purposes, DrugSpaceX also provides several subsets for download, including a 10% diversity subset, an extended drug-like subset, a drug-like subset, a lead-like subset, and a fragment-like subset. In addition to chemical properties and transformation instructions, DrugSpaceX can locate the position of transformation, which will enable medicinal chemists to easily integrate strategy planning and protection design.

Gut microbiome in neuroendocrine and neuroimmune interactions: The case of genistein.

The healthy and diverse microbes living in our gut provide numerous benefits to our health. It is increasingly recognized that the gut microbiome affects the host's neurobehavioral state through production of metabolites, modulation of intestinal immunity (e.g., cytokines) and other mechanisms (e.g., gut neuropeptides). By sending the sensed information (e.g., metabolic and immunologic mediators) about the state of the inner organs to the brain via afferent fibers, the vagus nerve maintains one of the connections between the brain and GI tract, and oversees many critical bodily functions (e.g., mood, immune response, digestion and heart rate). The microbiota-gut-brain axis is a bidirectional communication between the gut, its microbiome, and the nervous system. In the present review, the roles of microbiome in neuroendocrine and neuroimmune interactions have been discussed using naturally occurring isoflavones, particularly the phytoestrogen genistein, as there are sex differences in the interactions among the microbiome, hormones, immunity and disease susceptibility. A deep understanding of the mechanisms underlying the interactions among the endocrine modulators, brain, endocrine glands, gut immune cells, vagus nerve, enteric nervous system and gut microbiome will provide important knowledges that may ultimately lead to treatment and prevention of debilitating disorders characterized by deficits of microbiome-neuroendocrine-neuroimmune relationships.

Revisiting Aldehyde Oxidase Mediated Metabolism in Drug-like Molecules: An Improved Computational Model.

Aldehyde oxidase (AOX) is a drug metabolizing molybdo-flavoenzyme that has gained increasing attention because of contribution to the biotransformation in phase I metabolism of xenobiotics. Unfortunately, the intra- and interspecies variations in AOX activity and lack of reliable and predictive animal models make evaluation of AOX-catalyzed metabolism prone to be misleading. In this study, we developed an improved computational model integrating both atom-level and molecule-level features to predict whether a drug-like molecule is a potential human AOX (hAOX) substrate and to identify the corresponding sites of metabolism. Additionally, we combined the proposed computational strategy and in vitro experiments for evaluating the metabolic property of a series of epigenetic-related drug candidates still in the early stage of development. In summary, this study provides an improved strategy to evaluate the liability of molecules toward hAOX and offers useful information for accelerating the drug design and optimization stage.

Chronic oral exposure to glycated whey proteins increases survival of aged male NOD mice with autoimmune prostatitis by regulating the gut microbiome and anti-inflammatory responses.

Glycated whey proteins have been shown to be protective against type 1 diabetes in our previous studies, suggesting their potential application as medical food. To determine if the protection could be extended to other autoimmune diseases, aged male non-obese diabetic (NOD) mice that develop a wide spectrum of autoimmune pathologies, including spontaneous autoimmune prostatitis, were used. After a 6-month oral exposure to whey protein-derived early glycation products (EGPs), EGP-treated NOD mice had an increased survival rate, decreased macrophage infiltration in the anterior lobe and decreased inflammation in the prostate when compared to the mice that received non-reacted controls. The systemic immunity was regulated towards anti-inflammation, evidenced by an increase in serum IL-10 level and decreases in total splenocytes, splenic M1 macrophages, CD4+ T cells, CD8+ T cells and B cells. Consistent with an overall anti-inflammatory status, the gut microbiome was altered in abundance but not diversity, with increased Allobaculum, Anaerostipes, Bacteroides, Parabacteroides and Prevotella and decreased Adlercreutzia and Roseburia at the genus level. Moreover, increased Bacteroides acidifaciens correlated with most of the immune parameters measured. Collectively, chronic oral exposure to EGPs produced an anti-inflammatory effect in aged male NOD mice, which might contribute to the protective effects against spontaneous autoimmune prostatitis and/or other organ specific autoimmune diseases.

Subchronic exposure to cellulose nanofibrils induces nutritional risk by non-specifically reducing the intestinal absorption.

Previous studies of cellulose nanofibrils (CNF) in decreasing fat absorption and glucose release suggested their potential application as food additives or supplements in diets containing high contents of fat and sugars. However, the long-term effects of CNF uptake remained unknown. The purpose of this study was to determine the effects of subchronic oral CNF consumption on various health aspects of Western diets (WD)-fed mice. The results demonstrated that CNF decreased fat absorption in the jejunum and attenuated WD-induced fatty liver, but slightly decreased lean body mass and affected glucose homeostasis. Additional in vivo studies showed that CNF decreased the intestinal absorption. The in vitro studies suggested that CNF did not decrease the viability of any cells used; however, they prevented epithelial and T cells, but not macrophages, from accessing the viability dye. Taken together, CNF decreased the intestinal absorption non-specifically, which might lead to nutritional risks after long-term exposure.

Glycated Whey Proteins Protect NOD Mice against Type 1 Diabetes by Increasing Anti-Inflammatory Responses and Decreasing Autoreactivity to Self-Antigens.

Our previous studies suggested that early glycation products (EGPs) generated in the first step of Maillard reaction/glycation were anti-inflammatory. The objectives of the present study were to determine the effects of EGPs derived from the whey protein isolate-glucose system on type 1 diabetes (T1D), and the underlying immunological mechanisms. In non-obese diabetic (NOD) mice, EGPs at the physiological dose of 600 mg/kg/day increased glucose metabolism, decreased non-fasting blood glucose levels and T1D incidence, decreased insulin resistance, and decreased the pancreatic immune infiltration. The protective effects were accompanied with decreases in CD4-CD8+ thymocytes, CD8+ T cells and serum insulin autoantibody levels, and increases in splenic CD4+CD25+ T cells, macrophage M2/M1 ratio and serum IL-10 level. However, similar treatment with EGPs produced minimal effect on the multiple low-dose streptozotocin-induced hyperglycemia. In conclusion, EGPs protected NOD mice against T1D via increasing anti-inflammatory immune responses and decreasing autoreactivity to self-antigens.

The costs of dementia subtypes to California Medicare fee-for-service, 2015.

INTRODUCTION: Dementia is among the costliest of medical conditions, but it is not known how these costs vary by dementia subtype. METHODS: The effect of dementia diagnosis subtype on direct health care costs and utilization was estimated using 2015 California Medicare fee-for-service data. Potential drivers of increased costs in Lewy body dementia (LBD), in comparison to Alzheimer's disease, were tested. RESULTS: 3,001,987 Medicare beneficiaries were identified, of which 8.2% had a dementia diagnosis. Unspecified dementia was the most common diagnostic category (59.6%), followed by Alzheimer's disease (23.2%). LBD was the costliest subtype to Medicare, on average, followed by vascular dementia. The higher costs in LBD were explained in part by falls, urinary incontinence or infection, depression, anxiety, dehydration, and delirium. DISCUSSION: Dementia subtype is an important predictor of health care costs. Earlier identification and targeted treatment might mitigate the costs associated with co-occurring conditions in LBD.

Dietary Early Glycation Products Promote the Growth of Prostate Tumors More than Advanced Glycation End-Products through Modulation of Macrophage Polarization.

SCOPE: Glycation products are ubiquitous in food at high concentrations in the Western diet. The well-controlled glycation resulting in the production of early glycation products (EGPs) has been proposed as a strategy to improve the physicochemical properties of food proteins. However, the health effects of EGPs are unknown. It has been shown that the Western diet (glycation prone) is associated with a higher mortality in prostate cancer (PCa) patients than the prudent diet; therefore, the role of EGPs in prostate tumorigenesis is investigated. METHODS AND RESULTS: C57BL/6 male mice are treated with the vehicle (water), non-reacted samples, EGPs, and advanced glycation end-products (AGEs) by gavage. EGPs (600 mg kg-1 body weight per day) promoted the growth of subcutaneously transplanted TRAMP-C2 PCa cells the most among these groups. Significantly, increases in the circulation monocytes and tumor-associated M2 macrophages are observed in EGP-treated mice, and the M2/M1 ratio is also increased in the EGP group when compared to that of water and AGEs. In the human PCa cell and macrophage co-cultures, EGPs increase the spheroid size, and importantly, macrophages are also polarized toward M2. CONCLUSIONS: EGPs induce the proliferation of PCa cells either directly or by assisting PCa cells to polarize macrophages toward M2.