Corruption of coronary collateral growth in metabolic syndrome: Role of oxidative stress

The myocardium adapts to ischemic insults in a variety of ways.One adaptation is the phenomenon of acute preconditioning,which can greatly ameliorate ischemic damage.However,this effect wanes within a few hours and does not confer chronic protection.A more chronic adaptation is the so-called second window of preconditioning,which enables protection for a few days.The most potent adaptation invoked by the myocardium to minimize the effects of ischemia is the growth of blood vessels in the heart,angiogenesis and arteriogenesis (collateral growth),which prevent the development of ischemia by enabling flow to a jeopardized region of the heart.This brief review examines the mechanisms underlying angiogenesis and arteriogenesis in the heart.The concept of a redox window,which is an optimal redox state for vascular growth,is discussed along with signaling mechanisms invoked by reactive oxygen species that are stimulated during ischemia-reperfusion.Finally,the review discusses of some of the pathologies,especially the metabolic syndrome,that negatively affect collateral growth through the corruption of redox signaling processes.

Reversing multiple age-related pathologies by controlling the senescence-associated secretory phenotype of stem cells

Regenerative medicine by cell transplantation is a novel therapy for treating end-stage organ failure and tissue damage. Cell-based therapy based on the transplantation of neural stem/progenitor cells （NSPCs） represents an attractive strategy for the treatment of neurodegenerative diseases, but obtaining large numbers of these cells is difficult and their differentiation potential is strictly restricted in a spatiotemporally-regulated manner during central nervous system （CNS） development. Therefore, embryonic stem cells and induced pluripotent stem cells represent an attractive alternative for cell-transplantation therapy in regenerative medicine.

Familial pancreatic cancer: Concept, management and issues

Familial pancreatic cancer (FPC) is broadly defined as two first-degree-relatives with pancreatic cancer (PC) and accounts for 4%-10% of PC. Several genetic syndromes, including Peutz-Jeghers syndrome, hereditary pancreatitis, hereditary breast-ovarian cancer syndrome(HBOC), Lynch syndrome, and familial adenomatous polyposis (FAP), also have increased risks of PC, but the narrowest definition of FPC excludes these known syndromes. When compared with other familial tumors, proven genetic alterations are limited to a small proportion (<20%) and the familial aggregation is usually modest. However, an ethnic deviation (Ashkenazi Jewish>Caucasian) and a younger onset are common also in FPC. In European countries, "anticipation" is reported in FPC families, as with other hereditary syndromes; a trend toward younger age and worse prognosis is recognized in the late years. The resected pancreases of FPC kindred often show multiple pancreatic intraepithelial neoplasia (Pan IN) foci, with various K-ras mutations, similar to colorectal polyposis seen in the FAP patients. As with HBOC patients, a patient who is a BRCA mutation carrier with unresectable pancreatic cancer (accounting for 0%-19% of FPC patients) demonstrated better outcome following platinum and Poly (ADP-ribose) polymerase inhibitor treatment. Western countries have established FPC registries since the 1990 s and several surveillance projects for highrisk individuals are now ongoing to detect early PCs. Improvement in lifestyle habits, including non-smoking, is recommended for individuals at risk. In Japan, the FPC study group was initiated in 2013 and the Japanese FPC registry was established in 2014 by the Japan Pancreas Society.

Fiber-fluorescence in situ hybridization analyses as a diagnostic application for orientation of microduplications

Microduplications are normally invisible under microscopy and were not recognized before chromosomal microarray testing was available. Although it is difficult to confirm the orientation of duplicated segments by standard fluorescence in situ hybridization(FISH), our data indicates that fiber-FISH analysis has the potential to reveal the orientation of duplicated and triplicated segments of chromosomes. Recurrent microduplications reciprocal to microdeletions show tandem orientations of the duplicated segments, which is consistent with a non-allelic homologous recombination mechanism. Several random duplications showed tandem configurations and inverted duplications are rare. Further analysis is required to fully elucidate the basic mechanisms underlying such duplications/triplications.

National preparedness survey of pediatric intensive care units with simulation centers during the coronavirus pandemic

The coronavirus disease pandemic caught many pediatric hospitals unpreparedand has forced pediatric healthcare systems to scramble as they examine and planfor the optimal allocation of medical resources for the highest priority patients.There is limited data describing pediatric intensive care unit (PICU) preparednessand their health worker protections.AIMTo describe the current coronavirus disease 2019 (COVID-19) preparedness effortsamong a set of PICUs within a simulation-based network nationwide.METHODS A cross-sectional multi-center national survey of PICU medical director(s) fromchildren’s hospitals across the United States. The questionnaire was developedand reviewed by physicians with expertise in pediatric critical care, disasterreadiness, human factors, and survey development. Thirty-five children’shospitals were identified for recruitment through a long-established nationalresearch network. The questions focused on six themes: (1) PICU and medicaldirector demographics;(2) Pediatric patient flow during the pandemic;(3)Changes to the staffing models related to the pandemic;(4) Use of personalprotective equipment (PPE);(5) Changes in clinical practice and innovations;and(6) Current modalities of training including simulation.RESULTSWe report on survey responses from 22 of 35 PICUs (63%). The majority of PICUswere located within children’s hospitals (87%). All PICUs cared for pediatricpatients with COVID-19 at the time of the survey. The majority of PICUs (83.4%)witnessed decreases in non-COVID-19 patients, 43% had COVID-19 dedicatedunits, and 74.6% pivoted to accept adult COVID-19 patients. All PICUsimplemented changes to their staffing models with the most common changesbeing changes in COVID-19 patient room assignment in 50% of surveyed PICUsand introducing remote patient monitoring in 36% of the PICU units. Ninety-fivepercent of PICUs conducted training for donning and doffing of enhanced PPE.Even 6 months into the pandemic, one-third of PICUs across the United Statesreported shortages in PPE. The most common training formats for PPE werehands-on training (73%) and video-based content (82%). The most commonconcerns related to COVID-19 practice were changes in clinical protocols andguidelines (50%). The majority of PICUs implemented significant changes in theirairway management (82%) and cardiac arrest management protocols in COVID-19patients (68%). Simulation-based training was the most commonly utilizedtraining modality (82%), whereas team training (73%) and team dynamics (77%)were the most common training objectives.CONCLUSIONSA substantial proportion of surveyed PICUs reported on large changes in theirpreparedness and training efforts before and during the pandemic. PICUsimplemented broad strategies including modifications to staffing, PPE usage,workflow, and clinical practice, while using simulation as the preferred trainingmodality. Further research is needed to advance the level of preparedness,support staff assuredness, and support deep learning about which preparednessactions were effective and what lessons are needed to improve PICU care andstaff protection for the next COVID-19 patient waves.

Identification of telomere maintenance gene variations related to lung adenocarcinoma risk by genome-wide association and whole genome sequencing analyses

Dear editor,Lung carcinoma is responsible for the highest fatal-ity rate among cancer-related deaths globally,with lung adenocarcinoma(LADC)emerging as the prevailing sub-type.

Retinoic acid signaling in fatty liver disease

Retinoic acid(RA)is a metabolite of vitamin A and is essential for development and growth as well as cellular metabolism.Through genomic and nongenomic actions,RA regulates a variety of physiological functions.Dysregulation of RA signaling is associated with many diseases.Targeting RA signaling has been proven valuable to human health.All-trans-RA(AtRA)and anthracycline-based chemotherapy are the standard treatment of acute promyelocytic leukemia(APL).Both human and animal studies have shown a significant relationship between RA signaling and the development and progression of nonalcoholic fatty liver disease(NAFLD).In this review article,we will first summarize vitamin A metabolism and then focus on the role of RA signaling in NAFLD.AtRA inhibits the development and progression of NAFLD by regulating lipid metabolism,inflammation,thermogenesis,etc.

Circadian rhythms and inflammatory diseases of the liver and gut

Circadian rhythms play a central role in maintaining metabolic homeostasis and orchestrating interorgan crosstalk.Research evidence indicates that disruption to rhythms,which occurs through shift work,chronic sleep disruption,molecular clock polymorphisms,or the consumption of alcohol or highfat diets,can influence inflammatory status and disrupt timing between the brain and periphery or between the body and the external environment.Within the liver and gut,circadian rhythms direct the timing of glucose and lipid homeostasis,bile acid and xenobiotic metabolism,and nutrient absorption,making these systems particularly susceptible to the effects of disrupted rhythms.In this review,the impacts of circadian disruption will be discussed with emphasis on inflammatory conditions affecting the liver and gut,and the potential for chronotherapy for these conditions will be explored.

Circadian rhythms in liver metabolism and disease

Mounting research evidence demonstrates a significant negative impact of circadian disruption on human health. Shift work, chronic jet lag and sleep disturbances are associated with increased incidence of metabolic syndrome, and consequently result in obesity, type 2 diabetes and dyslipidemia.Here, these associations are reviewed with respect to liver metabolism and disease.

PCL2 regulates p53 stability and functions as a tumor suppressor in breast cancer

Polycomblike2(PCL2) is a well-known component of polycomb repressive complex 2(PRC2) and plays important roles in H3 K27 methylation and homeotic gene silencing.However,the involvement of PCL2 in breast cancer development remains unclear.Here,we established PCL2 as a tumor suppressor gene in breast cancer.Expression level of PCL2 was significantly downregulated in breast cancer tissue samples observed at different TNM stages.Ectopic expression of PCL2 could significantly inhibit cell proliferation and promoted apoptosis.PCL2 also remarkably elevated levels of p53 and its targets by increasing p53 stability.Mechanistically,PCL2 protected p53 proteins from MDM2-mediated ubiquitination and degradation by sequestering MDM2 into the nucleolus.Overexpression of PCL2 also suppressed migration and invasion by inhibiting epithelial-mesenchymal transition.PCL2 expression was correlated with Ecadherin expression and was inversely correlated with vimentin expression.Furthermore,PCL2 knockdown could attenuate anti-tumor effect of MLN4924.Taken together,our findings indicated that PCL2 played a tumor suppressor role in development and progression of breast cancer and may be a prognostic and predictive marker for breast cancer.

Hepatocyte nuclear factor 4α in the pathogenesis of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is emerging as the most common chronic liver disease worldwide. It refers to a range of liver conditions affecting people who drink little or no alcohol. NAFLD comprises non-alcoholic fatty liver and non-alcoholic steatohepatitis (NASH), the more aggressive form of NAFLD. NASH is featured by steatosis, lobular inflammation, hepatocyte injury, and various degrees of fibrosis. Although much progress has been made over the past decades, the pathogenic mechanism of NAFLD remains to be fully elucidated. Hepatocyte nuclear factor 4α (HNF4α) is a nuclear hormone receptor that is highly expressed in hepatocytes. Hepatic HNF4α expression is markedly reduced in NAFLD patients and mouse models of NASH. HNF4α has been shown to regulate bile acid, lipid, glucose, and drug metabolism. In this review, we summarize the recent advances in the understanding of the pathogenesis of NAFLD with a focus on the regulation of HNF4α and the role of hepatic HNF4α in NAFLD. Several lines of evidence have shown that hepatic HNF4α plays a key role in the initiation and progression of NAFLD. Recent data suggest that hepatic HNF4α may be a promising target for treatment of NAFLD.

Bile acid-based therapies for non-alcoholic steatohepatitis and alcoholic Iiver disease

Bile acids are synthesized from cholesterol only in hepatocytes.Bile acids circulating in the enterohepatic system act as physiological detergent molecules to help solubilize biliary cholesterol and emulsify dietary lipids and fat-soluble vitamins in small intestine.Bile acids are signaling molecules that activate nuclear receptor farnesoid X receptor(FXR)and cell surface G protein-coupled receptor TGR5.FXR critically regulates bile acid homeostasis by mediating bile acid feedback inhibition of hepatic bile acid synthesis.In addition,bile acid-activated cellular signaling pathways regulate metabolic homeostasis,immunity,and cell proliferation in various metabolically active organs.In the small and large intestine,gut bacterial enzymes modify primary bile acids to generate secondary bile acids to help shape the bile acid pool composition and subsequent biological effects.In turn,bile acids exhibit anti-microbial properties and modulate gut microbiota to influence host metabolism and immunity.Currently,bile acid-based therapies including systemic and intestine-restricted FXR agonists,TGR5 agonists,fibroblast growth factor 19 analogue,intestine FXR antagonists,and intestine apical sodium-bile acid transporter(ASBT)inhibitors have been developed as promising treatments for non-alcoholic steatohepatitis(NASH).These pharmacological agents improved metabolic and inflammatory disorders via distinct mechanisms of action that are subjects of extensive research interest.More recently,human and experimental alcoholic liver disease(ALD)has been associated with disrupted bile acid homeostasis.In additional,new findings showed that targeting bile acid metabolism and signaling may be promising therapeutic approaches for treating ALD.

Bile acid receptors and signaling crosstalk in the liver, gut and brain

Bile acids are physiological detergents derived from cholesterol that aid in digestion and nutrient ab-sorption,and they play roles in glucose,lipid,and energy metabolism and in gut microbiome and metabolic homeostasis.Bile acids mediate crosstalk between the liver and gut through bactericidal modulation of the gut microbiome,while gut microbes influence the composition of the circulating bile acid pool.Recent research indicates bile acids may also be important mediators of neurological disease by acting as peripheral signaling molecules that activate bile acid receptors in the blood-brain barrier and in the brain itself.This review highlights the role of bile acids in maintaining liver and gut microbe homeostasis,as well as their function as mediators of cellular signaling in the liver-gut-brain axis.

Bile acid metabolism and signaling in liver disease and therapy

Bile acids play a critical role in the regulation of glucose,lipid,and energy metabolism through activation of the nuclear bile acid receptor farnesoid X receptor(FXR)and membrane G protein-coupled bile acid receptor-1(Gpbar-1,aka TGR5).Agonist activation of FXR and TGR5 improves insulin and glucose sensitivity and stimulates energy metabolism to prevent diabetes,obesity,and non-alcoholic fatty liver disease(NAFLD).Bile acids have both pro-and anti-inflammatory actions through FXR and TGR5 in the intestine and liver.In the intestine,bile acids activate FXR and TGR5 to stimulate fibroblast growth factor 15 and glucagon-like peptide-1 secretion.FXR and TGR5 agonists may have therapeutic potential for treating liver-related metabolic diseases,such as diabetes and NAFLD.

Hunt for the tipping point during endocrine resistance process in breast cancer by dynamic network biomarkers

Acquired drug resistance is the major reason why patients fail to respond to cancer therapies.It is a challenging task to deter.mine the tipping point of endocrine resistance and detect the associated molecules.Derived from new systems biology theory, the dynamic network biomarker (DNB) method is designed to quantitatively identify the tipping point of a drastic system transition and can theoretically identify DNB genes that play key roles in acquiring drug resistance.We analyzed time-course mRNA sequence data generated from the tamoxifen-treated estrogen receptor (ER)-positive MCF-7 cell line, and identified the tipping point of endocrine resistance with its leading molecules.The results show that there is interplay between gene mutations and DNB genes, in which the accumulated mutations eventually affect the DNB genes that subsequently cause the change of transcriptional landscape, enabling full-blown drug resistance. Survival analyses based on clinical datasets validated that the DNB genes were associated with the poor survival of breast cancer patients.The results provided the detection for the pre-resistance state or early signs of endocrine resistance.Our predictive method may greatly benefit the scheduling of treatments for complex diseases in which patients are exposed to considerably different drugs and may become drug resistant.

Targeting macrophagic SHP2 for ameliorating osteoarthritis via TLR signaling

Osteoarthritis(OA),in which M1 macrophage polarization in the synovium exacerbates disease progression,is a major cause of cartilage degeneration and functional disabilities.Therapeutic strategies of OA designed to interfere with the polarization of macrophages have rarely been reported.Here,we report that SHP099,as an allosteric inhibitor of src-homology 2-containing protein tyrosine phosphatase 2(SHP2),attenuated osteoarthritis progression by inhibiting M1 macrophage polarization.We demonstrated that M1 macrophage polarization was accompanied by the overexpression of SHP2 in the synovial tissues of OA patients and OA model mice.Compared to wild-type(WT)mice,myeloid lineage conditional Shp2 knockout(c KO)mice showed decreased M1 macrophage polarization and attenuated severity of synovitis,an elevated expression of cartilage phenotype protein collagen II(COL2),and a decreased expression of cartilage degradation markers collagen X(COL10)and matrix metalloproteinase3(MMP3)in OA cartilage.Further mechanistic analysis showed that SHP099 inhibited lipopolysaccharide(LPS)-induced Toll-like receptor(TLR)signaling mediated by nuclear factor kappa B(NF-κB)and PI3K—AKT signaling.Moreover,intra-articular injection of SHP099 also significantly attenuated OA progression,including joint synovitis and cartilage damage.These results indicated that allosteric inhibition of SHP2 might be a promising therapeutic strategy for the treatment of OA.

Up to date on cholesterol 7 alpha-hydroxylase (CYP7A1) in bile acid synthesis

Cholesterol 7 alpha-hydroxylase(CYP7A1,EC1.14)is the first and rate-limiting enzyme in the classic bile acid synthesis pathway.Much progress has been made in understanding the transcriptional regulation of CYP7A1 gene expression and the underlying molecular mechanisms of bile acid feedback regulation of CYP7A1 and bile acid synthesis in the last three decades.Discovery of bile acid-activated receptors and their roles in the regulation of lipid,glucose and energy metabolism have been translated to the development of bile acid-based drug therapies for the treatment of liver-related metabolic diseases such as alcoholic and non-alcoholic fatty liver diseases,liver cirrhosis,diabetes,obesity and hepatocellular carcinoma.This review will provide an update on the advances in our understanding of the molecular biology and mechanistic insights of the regulation of CYP7A1 in bile acid synthesis in the last 40 years.

Hepatic lipid homeostasis by peroxisome proliferator-activated receptor gamma 2

Peroxisome proliferator-activated receptor gamma(PPARγor PPARG)is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily.It plays a master role in the differentiation and proliferation of adipose tissues.It has two major isoforms,PPARγ1 and PPARγ2,encoded from a single gene using two separate promoters and alternative splicing.Among them,PPARγ2 is most abundantly expressed in adipocytes and plays major adipogenic and lipogenic roles in the tissue.Furthermore,it has been shown that PPARγ2 is also expressed in the liver,specifically in hepatocytes,and its expression level positively correlates with fat accumulation induced by pathological conditions such as obesity and diabetes.Knockout of the hepatic Pparg gene ameliorates hepatic steatosis induced by diet or genetic manipulations.Transcriptional activation of Pparg in the liver induces the adipogenic program to store fatty acids in lipid droplets as observed in adipocytes.Understanding how the hepatic Pparg gene expression is regulated will help develop preventative and therapeutic treatments for non-alcoholic fatty liver disease(NAFLD).Due to the potential adverse effect of hepatic Pparg gene deletion on peripheral tissue functions,therapeutic interventions that target PPAR g for fatty liver diseases require fine-tuning of this gene's expression and transcriptional activity。

Efficient de novo assembly and modification of large DNA fragments

Synthetic genomics has provided new bottom-up platforms for the functional study of viral and microbial genomes.The construction of the large,gigabase(Gb)-sized genomes of higher organisms will deepen our understanding of genetic blueprints significantly.But for the synthesis and assembly of such large-scale genomes,the development of new or expanded methods is required.In this study,we develop an efficient pipeline for the construction of large DNA fragments sized 100 kilobases(kb)or above from scratches and describe an efficient method for“scar-free”engineering of the assembled sequences.Our method,therefore,should provide a standard framework for producing long DNA molecules,which are critical materials for synthetic genomics and metabolic engineering.

Bile acid metabolism and bile acid receptor signaling in metabolic diseases and therapy

Bile acids are nutrient sensors and metabolic regulators that control nutrient intake and gut bacteria growth to regulate glucose,lipid,and energy homeostasis.Dysregulation of bile acid meta-bolism causes dysbiosis leading to obesity,diabetes,and liver-related diseases.Bile acids and their derivatives have emerged as therapeutic drugs for treating liver metabolic and cholestatic dis-eases,type 2 diabetes,and non-alcoholic steatohepatitis(NASH).This special issue covers five emerging topics in bile acid research in metabolic diseases:(i)bile acid synthesis and metabolism in liver metabolic diseases;(ii)bile acid-activated receptors and signaling in liver metabolism and diseases;(iii)gut microbiome in liver path-ophysiology and cholestasis;(iv)bile acid metabolism in metabolic gastric surgery;and(v)cholestasis-associated renal injury,disease,and therapy.