The gut microbiota plays a key role in metabolic diseases.Gut-microbiota-derived metabolites are found in different dietary sources,including:Carbohydrate(acetate,propionate,butyrate,also known as short-chain fatty ac...The gut microbiota plays a key role in metabolic diseases.Gut-microbiota-derived metabolites are found in different dietary sources,including:Carbohydrate(acetate,propionate,butyrate,also known as short-chain fatty acids,as well as succinate);protein(hydrogen sulfide,indole,and phenylacetic acid);and lipids(resveratrol-,ferulic acid-,linoleic acid-,catechin-and berry-derived metabolites).Insulin resistance,which is a global pandemic metabolic disease that progresses to type 2 diabetes mellitus,can be directly targeted by these metabolites.Gutmicrobiota-derived metabolites have broad effects locally and in distinct organs,in particular skeletal muscle,adipose tissue,and liver.These metabolites can modulate glucose metabolism,including the increase in glucose uptake and lipid oxidation in skeletal muscle,and decrease in lipogenesis and gluconeogenesis associated with lipid oxidation in the liver through activation of phosphatidylinositol 3-kinase-serine/threonine-protein kinase B and AMP-activated protein kinase.In adipose tissue,gut-microbiota-derived metabolites stimulate adipogenesis and thermogenesis,inhibit lipolysis,and attenuate inflammation.Importantly,an increase in energy expenditure and fat oxidation occurs in the whole body.Therefore,the therapeutic potential of current pharmacological and non-pharmacological approaches used to treat diabetes mellitus can be tested to target specific metabolites derived from intestinal bacteria,which may ultimately ameliorate the hyperglycemic burden.展开更多
Non-invasive cardiac imaging has explored enormous advances in the last few decades.In particular,hybrid imaging represents the fusion of information from multiple imaging modalities,allowing to provide a more compreh...Non-invasive cardiac imaging has explored enormous advances in the last few decades.In particular,hybrid imaging represents the fusion of information from multiple imaging modalities,allowing to provide a more comprehensive dataset compared to traditional imaging techniques in patients with cardiovascular diseases.The complementary anatomical,functional and molecular information provided by hybrid systems are able to simplify the evaluation procedure of various pathologies in a routine clinical setting.The diagnostic capability of hybrid imaging modalities can be further enhanced by introducing novel and specific imaging biomarkers.The aim of this review is to cover the most recent advancements in radiotracers development for SPECT/CT,PET/CT,and PET/MRI for cardiovascular diseases.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is an aggressive subtype of liver cancer and is one of the most common cancers with high mortality worldwide.Reprogrammed lipid metabolism plays crucial roles in HCC cancer cell...BACKGROUND Hepatocellular carcinoma(HCC)is an aggressive subtype of liver cancer and is one of the most common cancers with high mortality worldwide.Reprogrammed lipid metabolism plays crucial roles in HCC cancer cell survival,growth,and evolution.Emerging evidence suggests the importance of fatty acid binding proteins(FABPs)in contribution to cancer progression and metastasis;however,how these FABPs are dysregulated in cancer cells,especially in HCC,and the roles of FABPs in cancer progression have not been well defined.AIM To understand the genetic alterations and expression of FABPs and their associated cancer hallmarks and oncogenes in contributing to cancer malignancies.METHODS We used The Cancer Genome Atlas datasets of pan cancer and liver hepatocellular carcinoma(LIHC)as well as patient cohorts with other cancer types in this study.We investigated genetic alterations of FABPs in various cancer types.mRNA expression was used to determine if FABPs are abnormally expressed in tumor tissues compared to non-tumor controls and to investigate whether their expression correlates with patient clinical outcome,enriched cancer hallmarks and oncogenes previously reported for patients with HCC.We determined the protein levels of FABP5 and its correlated genes in two HCC cell lines and assessed the potential of FABP5 inhibition in treating HCC cells.RESULTS We discovered that a gene cluster including five FABP family members(FABP4,FABP5,FABP8,FABP9 and FABP12)is frequently co-amplified in cancer.Amplification,in fact,is the most common genetic alteration for FABPs,leading to overexpression of FABPs.FABP5 showed the greatest differential mRNA expression comparing tumor with non-tumor tissues.High FABP5 expression correlates well with worse patient outcomes(P<0.05).FABP5 expression highly correlates with enrichment of G2M checkpoint(r=0.33,P=1.1e-10),TP53 signaling pathway(r=0.22,P=1.7e-5)and many genes in the gene sets such as CDK1(r=0.56,P=0),CDK4(r=0.49,P=0),and TP53(r=0.22,P=1.6e-5).Furthermore,FABP5 also correlates well with two co-expressed oncogenes PLK1 and BIRC5 in pan cancer especially in LIHC patients(r=0.58,P=0;r=0.58,P=0;respectively).FABP5high Huh7 cells also expressed higher protein levels of p53,BIRC5,CDK1,CDK2,and CDK4 than FABP5low HepG2 cells.FABP5 inhibition more potently inhibited the tumor cell growth in Huh7 cells than in HepG2 cells.CONCLUSION We discovered that FABP5 gene is frequently amplified in cancer,especially in HCC,leading to its significant elevated expression in HCC.Its high expression correlates well with worse patient outcome,enriched cancer hallmarks and oncogenes in HCC.FABP5 inhibition impaired the cell viability of FABP5high Huh7 cells.All these support that FABP5 is a novel therapeutic target for treating FABP5high HCC.展开更多
Oxidized low-density lipoprotein receptor 1(OLR1)is upregulated in neurons and participates in hypertension-induced neuronal apoptosis.OLR1 deletion exerts protective effects on cerebral damage induced by hypertensive...Oxidized low-density lipoprotein receptor 1(OLR1)is upregulated in neurons and participates in hypertension-induced neuronal apoptosis.OLR1 deletion exerts protective effects on cerebral damage induced by hypertensive-induced stroke.Therefore,OLR1 is likely involved in the progress of intracerebral hemorrhage.In this study,we examined the potential role of OLR1 in intracerebral hemorrhage using a rat model.OLR1 small interfering RNA(10μL;50 pmol/μL)was injected into the right basal ganglia to knock down OLR1.Twenty-four hours later,0.5 U collagenase type VII was injected to induce intracerebral hemorrhage.We found that knockdown of OLR1 attenuated neurological behavior impairment in rats with intracerebral hemorrhage and reduced hematoma,neuron loss,inflammatory reaction,and oxidative stress in rat brain tissue.We also found that silencing of OLR1 suppressed ferroptosis induced by intracerebral hemorrhage and the p38 signaling pathway.Therefore,silencing OLR1 exhibits protective effects against secondary injury of intracerebral hemorrhage.These findings suggest that OLR1 may be a novel potential therapeutic target for intracerebral hemorrhage.展开更多
Astrocytic Kir4.1 channels and spatial potassium buffering：Astrocytes play a crucial role in maintaining the structural and functional integrity of the brain,which includes formation of the blood-brain barrier,mainte...Astrocytic Kir4.1 channels and spatial potassium buffering：Astrocytes play a crucial role in maintaining the structural and functional integrity of the brain,which includes formation of the blood-brain barrier,maintenance of water and ion homeostasis,metabolism of neurotransmitters and secretion of various neuroactive molecules.展开更多
Parkinson＇s disease （PD） is the most common motor neurode- generative disorder affecting approximately 4 million people worldwide. Although PD presents primarily with motor dysfunction, non-motor symptoms including...Parkinson＇s disease （PD） is the most common motor neurode- generative disorder affecting approximately 4 million people worldwide. Although PD presents primarily with motor dysfunction, non-motor symptoms including cognitive decline, mood disorders, reduced olfaction and constipation are also of- ten present, with some of these non-motor symptoms even pre- senting prior to the onset of motor symptoms. It is well known that PD is largely caused by the gradual degeneration of dopa- minergic neurons within the substantia nigra pars compacta （SNc）, along with the presence of protein aggregates called Lewy bodies, which consist primarily of ct-synuclein and are found in the cytoplasm of surviving neurons. This ongoing cell loss and Lewy body pathology is not confined to the SNc, but is also seen in other brain regions implicated in PD pathogenesis such as the locus ceruleus.展开更多
BACKGROUND Gemcitabine plus nab-paclitaxel(GA) is a commonly used first-line treatment regimen for metastatic pancreatic cancer,and many studies will add a novel targeted agent to this regimen for improving patient su...BACKGROUND Gemcitabine plus nab-paclitaxel(GA) is a commonly used first-line treatment regimen for metastatic pancreatic cancer,and many studies will add a novel targeted agent to this regimen for improving patient survival rate.However,the clinical effectiveness of GA is the most controversial issue.AIM To compare the efficacy and safety of GA regimen with a targeted agent and GA regimen.METHODS Up to 1 December 2021,the eligible randomized controlled trials(RCTs) relating to GA and GA with a targeted agent were searched on Pub Med,EMBASE and Cochrane Library for eligible data.We screened out appropriate studies for overall survival(OS),progression-free survival(PFS),objective response rate(ORR),and toxicity,which had been pooled and finally analyzed by using Stata version 15.1.In addition,we use Reference Citation Analysis(https://www.referencecitationanalysis.com/) to collect the latest related literature to improve the latest cutting-edge research results.RESULTS Seven RCTs involving 1544 patients(848 men and 696 women) were included.There were no significant differences between GA with a targeted agent and GA in PFS [hazard ratio(HR):1.18 95% confidence interval(CI):0.91-1.53],OS(HR:1.12 95%CI:0.99-1.27),and ORR(HR:0.96 95%CI:0.71-1.29).There was no notable difference in the two groups in grade 3/4 toxicity(fatigue,anemia,vomiting and neutropenia),whereas the incidence of grade 3/4 diarrhea considerably increased in GA with a targeted drug.CONCLUSION Adding a novel targeted agent to the GA regimen did not improve survival rate of patients with metastatic pancreatic cancer.展开更多
With his keen insight,William Golding becomes very conscious of the darkness of the human heart and the necessity that we become aware of this darkness if we are to save ourselves. All his novels,therefore,attempt to ...With his keen insight,William Golding becomes very conscious of the darkness of the human heart and the necessity that we become aware of this darkness if we are to save ourselves. All his novels,therefore,attempt to deal with the essential human condition. All Golding's novels,products of his peculiar literary temperament and habit,are reactive experiments. Each of them represents a response to a specific book by an early writer.展开更多
Histamine—the main product of mast cells plays critical role in the pathogenetic pathways of both allergic rhinitis and asthma. The novel concept of the unique airway diseases its only supported by the similarities w...Histamine—the main product of mast cells plays critical role in the pathogenetic pathways of both allergic rhinitis and asthma. The novel concept of the unique airway diseases its only supported by the similarities within pathogenetic process. Antagonists of H1 and H2 receptors are quite effective in allergic rhinitis, but not effective enough in asthma. In an era of corticosteroids, leucotriene antagonists and Anti-IgE treatment, there is still a challenge to search for more effective, more acurate and more safe treatment option. Antagonists (inversive agonists) of histamine receptors H4 seems to be one of the promising targets in the allergic rhinitis and asthma treatment. The first H4 antagonist entered to clinics and the results from a proof-of-concept Phase II clinical study is expected to be disclosed soon. This review article summarizes current knowledge on H4R that have been collected in various studies sharing evidences about efficacy of H4R as a reasonable target for diseases with histamine involved pathogenetic pathways.展开更多
Gastric cancer(GC) is a common lethal malignancy.Gastroesophageal junction and gastric cardia tumors are the fastest rising malignancies due to increasing prevalence of obesity and acid reflex in the United States.Tra...Gastric cancer(GC) is a common lethal malignancy.Gastroesophageal junction and gastric cardia tumors are the fastest rising malignancies due to increasing prevalence of obesity and acid reflex in the United States.Traditional chemotherapy remains the main treatment with trastuzumab targeting human epidermal growth factor receptor 2 positive disease.The median overall survival(OS) is less than one year for advanced GC patients; thus,there is an urgent unmet need to develop novel therapy for GC.Although multiple targeted agents were studied,only the vascular endothelial growth factor receptor inhibitor ramucirumab was approved recently by the United States Food and Drug Administration because of its 1.4 mo OS benefit(5.2 mo vs 3.8 mo,P = 0.047) as a single agent; 2.2 mo improvement of survival(9.6 mo vs 7.4 mo,P = 0.017) when combined with paclitaxel in previously treated advanced GC patients.It is the first single agent approved for previously treated GC and the second biologic agent after trastuzumab.Even with limited success,targeted therapy may be improved by developing new biomarkers.Immune therapy is changing the paradigm of cancer treatment and is presently under active investigation for GC in clinical trials.More evidence supports GC stem cells existence and early stage studies are looking for its potential therapeutic possibilities.展开更多
基金Supported by São Paulo Research Foundation,No.2013/19560-6 and No.2017/23195-2EFSD(European Foundation for the Study of Diabetes)/Sanofi(to RangelÉB).
文摘The gut microbiota plays a key role in metabolic diseases.Gut-microbiota-derived metabolites are found in different dietary sources,including:Carbohydrate(acetate,propionate,butyrate,also known as short-chain fatty acids,as well as succinate);protein(hydrogen sulfide,indole,and phenylacetic acid);and lipids(resveratrol-,ferulic acid-,linoleic acid-,catechin-and berry-derived metabolites).Insulin resistance,which is a global pandemic metabolic disease that progresses to type 2 diabetes mellitus,can be directly targeted by these metabolites.Gutmicrobiota-derived metabolites have broad effects locally and in distinct organs,in particular skeletal muscle,adipose tissue,and liver.These metabolites can modulate glucose metabolism,including the increase in glucose uptake and lipid oxidation in skeletal muscle,and decrease in lipogenesis and gluconeogenesis associated with lipid oxidation in the liver through activation of phosphatidylinositol 3-kinase-serine/threonine-protein kinase B and AMP-activated protein kinase.In adipose tissue,gut-microbiota-derived metabolites stimulate adipogenesis and thermogenesis,inhibit lipolysis,and attenuate inflammation.Importantly,an increase in energy expenditure and fat oxidation occurs in the whole body.Therefore,the therapeutic potential of current pharmacological and non-pharmacological approaches used to treat diabetes mellitus can be tested to target specific metabolites derived from intestinal bacteria,which may ultimately ameliorate the hyperglycemic burden.
文摘Non-invasive cardiac imaging has explored enormous advances in the last few decades.In particular,hybrid imaging represents the fusion of information from multiple imaging modalities,allowing to provide a more comprehensive dataset compared to traditional imaging techniques in patients with cardiovascular diseases.The complementary anatomical,functional and molecular information provided by hybrid systems are able to simplify the evaluation procedure of various pathologies in a routine clinical setting.The diagnostic capability of hybrid imaging modalities can be further enhanced by introducing novel and specific imaging biomarkers.The aim of this review is to cover the most recent advancements in radiotracers development for SPECT/CT,PET/CT,and PET/MRI for cardiovascular diseases.
基金Tianjin Key Medical Discipline Construction Project,No.TJYXZDXK-034A.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is an aggressive subtype of liver cancer and is one of the most common cancers with high mortality worldwide.Reprogrammed lipid metabolism plays crucial roles in HCC cancer cell survival,growth,and evolution.Emerging evidence suggests the importance of fatty acid binding proteins(FABPs)in contribution to cancer progression and metastasis;however,how these FABPs are dysregulated in cancer cells,especially in HCC,and the roles of FABPs in cancer progression have not been well defined.AIM To understand the genetic alterations and expression of FABPs and their associated cancer hallmarks and oncogenes in contributing to cancer malignancies.METHODS We used The Cancer Genome Atlas datasets of pan cancer and liver hepatocellular carcinoma(LIHC)as well as patient cohorts with other cancer types in this study.We investigated genetic alterations of FABPs in various cancer types.mRNA expression was used to determine if FABPs are abnormally expressed in tumor tissues compared to non-tumor controls and to investigate whether their expression correlates with patient clinical outcome,enriched cancer hallmarks and oncogenes previously reported for patients with HCC.We determined the protein levels of FABP5 and its correlated genes in two HCC cell lines and assessed the potential of FABP5 inhibition in treating HCC cells.RESULTS We discovered that a gene cluster including five FABP family members(FABP4,FABP5,FABP8,FABP9 and FABP12)is frequently co-amplified in cancer.Amplification,in fact,is the most common genetic alteration for FABPs,leading to overexpression of FABPs.FABP5 showed the greatest differential mRNA expression comparing tumor with non-tumor tissues.High FABP5 expression correlates well with worse patient outcomes(P<0.05).FABP5 expression highly correlates with enrichment of G2M checkpoint(r=0.33,P=1.1e-10),TP53 signaling pathway(r=0.22,P=1.7e-5)and many genes in the gene sets such as CDK1(r=0.56,P=0),CDK4(r=0.49,P=0),and TP53(r=0.22,P=1.6e-5).Furthermore,FABP5 also correlates well with two co-expressed oncogenes PLK1 and BIRC5 in pan cancer especially in LIHC patients(r=0.58,P=0;r=0.58,P=0;respectively).FABP5high Huh7 cells also expressed higher protein levels of p53,BIRC5,CDK1,CDK2,and CDK4 than FABP5low HepG2 cells.FABP5 inhibition more potently inhibited the tumor cell growth in Huh7 cells than in HepG2 cells.CONCLUSION We discovered that FABP5 gene is frequently amplified in cancer,especially in HCC,leading to its significant elevated expression in HCC.Its high expression correlates well with worse patient outcome,enriched cancer hallmarks and oncogenes in HCC.FABP5 inhibition impaired the cell viability of FABP5high Huh7 cells.All these support that FABP5 is a novel therapeutic target for treating FABP5high HCC.
基金supported by the National Natural Science Foundation of China,No.81971125(to ZYH).
文摘Oxidized low-density lipoprotein receptor 1(OLR1)is upregulated in neurons and participates in hypertension-induced neuronal apoptosis.OLR1 deletion exerts protective effects on cerebral damage induced by hypertensive-induced stroke.Therefore,OLR1 is likely involved in the progress of intracerebral hemorrhage.In this study,we examined the potential role of OLR1 in intracerebral hemorrhage using a rat model.OLR1 small interfering RNA(10μL;50 pmol/μL)was injected into the right basal ganglia to knock down OLR1.Twenty-four hours later,0.5 U collagenase type VII was injected to induce intracerebral hemorrhage.We found that knockdown of OLR1 attenuated neurological behavior impairment in rats with intracerebral hemorrhage and reduced hematoma,neuron loss,inflammatory reaction,and oxidative stress in rat brain tissue.We also found that silencing of OLR1 suppressed ferroptosis induced by intracerebral hemorrhage and the p38 signaling pathway.Therefore,silencing OLR1 exhibits protective effects against secondary injury of intracerebral hemorrhage.These findings suggest that OLR1 may be a novel potential therapeutic target for intracerebral hemorrhage.
基金supported in part by a Grant from AMED(17ek0109120h0003)a Grant-in-Aid for Scientific Research from the Ministry of Education,Culture,Sports,Science and Technology(17K08324 and 15H04892)
文摘Astrocytic Kir4.1 channels and spatial potassium buffering：Astrocytes play a crucial role in maintaining the structural and functional integrity of the brain,which includes formation of the blood-brain barrier,maintenance of water and ion homeostasis,metabolism of neurotransmitters and secretion of various neuroactive molecules.
基金in part has been supported by the Neurosurgical Research Foundation, South Australia, Australia
文摘Parkinson＇s disease （PD） is the most common motor neurode- generative disorder affecting approximately 4 million people worldwide. Although PD presents primarily with motor dysfunction, non-motor symptoms including cognitive decline, mood disorders, reduced olfaction and constipation are also of- ten present, with some of these non-motor symptoms even pre- senting prior to the onset of motor symptoms. It is well known that PD is largely caused by the gradual degeneration of dopa- minergic neurons within the substantia nigra pars compacta （SNc）, along with the presence of protein aggregates called Lewy bodies, which consist primarily of ct-synuclein and are found in the cytoplasm of surviving neurons. This ongoing cell loss and Lewy body pathology is not confined to the SNc, but is also seen in other brain regions implicated in PD pathogenesis such as the locus ceruleus.
文摘BACKGROUND Gemcitabine plus nab-paclitaxel(GA) is a commonly used first-line treatment regimen for metastatic pancreatic cancer,and many studies will add a novel targeted agent to this regimen for improving patient survival rate.However,the clinical effectiveness of GA is the most controversial issue.AIM To compare the efficacy and safety of GA regimen with a targeted agent and GA regimen.METHODS Up to 1 December 2021,the eligible randomized controlled trials(RCTs) relating to GA and GA with a targeted agent were searched on Pub Med,EMBASE and Cochrane Library for eligible data.We screened out appropriate studies for overall survival(OS),progression-free survival(PFS),objective response rate(ORR),and toxicity,which had been pooled and finally analyzed by using Stata version 15.1.In addition,we use Reference Citation Analysis(https://www.referencecitationanalysis.com/) to collect the latest related literature to improve the latest cutting-edge research results.RESULTS Seven RCTs involving 1544 patients(848 men and 696 women) were included.There were no significant differences between GA with a targeted agent and GA in PFS [hazard ratio(HR):1.18 95% confidence interval(CI):0.91-1.53],OS(HR:1.12 95%CI:0.99-1.27),and ORR(HR:0.96 95%CI:0.71-1.29).There was no notable difference in the two groups in grade 3/4 toxicity(fatigue,anemia,vomiting and neutropenia),whereas the incidence of grade 3/4 diarrhea considerably increased in GA with a targeted drug.CONCLUSION Adding a novel targeted agent to the GA regimen did not improve survival rate of patients with metastatic pancreatic cancer.
文摘With his keen insight,William Golding becomes very conscious of the darkness of the human heart and the necessity that we become aware of this darkness if we are to save ourselves. All his novels,therefore,attempt to deal with the essential human condition. All Golding's novels,products of his peculiar literary temperament and habit,are reactive experiments. Each of them represents a response to a specific book by an early writer.
文摘Histamine—the main product of mast cells plays critical role in the pathogenetic pathways of both allergic rhinitis and asthma. The novel concept of the unique airway diseases its only supported by the similarities within pathogenetic process. Antagonists of H1 and H2 receptors are quite effective in allergic rhinitis, but not effective enough in asthma. In an era of corticosteroids, leucotriene antagonists and Anti-IgE treatment, there is still a challenge to search for more effective, more acurate and more safe treatment option. Antagonists (inversive agonists) of histamine receptors H4 seems to be one of the promising targets in the allergic rhinitis and asthma treatment. The first H4 antagonist entered to clinics and the results from a proof-of-concept Phase II clinical study is expected to be disclosed soon. This review article summarizes current knowledge on H4R that have been collected in various studies sharing evidences about efficacy of H4R as a reasonable target for diseases with histamine involved pathogenetic pathways.
文摘Gastric cancer(GC) is a common lethal malignancy.Gastroesophageal junction and gastric cardia tumors are the fastest rising malignancies due to increasing prevalence of obesity and acid reflex in the United States.Traditional chemotherapy remains the main treatment with trastuzumab targeting human epidermal growth factor receptor 2 positive disease.The median overall survival(OS) is less than one year for advanced GC patients; thus,there is an urgent unmet need to develop novel therapy for GC.Although multiple targeted agents were studied,only the vascular endothelial growth factor receptor inhibitor ramucirumab was approved recently by the United States Food and Drug Administration because of its 1.4 mo OS benefit(5.2 mo vs 3.8 mo,P = 0.047) as a single agent; 2.2 mo improvement of survival(9.6 mo vs 7.4 mo,P = 0.017) when combined with paclitaxel in previously treated advanced GC patients.It is the first single agent approved for previously treated GC and the second biologic agent after trastuzumab.Even with limited success,targeted therapy may be improved by developing new biomarkers.Immune therapy is changing the paradigm of cancer treatment and is presently under active investigation for GC in clinical trials.More evidence supports GC stem cells existence and early stage studies are looking for its potential therapeutic possibilities.
