scholarly journals Early alterations of neurovascular unit in the retina in mouse models of tauopathy

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Fan Xia ◽  
Yonju Ha ◽  
Shuizhen Shi ◽  
Yi Li ◽  
Shengguo Li ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Mouse Models ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Leukocyte Adhesion ◽  
Neurovascular Unit ◽  
Integrated Analysis ◽  
Therapeutic Effects ◽  
Retinal Ganglion ◽  
Potential Biomarker

AbstractThe retina, as the only visually accessible tissue in the central nervous system, has attracted significant attention for evaluating it as a biomarker for neurodegenerative diseases. Yet, most of studies focus on characterizing the loss of retinal ganglion cells (RGCs) and degeneration of their axons. There is no integrated analysis addressing temporal alterations of different retinal cells in the neurovascular unit (NVU) in particular retinal vessels. Here we assessed NVU changes in two mouse models of tauopathy, P301S and P301L transgenic mice overexpressing the human tau mutated gene, and evaluated the therapeutic effects of a tau oligomer monoclonal antibody (TOMA). We found that retinal edema and breakdown of blood–retina barrier were observed at the very early stage of tauopathy. Leukocyte adhesion/infiltration, and microglial recruitment/activation were constantly increased in the retinal ganglion cell layer of tau transgenic mice at different ages, while Müller cell gliosis was only detected in relatively older tau mice. Concomitantly, the number and function of RGCs progressively decreased during aging although they were not considerably altered in the very early stage of tauopathy. Moreover, intrinsically photosensitive RGCs appeared more sensitive to tauopathy. Remarkably, TOMA treatment in young tau transgenic mice significantly attenuated vascular leakage, inflammation and RGC loss. Our data provide compelling evidence that abnormal tau accumulation can lead to pathology in the retinal NVU, and vascular alterations occur more manifest and earlier than neurodegeneration in the retina. Oligomeric tau-targeted immunotherapy has the potential to treat tau-induced retinopathies. These data suggest that retinal NVU may serve as a potential biomarker for diagnosis and staging of tauopathy as well as a platform to study the molecular mechanisms of neurodegeneration.

scholarly journals Discovery and validation of novel protein markers in mucosa of portal hypertensive gastropathy

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ying Zhu ◽  
Wen Xu ◽  
Wei Hu ◽  
Fang Wang ◽  
Yan Zhou ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Gastric Mucosa ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Trial Registration ◽  
Portal Hypertensive Gastropathy ◽  
Protein Markers ◽  
Decompensated Liver Cirrhosis ◽  
Potential Biomarker ◽  
Normal Controls

Abstract Background Portal hypertension induced esophageal and gastric variceal bleeding is the main cause of death among patients of decompensated liver cirrhosis. Therefore, a standardized, biomarker-based test, to make an early-stage non-invasive risk assessment of portal hypertension, is highly desirable. However, no fit-for-purpose biomarkers have yet been identified. Methods We conducted a pilot study consisting of 5 portal hypertensive gastropathy (PHG) patients and 5 normal controls, sampling the gastric mucosa of normal controls and PHG patients before and after endoscopic cyanoacrylate injection, using label-free quantitative (LFQ) mass spectrometry, to identify potential biomarker candidates in gastric mucosa from PHG patients and normal controls. Then we further used parallel reaction monitoring (PRM) to verify the abundance of the targeted protein. Results LFQ analyses identified 423 significantly differentially expressed proteins. 17 proteins that significantly elevated in the gastric mucosa of PHG patients were further validated using PRM. Conclusions This is the first application of an LFQ-PRM workflow to identify and validate PHG–specific biomarkers in patient gastric mucosa samples. Our findings lay the foundation for comprehending the molecular mechanisms of PHG pathogenesis, and provide potential applications for useful biomarkers in early diagnosis and treatment. Trial registration and ethics approval: Trial registration was completed (ChiCTR2000029840) on February 25, 2020. Ethics Approvals were completed on July 17, 2017 (NYSZYYEC20180003) and February 15, 2020 (NYSZYYEC20200005).

scholarly journals Kill two birds with one stone: making multi-transgenic pre-diabetes mouse models through insulin resistance and pancreatic apoptosis pathogenesis

2017 ◽  
Author(s):  
Siyuan Kong ◽  
Jinxue Ruan ◽  
Kaiyi Zhang ◽  
Bingjun Hu ◽  
Yuzhu Cheng ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Transgenic Mice ◽  
Mouse Models ◽  
Early Stage ◽  
Transgenic Animals ◽  
High Fat ◽  
Adipose Tissues ◽  
High Sucrose

Background. Type 2 diabetes, a chronic disease to which susceptibility is hereditary, is characterized by insulin resistance accompanied by defective insulin secretion. Mouse models, especially transgenic mice, play an important role in medical research. However, the transgenic mouse models that have been used in diabetes research are involved with single transgenes, focusing on the insulin gene or its mutants. Thus they mainly provide information related to Type 1 diabetes. Methods. Here, we attempted to focus comprehensively on genes related to pancreatic islet damage, peripheral insulin resistance and related environmental inducing factors by generating single-transgenic mice (CHOP), dual-transgenic mice (hIAPP-CHOP) and triple-transgenic mice (11β-HSD1-hIAPP-CHOP). The latter two types of transgenic animals were induced with high-fat, high-sucrose diets (HFHSD). We evaluated and analyzed the diabetes-related symptoms and the histopathological and immunohistochemical features of the transgenic animals. Results. Specifically, in the triple-transgene animals, the results of intraperitoneal glucose tolerance tests (IPGTT) began to change 60 days after induction (p<0.001). After 190 days of induction, the body weights (p<0.01) and plasma glucose levels of the animals in the Tg group were higher than those of the animals in the Nc group. After the mice were sacrificed, large amounts of lipid were found deposited in the adipose tissues (p<0.01) and ectopically deposited in the non-adipose tissues (p<0.05 or 0.01) of the animals in the Tg HFHSD group. The weights of the kidneys and hearts of the Tg animals were significantly increased (p<0.01). Serum C-P was decreased due to transgene effects, and insulin levels were increased due to the effects of the high-fat high-sucrose diet in the Tg HFHSD group, indicating that damaged insulin secretion and insulin resistance hyperinsulinemia existed simultaneously in these animals. The serum corticosterone levels of the animals in the Tg group were slightly higher than those of the Nc animals due to the effects of the 11βHSD-1 transgene and obesity. In the Tg HFHSD group, hepatic adipose deposition was more severe and the pancreatic islet area was enlarged under compensation, accompanying apoptosis. In the Tg ControlD group, hepatic adipose deposition was also severe, pancreatic islets were damaged, and their areas were decreased (p<0.05), and apoptosis of pancreatic cells occurred. Taken together, these data show that the transgenes led to early-stage pathological changes characteristic of type 2 diabetes in the triple-transgene HFHSD group. The disease of triple-transgenic mice was more severe than that of dual or single-transgenic mice. Conclusion. The use of multi-transgenes involved in insulin resistance and pancreatic apoptosis is a better way to generate polygene-related early-stage diabetes models.

scholarly journals Xiaoxuming Decoction: A Traditional Herbal Recipe for Stroke With Emerging Therapeutic Mechanisms

2021 ◽  
Vol 12 ◽  
Author(s):  
Qian Zhang ◽  
Yue Wang ◽  
Aiwen Chen ◽  
Xinwei Huang ◽  
Qianyu Dong ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Molecular Mechanisms ◽  
Neurovascular Unit ◽  
Alternative Therapy ◽  
Acute Stage ◽  
Therapeutic Effects ◽  
Active Compounds ◽  
Endovascular Thrombectomy ◽  
Therapeutic Mechanisms ◽  
New Perspective

Xiaoxuming decoction (XXMD) has been traditionally used to manage stroke though debates on its clinical efficacy were present in the history. Till nowadays, it is still one of the most commonly used herbal recipes for stroke. One of the reasons is that a decent proportion of ischemic stroke patients still have residue symptoms even after thrombolysis with rt-PA or endovascular thrombectomy. Numerous clinical studies have shown that XXMD is an effective alternative therapy not only at the acute stage, but also at the chronic sequelae stage of ischemic stroke. Modern techniques have isolated groups of compounds from XXMD which have shown therapeutic effects, such as dilating blood vessels, inhibiting thrombosis, suppressing oxidative stress, attenuating nitric oxide induced damage, protecting the blood brain barrier and the neurovascular unit. However, which of the active compounds is responsible for its therapeutic effects is still unknown. Emerging studies have screened and tested these active compounds aiming to find individual compounds that can be used as drugs to treat stroke. The present study summarized both clinical evidence of XXMD in managing stroke and experimental evidence on its molecular mechanisms that have been reported recently using advanced techniques. A new perspective has also been discussed with an aim to provide new targets that can be used for screening active compounds from XXMD.

scholarly journals Neuroinflammation in Parkinson's Disease and Related Disorders: A Lesson from Genetically Manipulated Mouse Models ofα-Synucleinopathies

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Kazunari Sekiyama ◽  
Shuei Sugama ◽  
Masayo Fujita ◽  
Akio Sekigawa ◽  
Yoshiki Takamatsu ◽  
...  
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transgenic Mice ◽  
Mouse Models ◽  
Glial Cells ◽  
Genetic Modification ◽  
Early Stage ◽  
Related Model ◽  
Genetically Manipulated

Neuroinflammation in Parkinson's disease (PD) is a chronic process that is associated with alteration of glial cells, including astrocytes and microglia. However, the precise mechanisms remain obscure. To better understand neuroinflammation in PD, we focused on glial activation inα-synuclein (αS) transgenic and related model mice. In the majority ofαS transgenic mice, astrogliosis was observed concomitantly with accumulation ofαS during the early stage of neurodegeneration. However, microglia were not extensively activated unless the mice were treated with lipopolysaccharides or through further genetic modification of other molecules, including familial PD risk factors. Thus, the results inαS transgenic mice and related model mice are consistent with the idea that neuroinflammation in PD is a double-edged sword that is protective in the early stage of neurodegeneration but becomes detrimental with disease progression.

scholarly journals Repair Mechanisms of the Neurovascular Unit after Ischemic Stroke with a Focus on VEGF

2021 ◽  
Vol 22 (16) ◽  
pp. 8543
Author(s):  
Sunhong Moon ◽  
Mi-Sook Chang ◽  
Seong-Ho Koh ◽  
Yoon Kyung Choi
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Ischemic Stroke ◽  
Neural Stem Cells ◽  
Molecular Mechanisms ◽  
Late Phase ◽  
Neurovascular Unit ◽  
Regeneration Ability ◽  
Therapeutic Effects ◽  
Related Factors

The functional neural circuits are partially repaired after an ischemic stroke in the central nervous system (CNS). In the CNS, neurovascular units, including neurons, endothelial cells, astrocytes, pericytes, microglia, and oligodendrocytes maintain homeostasis; however, these cellular networks are damaged after an ischemic stroke. The present review discusses the repair potential of stem cells (i.e., mesenchymal stem cells, endothelial precursor cells, and neural stem cells) and gaseous molecules (i.e., nitric oxide and carbon monoxide) with respect to neuroprotection in the acute phase and regeneration in the late phase after an ischemic stroke. Commonly shared molecular mechanisms in the neurovascular unit are associated with the vascular endothelial growth factor (VEGF) and its related factors. Stem cells and gaseous molecules may exert therapeutic effects by diminishing VEGF-mediated vascular leakage and facilitating VEGF-mediated regenerative capacity. This review presents an in-depth discussion of the regeneration ability by which endogenous neural stem cells and endothelial cells produce neurons and vessels capable of replacing injured neurons and vessels in the CNS.

scholarly journals Kill two birds with one stone: making multi-transgenic pre-diabetes mouse models through insulin resistance and pancreatic apoptosis pathogenesis

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e4542 ◽  
Author(s):  
Siyuan Kong ◽  
Jinxue Ruan ◽  
Kaiyi Zhang ◽  
Bingjun Hu ◽  
Yuzhu Cheng ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Transgenic Mice ◽  
Transgenic Mouse ◽  
Mouse Models ◽  
Pancreatic Islet ◽  
Early Stage ◽  
Transgenic Mouse Models

Background Type 2 diabetes is characterized by insulin resistance accompanied by defective insulin secretion. Transgenic mouse models play an important role in medical research. However, single transgenic mouse models may not mimic the complex phenotypes of most cases of type 2 diabetes. Methods Focusing on genes related to pancreatic islet damage, peripheral insulin resistance and related environmental inducing factors, we generated single-transgenic (C/EBP homology protein, CHOP) mice (CHOP mice), dual-transgenic (human islet amyloid polypeptide, hIAPP; CHOP) mice (hIAPP-CHOP mice) and triple-transgenic (11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1; hIAPP; CHOP) mice (11β-HSD1-hIAPP- CHOP mice). The latter two types of transgenic (Tg) animals were induced with high-fat high-sucrose diets (HFHSD). We analyzed the diabetes-related symptoms and histology features of the transgenic animals. Results Comparing symptoms on the spot-checked points, we determined that the triple-transgene mice were more suitable for systematic study. The results of intraperitoneal glucose tolerance tests (IPGTT) of triple-transgene animals began to change 60 days after induction (p < 0.001). After 190 days of induction, the body weights (p < 0.01) and plasma glucose of the animals in Tg were higher than those of the animals in Negative Control (Nc). After sacrificed, large amounts of lipid were found deposited in adipose (p < 0.01) and ectopically deposited in the non-adipose tissues (p < 0.05 or 0.01) of the animals in the Tg HFHSD group. The weights of kidneys and hearts of Tg animals were significantly increased (p < 0.01). Serum C peptide (C-P) was decreased due to Tg effects, and insulin levels were increased due to the effects of the HFHSD in the Tg HFHSD group, indicating that damaged insulin secretion and insulin resistance hyperinsulinemia existed simultaneously in these animals. The serum corticosterone of Tg was slightly higher than those of Nc due to the effects of the 11βHSD-1 transgene and obesity. In Tg HFHSD, hepatic adipose deposition was more severe and the pancreatic islet area was enlarged under compensation, accompanying apoptosis. In the transgenic control diet (Tg ControlD) group, hepatic adipose deposition was also severe, pancreatic islets were damaged, and their areas were decreased (p < 0.05), and apoptosis of pancreatic cells occurred. Taken together, these data show the transgenes led to early-stage pathological changes characteristic of type 2 diabetes in the triple-transgene HFHSD group. The disease of triple-transgenic mice was more severe than that of dual or single-transgenic mice. Conclusion The use of multi-transgenes involved in insulin resistance and pancreatic apoptosis is a better way to generate polygene-related early-stage diabetes models.

scholarly journals Discovery and Validation of Novel Protein Markers in Mucosa of Portal Hypertensive Gastropathy

2021 ◽  
Author(s):  
Ying Zhu ◽  
Wen Xu ◽  
Wei Hu ◽  
Fang Wang ◽  
Yan Zhou ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Gastric Mucosa ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Trial Registration ◽  
Portal Hypertensive Gastropathy ◽  
Protein Markers ◽  
Decompensated Liver Cirrhosis ◽  
Potential Biomarker ◽  
Normal Controls

Abstract Background: Portal hypertension induced esophageal and gastric varix bleeding is the main cause of death among patients of decompensated liver cirrhosis. Therefore, a standardized, biomarker-based test, to make an early-stage non-invasive risk assessment of portal hypertension, is highly desirable. However, no fit-for-purpose biomarkers have yet been identified. Methods: We conducted a pilot study consisting of 5 portal hypertensive gastropathy (PHG) patients and 5 normal controls, sampling the gastric mucosa of normal controls and PHG patients before and after endoscopic cyanoacrylate injection, using label-free quantitative (LFQ) mass spectrometry, to identify potential biomarker candidates in gastric mucosa from PHG patients and normal controls. Then we further used parallel reaction monitoring (PRM) to verify the abundance of the targeted protein. Results: LFQ analyses identified 423 significantly differentially expressed proteins. 17 protein that significantly elevated in the gastric mucosa of PHG patients were further validated using PRM. Conclusions: This is the first application of an LFQ-PRM workflow to identify and validate PHG–specific biomarkers in patient gastric mucosa samples. Our findings lay the foundation for comprehending the molecular mechanisms of PHG pathogenesis, and provide potential applications for useful biomarkers in early diagnosis and treatment.Trial Registration: Trial registration was completed (ChiCTR2000029840) on February 25, 2020.

scholarly journals Diagnostic and Prognostic Potential of AKR1B10 in Human Hepatocellular Carcinoma

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 486 ◽  
Author(s):  
Johanna DiStefano ◽  
Bethany Davis
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Acquired Resistance ◽  
Experimental Studies ◽  
Chemotherapeutic Agents ◽  
Clinical Value ◽  
Surgical Interventions ◽  
Diagnostic Measures ◽  
Potential Biomarker

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Although diagnostic measures and surgical interventions have improved in recent years, the five-year survival rate for patients with advanced HCC remains bleak—a reality that is largely attributable to an absence of early stage symptoms, lack of adequate diagnostic and prognostic biomarkers, and the common occurrence of acquired resistance to chemotherapeutic agents during HCC treatment. A limited understanding of the molecular mechanisms underlying HCC pathogenesis also presents a challenge for the development of specific and efficacious pharmacological strategies to treat, halt, or prevent progression to advanced stages. Over the past decade, aldo-keto reductase family 1 member 10 (AKR1B10) has emerged as a potential biomarker for the diagnosis and prognosis of HCC, and experimental studies have demonstrated roles for this enzyme in biological pathways underlying the development and progression of HCC and acquired resistance to chemotherapeutic agents used in the treatment of HCC. Here we provide an overview of studies supporting the diagnostic and prognostic utility of AKR1B10, summarize the experimental evidence linking AKR1B10 with HCC and the induction of chemoresistance, and discuss the clinical value of AKR1B10 as a potential target for HCC-directed drug development. We conclude that AKR1B10-based therapies in the clinical management of specific HCC subtypes warrant further investigation.

scholarly journals Kill two birds with one stone: making multi-transgenic pre-diabetes mouse models through insulin resistance and pancreatic apoptosis pathogenesis

2017 ◽  
Author(s):  
Siyuan Kong ◽  
Jinxue Ruan ◽  
Kaiyi Zhang ◽  
Bingjun Hu ◽  
Yuzhu Cheng ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Transgenic Mice ◽  
Mouse Models ◽  
Early Stage ◽  
Transgenic Animals ◽  
High Fat ◽  
Adipose Tissues ◽  
High Sucrose

Background. Type 2 diabetes, a chronic disease to which susceptibility is hereditary, is characterized by insulin resistance accompanied by defective insulin secretion. Mouse models, especially transgenic mice, play an important role in medical research. However, the transgenic mouse models that have been used in diabetes research are involved with single transgenes, focusing on the insulin gene or its mutants. Thus they mainly provide information related to Type 1 diabetes. Methods. Here, we attempted to focus comprehensively on genes related to pancreatic islet damage, peripheral insulin resistance and related environmental inducing factors by generating single-transgenic mice (CHOP), dual-transgenic mice (hIAPP-CHOP) and triple-transgenic mice (11β-HSD1-hIAPP-CHOP). The latter two types of transgenic animals were induced with high-fat, high-sucrose diets (HFHSD). We evaluated and analyzed the diabetes-related symptoms and the histopathological and immunohistochemical features of the transgenic animals. Results. Specifically, in the triple-transgene animals, the results of intraperitoneal glucose tolerance tests (IPGTT) began to change 60 days after induction (p<0.001). After 190 days of induction, the body weights (p<0.01) and plasma glucose levels of the animals in the Tg group were higher than those of the animals in the Nc group. After the mice were sacrificed, large amounts of lipid were found deposited in the adipose tissues (p<0.01) and ectopically deposited in the non-adipose tissues (p<0.05 or 0.01) of the animals in the Tg HFHSD group. The weights of the kidneys and hearts of the Tg animals were significantly increased (p<0.01). Serum C-P was decreased due to transgene effects, and insulin levels were increased due to the effects of the high-fat high-sucrose diet in the Tg HFHSD group, indicating that damaged insulin secretion and insulin resistance hyperinsulinemia existed simultaneously in these animals. The serum corticosterone levels of the animals in the Tg group were slightly higher than those of the Nc animals due to the effects of the 11βHSD-1 transgene and obesity. In the Tg HFHSD group, hepatic adipose deposition was more severe and the pancreatic islet area was enlarged under compensation, accompanying apoptosis. In the Tg ControlD group, hepatic adipose deposition was also severe, pancreatic islets were damaged, and their areas were decreased (p<0.05), and apoptosis of pancreatic cells occurred. Taken together, these data show that the transgenes led to early-stage pathological changes characteristic of type 2 diabetes in the triple-transgene HFHSD group. The disease of triple-transgenic mice was more severe than that of dual or single-transgenic mice. Conclusion. The use of multi-transgenes involved in insulin resistance and pancreatic apoptosis is a better way to generate polygene-related early-stage diabetes models.

scholarly journals Pupillary Response to Chromatic Light Stimuli as a Biomarker at the Early Stage of Glaucoma

2021 ◽  
Author(s):  
Carla Arévalo López ◽  
Samuel Madariaga Román ◽  
Ivan Plaza
Keyword(s):  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Early Stage ◽  
Open Angle Glaucoma ◽  
Visual Image ◽  
Pupillary Response ◽  
Retinal Ganglion ◽  
Irreversible Damage ◽  
Pupillary Reflex ◽  
Potential Biomarker

Abstract Glaucoma is a multifactorial neurodegenerative disease of the optic nerve currently considered a severe health problem because of its high prevalence, being the primary cause of irreversible blindness worldwide. The most common type corresponds to Primary Open-Angle Glaucoma (POAG). Glaucoma produces, among other alterations, a progressive loss of Retinal Ganglion Cells (RGC) and its axons, key to generate the action potential that reaches the visual cortex to create the visual image. It indicates a Visual Field (VF) loss whose main feature is to be painless, and this makes early detection difficult, causing a late diagnosis and delaying a timely treatment indication that slows down its progression. Intrinsically photosensitive Retinal Ganglion Cells (ipRGCs), which represent a subgroup of RGCs being sensitive to damage, are characterized by reacting to short-wave light stimulation close to 480 nm and among their non-visual function, the role in the generation of the pupillary reflex stands out. Currently, the sensitivity of clinical trials correlates to RGC damage, however the need for an early damage biomarker is still relevant. It is an urgent task to create new diagnostic approaches to detect an early stage of glaucoma in a prompt, quick, and economical manner. We suggest evaluating the pupillary response to chromatic light as a potential biomarker of disease, its diagnostic benefit, and its cost-effectiveness in clinical practice to reduce irreversible damage caused by glaucoma.

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