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Frontiers in Neuroscience 2022Spinal cord injury (SCI) is a devastating condition with few treatment options. Metformin, a classical antidiabetic and antioxidant, has extended its application to...
The effect of metformin on ameliorating neurological function deficits and tissue damage in rats following spinal cord injury: A systematic review and network meta-analysis.
Spinal cord injury (SCI) is a devastating condition with few treatment options. Metformin, a classical antidiabetic and antioxidant, has extended its application to experimental SCI treatment. Here, we performed a systematic review to evaluate the neurobiological roles of metformin for treating SCI in rats, and to assess the potential for clinical translation. PubMed, Embase, China National Knowledge Infrastructure, WanFang data, SinoMed, and Vip Journal Integration Platform databases were searched from their inception dates to October 2021. Two reviewers independently selected controlled studies evaluating the neurobiological roles of metformin in rats following SCI, extracted data, and assessed the quality of methodology and evidence. Pairwise meta-analyses, subgroup analyses and network analysis were performed to assess the roles of metformin in neurological function and tissue damage in SCI rats. Twelve articles were included in this systematic review. Most of them were of moderate-to-high methodological quality, while the quality of evidence from those studies was not high. Generally, Basso, Beattie, and Bresnahan scores were increased in rats treated with metformin compared with controls, and the weighted mean differences (WMDs) between metformin and control groups exhibited a gradual upward trend from the 3rd (nine studies, = 164, WMD = 0.42, 95% CI = -0.01 to 0.85, = 0.06) to the 28th day after treatment (nine studies, = 136, WMD = 3.48, 95% CI = 2.04 to 4.92, < 0.00001). Metformin intervention was associated with improved inclined plane scores, tissue preservation ratio and number of anterior horn motor neurons. Subgroup analyses indicated an association between neuroprotection and metformin dose. Network meta-analysis showed that 50 mg/kg metformin exhibited greater protection than 10 and 100 mg/kg metformin. The action mechanisms behind metformin were associated with activating adenosine monophosphate-activated protein kinase signaling, regulating mitochondrial function and relieving endoplasmic reticulum stress. Collectively, this review indicates that metformin has a protective effect on SCI with satisfactory safety and we demonstrate a rational mechanism of action; therefore, metformin is a promising candidate for future clinical trials. However, given the limitations of animal experimental methodological and evidence quality, the findings of this pre-clinical review should be interpreted with caution.
PubMed: 36117612
DOI: 10.3389/fnins.2022.946879 -
Molecular Neurobiology Feb 2024The development of central nervous system (CNS) can form perceptual, memory, and cognitive functions, while injuries to CNS often lead to severe neurological dysfunction... (Review)
Review
The development of central nervous system (CNS) can form perceptual, memory, and cognitive functions, while injuries to CNS often lead to severe neurological dysfunction and even death. As one of the prevalent post-translational modifications (PTMs), O-GlcNAcylation has recently attracted great attentions due to its functions in regulating the activity, subcellular localization, and stability of target proteins. It has been indicated that O-GlcNAcylation could interact with phosphorylation, ubiquitination, and methylation to jointly regulate the function and activity of proteins. Furthermore, a growing number of studies have suggested that O-GlcNAcylation played an important role in the CNS. During development, O-GlcNAcylation participated in the neurogenesis, neuronal development, and neuronal function. In addition, O-GlcNAcylation was involved in the progress of CNS injuries including ischemic stroke, subarachnoid hemorrhage (SAH), and intracerebral hemorrhage (ICH) and played a crucial role in the improvement of brain damage such as attenuating cognitive impairment, inhibiting neuroinflammation, suppressing endoplasmic reticulum (ER) stress, and maintaining blood-brain barrier (BBB) integrity. Therefore, O-GlcNAcylation showed great promise as a potential target in CNS development and injuries. In this article, we presented a review highlighting the role of O-GlcNAcylation in CNS development and injuries. Hence, on the basis of these properties and effects, intervention with O-GlcNAcylation may be developed as therapeutic agents for CNS diseases.
PubMed: 38367136
DOI: 10.1007/s12035-024-04045-3 -
International Journal of Oncology Aug 2020Over the past two decades, quantitative proteomics has emerged as an important tool for deciphering the complex molecular events involved in cancers. The number of...
Over the past two decades, quantitative proteomics has emerged as an important tool for deciphering the complex molecular events involved in cancers. The number of references involving studies on the cancer metastatic process has doubled since 2010, while the last 5 years have seen the development of novel technologies combining deep proteome coverage capabilities with quantitative consistency and accuracy. To highlight key findings within this huge amount of information, the present review identified a list of tumor invasive biomarkers based on both the literature and data collected on a biocollection of experimental cell lines, tumor models of increasing invasiveness and tumor samples from patients with colorectal or breast cancer. Crossing these different data sources led to 76 proteins of interest out of 1,245 mentioned in the literature. Information on these proteins can potentially be translated into clinical prospects, since they represent potential targets for the development and evaluation of innovative therapies, alone or in combination. Herein, a systematical review of the biology of each of these proteins, including their specific subcellular/extracellular or multiple localizations is presented. Finally, as an important advantage of quantitative proteomics is the ability to provide data on all these molecules simultaneously in cell pellets, body fluids or paraffin‑embedded sections of tumors/invaded tissues, the significance of some of their interconnections is discussed.
Topics: Animals; Biomarkers, Tumor; Cell Line, Tumor; Disease Models, Animal; Humans; Neoplasm Invasiveness; Neoplasms; Proteomics
PubMed: 32468071
DOI: 10.3892/ijo.2020.5075 -
Croatian Medical Journal Apr 2019Cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) are proteins that have received increasing attention in the...
Neuroprotective and reparative effects of endoplasmic reticulum luminal proteins - mesencephalic astrocyte-derived neurotrophic factor and cerebral dopamine neurotrophic factor.
Cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) are proteins that have received increasing attention in the last decades. Although they are called neurotrophic factors they are drastically different from neurotrophic factors in their expression and physiological actions. They are located in the lumen of the endoplasmic reticulum (ER) and their basal secretion from neurons is very low. However their secretion is stimulated upon ER calcium depletion by chemical probes such as thapsigargin, a sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitor. Exogenous MANF and CDNF possess therapeutic properties in several neurological disease models, including Parkinson disease and stroke. Endogenous MANF expression has been shown to be neuroprotective, as well as administration of either CDNF or MANF into the extracellular space. In this review, we focus on their therapeutic effects, regulation of expression and secretion, comparison of their mechanisms of action, and their application to the brain parenchyma as recombinant proteins.
Topics: Animals; Endoplasmic Reticulum; Humans; Nerve Growth Factors; Neurons; Parkinson Disease; Stroke; Structure-Activity Relationship
PubMed: 31044581
DOI: 10.3325/cmj.2019.60.99 -
Frontiers in Pharmacology 2024Matrine, an alkaloid derived from the dried roots of Aiton, has been utilized for the treatment of liver diseases, but its potential hepatotoxicity raises concerns....
Matrine, an alkaloid derived from the dried roots of Aiton, has been utilized for the treatment of liver diseases, but its potential hepatotoxicity raises concerns. However, the precise condition and mechanism of action of matrine on the liver remain inconclusive. Therefore, the objective of this systematic review and meta-analysis is to comprehensively evaluate both the hepatoprotective and hepatotoxic effects of matrine and provide therapeutic guidance based on the findings. The meta-analysis systematically searched relevant preclinical literature up to May 2023 from eight databases, including PubMed, Web of Science, Cochrane Library, Embase, China National Knowledge Infrastructure, WanFang Med Online, China Science and Technology Journal Database, and China Biomedical Literature Service System. The CAMARADES system assessed the quality and bias of the evidence. Statistical analysis was conducted using STATA, which included the use of 3D maps and radar charts to display the effects of matrine dosage and frequency on hepatoprotection and hepatotoxicity. After a thorough screening, 24 studies involving 657 rodents were selected for inclusion. The results demonstrate that matrine has bidirectional effects on ALT and AST levels, and it also regulates SOD, MDA, serum TG, serum TC, IL-6, TNF-α, and CAT levels. Based on our comprehensive three-dimensional analysis, the optimal bidirectional effective dosage of matrine ranges from 10 to 69.1 mg/kg. However, at a dose of 20-30 mg/kg/d for 0.02-0.86 weeks, it demonstrated high liver protection and low toxicity. The molecular docking analysis revealed the interaction between MT and SERCA as well as SREBP-SCAP complexes. Matrine could alter Ca homeostasis in liver injury via multiple pathways, including the SREBP1c/SCAP, Notch/RBP-J/HES1, IκK/NF-κB, and Cul3/Rbx1/Keap1/Nrf2. Matrine has bidirectional effects on the liver at doses ranging from 10 to 69.1 mg/kg by influencing Ca homeostasis in the cytoplasm, endoplasmic reticulum, Golgi apparatus, and mitochondria. https://inplasy.com/, identifier INPLASY202340114.
PubMed: 38348397
DOI: 10.3389/fphar.2024.1315584 -
Current Diabetes Reviews 2020This article presents a scoping review and synthesis of research findings investigating the toxic cellular accumulation of dysregulated inorganic phosphate-phosphate...
This article presents a scoping review and synthesis of research findings investigating the toxic cellular accumulation of dysregulated inorganic phosphate-phosphate toxicity-as a pathophysiological determinant of diabetes and diabetic complications. Phosphorus, an essential micronutrient, is closely linked to the cellular metabolism of glucose for energy production, and serum inorganic phosphate is often transported into cells along with glucose during insulin therapy. Mitochondrial dysfunction and apoptosis, endoplasmic reticulum stress, neuronal degeneration, and pancreatic cancer are associated with dysregulated levels of phosphate in diabetes. Ectopic calcification involving deposition of calcium-phosphate crystals is prevalent throughout diabetic complications, including vascular calcification, nephropathy, retinopathy, and bone disorders. A low-glycemic, low-phosphate dietary intervention is proposed for further investigations in the treatment and prevention of diabetes and related diabetic pathologies.
Topics: Cell Physiological Phenomena; Cells; Diabetes Complications; Diabetes Mellitus; Glucose; Humans; Micronutrients; Phosphates
PubMed: 31686640
DOI: 10.2174/1573399815666191104113236 -
Microsurgery Feb 2024Ischemia and ischemia-reperfusion injury contribute to partial or complete flap necrosis. Traditionally, skin histology has been used to evaluate morphological and... (Review)
Review
Systematic review of pathologic markers in skin ischemia with and without reperfusion injury in microsurgical reconstruction: Biomarker alterations precede histological structure changes.
BACKGROUND
Ischemia and ischemia-reperfusion injury contribute to partial or complete flap necrosis. Traditionally, skin histology has been used to evaluate morphological and structural changes, however histology does not detect early changes. We hypothesize that morphological and structural skin changes in response to ischemia and IRI occur late, and modification of gene and protein expression are the earliest changes in ischemia and IRI.
METHODS
A systematic review was performed in accordance with PRISMA guidelines. Studies reporting skin histology or gene/protein expression changes following ischemia with or without reperfusion injury published between 2002 and 2022 were included. The primary outcomes were descriptive and semi-quantitative histological structural changes, leukocyte infiltration, edema, vessel density; secondary outcomes were quantitative gene and protein expression intensity (PCR and western blot). Model type, experimental intervention, ischemia method and duration, reperfusion duration, biopsy location and time point were collected.
RESULTS
One hundred and one articles were included. Hematoxylin and eosin (H&E) showed inflammatory infiltration in early responses (12-24 h), with structural modifications (3-14 days) and neovascularization (5-14 days) as delayed responses. Immunohistochemistry (IHC) identified angiogenesis (CD31, CD34), apoptosis (TUNEL, caspase-3, Bax/Bcl-2), and protein localization (NF-κB). Gene (PCR) and protein expression (western blot) detected inflammation and apoptosis; endoplasmic reticulum stress/oxidative stress and hypoxia; and neovascularization. The most common markers were TNF-α, IL-6 and IL-1β (inflammation), caspase-3 (apoptosis), VEGF (neovascularization), and HIF-1α (hypoxia).
CONCLUSION
There is no consensus or standard for reporting skin injury during ischemia and IRI. H&E histology is most frequently performed but is primarily descriptive and lacks sensitivity for early skin injury. Immunohistochemistry and gene/protein expression reveal immediate and quantitative cellular responses to skin ischemia and IRI. Future research is needed towards a universally-accepted skin injury scoring system.
Topics: Humans; Caspase 3; Reperfusion Injury; Ischemia; Biomarkers; Inflammation; Hypoxia; Apoptosis
PubMed: 38361264
DOI: 10.1002/micr.31141 -
Pathology, Research and Practice Feb 2023GRP78 is a chaperone with anti-apoptotic function associated with aggressive tumors. This systematic review aimed to evaluate GRP78 expression in cancer and its relation... (Meta-Analysis)
Meta-Analysis Review
GRP78 is a chaperone with anti-apoptotic function associated with aggressive tumors. This systematic review aimed to evaluate GRP78 expression in cancer and its relation to prognosis outcomes. This review was conducted in different databases searching for human cancer studies assessing GRP78 immunohistochemical levels on tissue samples. A total of 98 manuscripts were included. In 62% of the studies, GRP78 was associated with a worse prognosis. A meta-analysis included 29 studies that detected a significantly higher expression of GRP78 in cancer tissues (RR= 2.35, 95% CI 1.75-3.15) compared to control. A meta-analysis of 3 and 5-years Overall Survival revealed an increased risk of death for tumors with high expression of GRP78 (RR=1.36, 95%CI 1.16-1,59, I = 57%) and (RR=1.65, 95%CI 1.22-2.21, I =64%), respectively. GRP78 is an important prognostic biomarker for different types of cancer and a promising therapeutic target.
Topics: Humans; Endoplasmic Reticulum Chaperone BiP; Heat-Shock Proteins; Prognosis; Neoplasms; Biomarkers; Glucose
PubMed: 36610326
DOI: 10.1016/j.prp.2023.154301 -
Toxicology Letters Jan 2024This systematic review aimed to assess the association between neuropsychiatric effects of substance use and occurrence of ER stress and unfolded protein response (UPR)...
INTRODUCTION
This systematic review aimed to assess the association between neuropsychiatric effects of substance use and occurrence of ER stress and unfolded protein response (UPR) through comprehensive electronic search of existing literature and review of their findings.
METHODS
A comprehensive electronic literature search was carried out on research articles published between 1950 to July 2023 through major databases, such as Scopus, Web of Science, Google Scholar, PubMed, PsycINFO, EMBASE, Medline and Cochrane Library.
RESULTS
A total of 21 research articles were selected for review, which were comprised of sixteen animal studies, four human studies and one study on postmortem human brain samples. The selected studies revealed that alcohol, methamphetamine, cocaine, opioid and kratom exposures contributed to neuropsychiatric effects: such as decline in learning and memory function, executive dysfunction, alcohol, methamphetamine, opioid, and kratom dependence. These effects were associated with activation and persistent of ER stress and UPR with elevation of BiP and CHOP expression and the direction of ER stress is progressing towards the PERK-eIF2α-ATF4-CHOP pathway and neuronal apoptosis and neurodegeneration at various regions of the brain. In addition, regular kratom use in humans also contributed to elevation of p-JNK expression, denoting progress of ER stress towards the IRE1-ASK1-JNK-p-JNK pathway which was linked to kratom use disorder. However, treatment with certain compounds or biological agents could reverse the activation of ER stress.
CONCLUSIONS
The neuropsychiatric effects of alcohol, methamphetamine, cocaine, opioid and kratom use may be associated with persistent ER stress and UPR.
Topics: Animals; Humans; Endoplasmic Reticulum Stress; eIF-2 Kinase; Analgesics, Opioid; Unfolded Protein Response; Endoplasmic Reticulum; Apoptosis; Methamphetamine; Substance-Related Disorders; Cocaine
PubMed: 38101493
DOI: 10.1016/j.toxlet.2023.12.008 -
Current Neuropharmacology 2024Tauroursodeoxycholic acid (TUDCA) is a naturally produced hydrophilic bile acid that has been used for centuries in Chinese medicine. Numerous recent and studies have...
BACKGROUND
Tauroursodeoxycholic acid (TUDCA) is a naturally produced hydrophilic bile acid that has been used for centuries in Chinese medicine. Numerous recent and studies have shown that TUDCA has neuroprotective action in various models of retinal disorders.
OBJECTIVE
To systematically review the scientific literature and provide a comprehensive summary on the neuroprotective action and the mechanisms involved in the cytoprotective effects of TUDCA.
METHODS
A systematic review was conducted in accordance with the PRISMA (The Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Systematic literature search of United States National Library of Medicine (PubMed), Web of Science, Embase, Scopus and Cochrane Library was performed, which covered all original articles published up to July 2022. The terms, "TUDCA" in combination with "retina", "retinal protection", "neuroprotection" were searched. Possible biases were identified with the adopted SYRCLE's tool.
RESULTS
Of the 423 initially gathered studies, 24 articles met inclusion/exclusion criteria for full-text review. Six of them were experiments, 17 studies reported data and one study described both and data. The results revealed the effect of TUDCA on different retinal diseases, such as retinitis pigmentosa (RP), diabetic retinopathy (DR), retinal degeneration (RD), retinal ganglion cell (RGC) injury, Leber's hereditary optic neuropathy (LHON), choroidal neovascularization (CNV), and retinal detachment (RDT). The quality scores of the studies were ranged from 5 to 7 points (total 10 points), according to SYRCLE's risk of bias tool. Both and data suggested that TUDCA could effectively delay degeneration and apoptosis of retinal neurons, preserve retinal structure and function, and its mechanism of actions might be related with inhibiting apoptosis, decreasing inflammation, attenuating oxidative stress, suppressing endoplasmic reticulum (ER) stress, and reducing angiogenesis.
CONCLUSION
This systematic review demonstrated that TUDCA has neuroprotective effect on and models of retinal disorders, reinforcing the currently available evidence that TUDCA could be a promising therapeutic agent in retinal diseases treatment. However, well designed clinical trials are necessary to appraise the efficacy of TUDCA in clinical setting.
Topics: Taurochenodeoxycholic Acid; Animals; Neuroprotective Agents; Humans; Retinal Diseases; Disease Models, Animal
PubMed: 37691227
DOI: 10.2174/1570159X21666230907152207