Publications by authors named "Jianjie Ma"

190 Publications

MG53 Preserves Neuromuscular Junction Integrity and Alleviates ALS Disease Progression.

Antioxidants (Basel) 2021 Sep 25;10(10). Epub 2021 Sep 25.

Department of Kinesiology, College of Nursing and Health Innovation, University of Texas at Arlington, Arlington, TX 76019, USA.

Respiratory failure from progressive respiratory muscle weakness is the most common cause of death in amyotrophic lateral sclerosis (ALS). Defects in neuromuscular junctions (NMJs) and progressive NMJ loss occur at early stages, thus stabilizing and preserving NMJs represents a potential therapeutic strategy to slow ALS disease progression. Here we demonstrate that NMJ damage is repaired by MG53, an intrinsic muscle protein involved in plasma membrane repair. Compromised diaphragm muscle membrane repair and NMJ integrity are early pathological events in ALS. Diaphragm muscles from ALS mouse models show increased susceptibility to injury and intracellular MG53 aggregation, which is also a hallmark of human muscle samples from ALS patients. We show that systemic administration of recombinant human MG53 protein in ALS mice protects against injury to diaphragm muscle, preserves NMJ integrity, and slows ALS disease progression. As MG53 is present in circulation in rodents and humans under physiological conditions, our findings provide proof-of-concept data supporting MG53 as a potentially safe and effective therapy to mitigate ALS progression.
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http://dx.doi.org/10.3390/antiox10101522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8532806PMC
September 2021

MG53 suppresses tumor progression and stress granule formation by modulating G3BP2 activity in non-small cell lung cancer.

Mol Cancer 2021 09 14;20(1):118. Epub 2021 Sep 14.

Department of Surgery, The Ohio State University College of Medicine, Columbus, OH, 43210, USA.

Background: Cancer cells develop resistance to chemotherapeutic intervention by excessive formation of stress granules (SGs), which are modulated by an oncogenic protein G3BP2. Selective control of G3BP2/SG signaling is a potential means to treat non-small cell lung cancer (NSCLC).

Methods: Co-immunoprecipitation was conducted to identify the interaction of MG53 and G3BP2. Immunohistochemistry and live cell imaging were performed to visualize the subcellular expression or co-localization. We used shRNA to knock-down the expression MG53 or G3BP2 to test the cell migration and colony formation. The expression level of MG53 and G3BP2 in human NSCLC tissues was tested by western blot analysis. The ATO-induced oxidative stress model was used to examine the effect of rhMG53 on SG formation. Moue NSCLC allograft experiments were performed on wild type and transgenic mice with either knockout of MG53, or overexpression of MG53. Human NSCLC xenograft model in mice was used to evaluate the effect of MG53 overexpression on tumorigenesis.

Results: We show that MG53, a member of the TRIM protein family (TRIM72), modulates G3BP2 activity to control lung cancer progression. Loss of MG53 results in the progressive development of lung cancer in mg53 mice. Transgenic mice with sustained elevation of MG53 in the bloodstream demonstrate reduced tumor growth following allograft transplantation of mouse NSCLC cells. Biochemical assay reveals physical interaction between G3BP2 and MG53 through the TRIM domain of MG53. Knockdown of MG53 enhances proliferation and migration of NSCLC cells, whereas reduced tumorigenicity is seen in NSCLC cells with knockdown of G3BP2 expression. The recombinant human MG53 (rhMG53) protein can enter the NSCLC cells to induce nuclear translation of G3BP2 and block arsenic trioxide-induced SG formation. The anti-proliferative effect of rhMG53 on NSCLC cells was abolished with knockout of G3BP2. rhMG53 can enhance sensitivity of NSCLC cells to undergo cell death upon treatment with cisplatin. Tailored induction of MG53 expression in NSCLC cells suppresses lung cancer growth via reduced SG formation in a xenograft model.

Conclusion: Overall, these findings support the notion that MG53 functions as a tumor suppressor by targeting G3BP2/SG activity in NSCLCs.
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http://dx.doi.org/10.1186/s12943-021-01418-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439062PMC
September 2021

Butyrate Feeding Reverses CypD-Related Mitoflash Phenotypes in Mouse Myofibers.

Int J Mol Sci 2021 Jul 10;22(14). Epub 2021 Jul 10.

Department of Kinesiology, College of Nursing and Health Innovation, University of Texas at Arlington, Arlington, TX 76010, USA.

Mitoflashes are spontaneous transients of the biosensor mt-cpYFP. In cardiomyocytes, mitoflashes are associated with the cyclophilin D (CypD) mediated opening of mitochondrial permeability transition pore (mPTP), while in skeletal muscle they are considered hallmarks of mitochondrial respiration burst under physiological conditions. Here, we evaluated the potential association between mitoflashes and the mPTP opening at different CypD levels and phosphorylation status by generating three CypD derived fusion constructs with a red shifted, pH stable Ca sensor jRCaMP1b. We observed perinuclear mitochondrial Ca efflux accompanying mitoflashes in CypD and CypDS42A (a phosphor-resistant mutation at Serine 42) overexpressed myofibers but not the control myofibers expressing the mitochondria-targeting sequence of CypD (CypDN30). Assisted by a newly developed analysis program, we identified shorter, more frequent mitoflash activities occurring over larger areas in CypD and CypDS42A overexpressed myofibers than the control CypDN30 myofibers. These observations provide an association between the elevated CypD expression and increased mitoflash activities in hindlimb muscles in an amyotrophic lateral sclerosis (ALS) mouse model previously observed. More importantly, feeding the mice with sodium butyrate reversed the CypD-associated mitoflash phenotypes and protected against ectopic upregulation of CypD, unveiling a novel molecular mechanism underlying butyrate mediated alleviation of ALS progression in the mouse model.
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http://dx.doi.org/10.3390/ijms22147412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304904PMC
July 2021

MG53 suppresses NF-κB activation to mitigate age-related heart failure.

JCI Insight 2021 Sep 8;6(17). Epub 2021 Sep 8.

Department of Surgery, Division of Cardiac Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.

Aging is associated with chronic oxidative stress and inflammation that affect tissue repair and regeneration capacity. MG53 is a TRIM family protein that facilitates repair of cell membrane injury in a redox-dependent manner. Here, we demonstrate that the expression of MG53 was reduced in failing human hearts and aged mouse hearts, concomitant with elevated NF-κB activation. We evaluated the safety and efficacy of longitudinal, systemic administration of recombinant human MG53 (rhMG53) protein in aged mice. Echocardiography and pressure-volume loop measurements revealed beneficial effects of rhMG53 treatment in improving heart function of aged mice. Biochemical and histological studies demonstrated that the cardioprotective effects of rhMG53 are linked to suppression of NF-κB-mediated inflammation, reducing apoptotic cell death and oxidative stress in the aged heart. Repetitive administration of rhMG53 in aged mice did not have adverse effects on major vital organ functions. These findings support the therapeutic value of rhMG53 in treating age-related decline in cardiac function.
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http://dx.doi.org/10.1172/jci.insight.148375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492351PMC
September 2021

Cardiac effects and clinical applications of MG53.

Cell Biosci 2021 Jun 28;11(1):115. Epub 2021 Jun 28.

Department of Surgery, The Ohio State University, Columbus, OH, USA.

Heart disease remains the leading cause of mortality globally, so further investigation is required to identify its underlying mechanisms and potential targets for treatment and prevention. Mitsugumin 53 (MG53), also known as TRIM72, is a TRIM family protein that was found to be involved in cell membrane repair and primarily found in striated muscle. Its role in skeletal muscle regeneration and myogenesis has been well documented. However, accumulating evidence suggests that MG53 has a potentially protective role in heart tissue, including in ischemia/reperfusion injury of the heart, cardiomyocyte membrane injury repair, and atrial fibrosis. This review summarizes the regulatory role of MG53 in cardiac tissues, current debates regarding MG53 in diabetes and diabetic cardiomyopathy, as well as highlights potential clinical applications of MG53 in treating cardiac pathologies.
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http://dx.doi.org/10.1186/s13578-021-00629-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240287PMC
June 2021

Efficient precise in vivo base editing in adult dystrophic mice.

Nat Commun 2021 06 17;12(1):3719. Epub 2021 Jun 17.

Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

Recent advances in base editing have created an exciting opportunity to precisely correct disease-causing mutations. However, the large size of base editors and their inherited off-target activities pose challenges for in vivo base editing. Moreover, the requirement of a protospacer adjacent motif (PAM) nearby the mutation site further limits the targeting feasibility. Here we modify the NG-targeting adenine base editor (iABE-NGA) to overcome these challenges and demonstrate the high efficiency to precisely edit a Duchenne muscular dystrophy (DMD) mutation in adult mice. Systemic delivery of AAV9-iABE-NGA results in dystrophin restoration and functional improvement. At 10 months after AAV9-iABE-NGA treatment, a near complete rescue of dystrophin is measured in mdx mouse hearts with up to 15% rescue in skeletal muscle fibers. The off-target activities remains low and no obvious toxicity is detected. This study highlights the promise of permanent base editing using iABE-NGA for the treatment of monogenic diseases.
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http://dx.doi.org/10.1038/s41467-021-23996-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211797PMC
June 2021

Muscle multiorgan crosstalk with MG53 as a myokine for tissue repair and regeneration.

Curr Opin Pharmacol 2021 08 27;59:26-32. Epub 2021 May 27.

Department of Surgery Division of Cardiac Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA. Electronic address:

Through stress and injury to tissues, the cell membrane is damaged and can lead to cell death and a cascade of inflammatory events. Soluble factors that mitigate and repair membrane injury are important to normal homeostasis and are a potential therapeutic intervention for regenerative medicine. A myokine is a type of naturally occurring factors that come from muscle and have impact on remote organs. MG53, a tripartite motif-containing family protein, is such a myokine which has protective effects on lungs, kidneys, liver, heart, eye, and brain. Three mechanisms of action for the beneficial regenerative medicine potential of MG53 have been identified and consist of 1) repair of acute injury to the cellular membrane, 2) anti-inflammatory effects associated with chronic injuries, and 3) rejuvenation of stem cells for tissue regeneration. As such, MG53 has the potential to be a novel and effective regeneration medicine therapeutic.
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http://dx.doi.org/10.1016/j.coph.2021.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8513491PMC
August 2021

Recombinant Human MG53 Protein Protects Against Alkaline-Induced Corneal Injuries in Mice.

Mil Med 2021 01;186(Suppl 1):486-490

Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA.

Introduction: The current study was designed to test the potential role of recombinant human MG53 (rhMG53) protein on protecting against alkaline-induced corneal injury in mice.

Materials And Methods: A round filter paper with 2-mm diameter was soaked in 1 mol/L of NaOH solution. The mouse alkaline injury was generated by placing the filter paper directly on the cornea for 30 seconds and washed with 30-mL saline; 10 µL of rhMG53 solution (20 µg/mL) or saline control was topically administrated on the mouse corneas (twice per day for 10 days). Re-epithelialization was measured by fluorescein staining and imaged by a slit lamp equipped with a digital camera. Clinical neovascularization and opacity scores were measured every day after injury. Ten days after injury, mice were sacrificed and corneas were dissected out for flat mount staining of CD31 for neovascularization.

Results: MG53 was present in both dog aqueous humor and human tears. mg53-/- corneas were more susceptible to alkaline-induced corneal injury. Topical treatment of rhMG53 improved re-epithelialization, suppressed neovascularization, and fibrosis induced by alkaline injury.

Conclusions: rhMG53 may be an effective means to treat corneal wounding.
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http://dx.doi.org/10.1093/milmed/usaa357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980491PMC
January 2021

MG53 as a Novel Therapeutic Protein to Treat Acute Lung Injury.

Mil Med 2021 01;186(Suppl 1):339-345

Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA.

Introduction: Lung injury has several inciting etiologies ranging from trauma (contusion and hemorrhage) to ischemia reperfusion injury. Reflective of the injury, tissue and cellular injury increases proportionally with the injury stress and is an area of potential intervention to mitigate the injury. This study aims to evaluate the therapeutic benefits of recombinant human MG53 (rhMG53) protein in porcine models of acute lung injury (ALI).

Materials And Methods: We utilized live cell imaging to monitor the movement of MG53 in cultured human bronchial epithelial cells following mechanical injury. The in vivo efficacy of rhMG53 was evaluated in a porcine model of hemorrhagic shock/contusive lung injury. Varying doses of rhMG53 (0, 0.2, or 1 mg/kg) were administered intravenously to pigs after induction of hemorrhagic shock/contusive induced ALI. Ex vivo lung perfusion system enabled assessment of the isolated porcine lung after a warm ischemic induced injury with rhMG53 supplementation in the perfusate (1 mg/mL).

Results: MG53-mediated cell membrane repair is preserved in human bronchial epithelial cells. rhMG53 mitigates lung injury in the porcine model of combined hemorrhagic shock/contusive lung injury. Ex vivo lung perfusion administration of rhMG53 reduces warm ischemia-induced injury to the isolated porcine lung.

Conclusions: MG53 is an endogenous protein that circulates in the bloodstream. Therapeutic treatment with exogenous rhMG53 may be part of a strategy to restore (partially or completely) structural morphology and/or functional lung integrity. Systemic administration of rhMG53 constitutes a potential effective therapeutic means to combat ALI.
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http://dx.doi.org/10.1093/milmed/usaa313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980479PMC
January 2021

TRIC-A regulates intracellular Ca homeostasis in cardiomyocytes.

Pflugers Arch 2021 03 21;473(3):547-556. Epub 2021 Jan 21.

Department of Surgery, The Ohio State University Columbus, Columbus, OH, 43210, USA.

Trimeric intracellular cation (TRIC) channels have been identified as monovalent cation channels that are located in the ER/SR membrane. Two isoforms discovered in mammals are TRIC-A (TMEM38a) and TRIC-B (TMEM38b). TRIC-B ubiquitously expresses in all tissues, and TRIC-B mice is lethal at the neonatal stage. TRIC-A mainly expresses in excitable cells. TRIC-A mice survive normally but show abnormal SR Ca handling in both skeletal and cardiac muscle cells. Importantly, TRIC-A mutations have been identified in human patients with stress-induced arrhythmia. In the past decade, important discoveries have been made to understand the structure and function of TRIC channels, especially its role in regulating intracellular Ca homeostasis. In this review article, we focus on the potential roles of TRIC-A in regulating cardiac function, particularly its effects on intracellular Ca signaling of cardiomyocytes and discuss the current knowledge gaps.
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http://dx.doi.org/10.1007/s00424-021-02513-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940156PMC
March 2021

MG53, A Tissue Repair Protein with Broad Applications in Regenerative Medicine.

Cells 2021 01 11;10(1). Epub 2021 Jan 11.

Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.

Under natural conditions, injured cells can be repaired rapidly through inherent biological processes. However, in the case of diabetes, cardiovascular disease, muscular dystrophy, and other degenerative conditions, the natural repair process is impaired. Repair of injury to the cell membrane is an important aspect of physiology. Inadequate membrane repair function is implicated in the pathophysiology of many human disorders. Recent studies show that Mitsugumin 53 (MG53), a TRIM family protein, plays a key role in repairing cell membrane damage and facilitating tissue regeneration. Clarifying the role of MG53 and its molecular mechanism are important for the application of MG53 in regenerative medicine. In this review, we analyze current research dissecting MG53's function in cell membrane repair and tissue regeneration, and highlight the development of recombinant human MG53 protein as a potential therapeutic agent to repair multiple-organ injuries.
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http://dx.doi.org/10.3390/cells10010122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827922PMC
January 2021

Multi-Cellular Functions of MG53 in Muscle Calcium Signaling and Regeneration.

Front Physiol 2020 6;11:583393. Epub 2020 Nov 6.

Department of Surgery, The Ohio State University, Columbus, OH, United States.

Since its identification in 2009, multiple studies have indicated the importance of MG53 in muscle physiology. The protein is produced in striated muscles but has physiologic implications reaching beyond the confines of striated muscles. Roles in muscle regeneration, calcium homeostasis, excitation-contraction coupling, myogenesis, and the mitochondria highlight the protein's wide-reaching impact. Numerous therapeutic applications could potentially emerge from these physiologic roles. This review summarizes the current literature regarding the role of MG53 in the skeletal muscle. Therapeutic applications are discussed.
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http://dx.doi.org/10.3389/fphys.2020.583393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677405PMC
November 2020

Peptidylarginine deiminase 2 has potential as both a biomarker and therapeutic target of sepsis.

JCI Insight 2020 10 15;5(20). Epub 2020 Oct 15.

Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.

Peptidylarginine deiminases (PADs) are a family of calcium-dependent enzymes that are involved in a variety of human disorders, including cancer and autoimmune diseases. Although targeting PAD4 has shown no benefit in sepsis, the role of PAD2 remains unknown. Here, we report that PAD2 is engaged in sepsis and sepsis-induced acute lung injury in both human patients and mice. Pad2-/- or selective inhibition of PAD2 by a small molecule inhibitor increased survival and improved overall outcomes in mouse models of sepsis. Pad2 deficiency decreased neutrophil extracellular trap (NET) formation. Importantly, Pad2 deficiency inhibited Caspase-11-dependent pyroptosis in vivo and in vitro. Suppression of PAD2 expression reduced inflammation and increased macrophage bactericidal activity. In contrast to Pad2-/-, Pad4 deficiency enhanced activation of Caspase-11-dependent pyroptosis in BM-derived macrophages and displayed no survival improvement in a mouse sepsis model. Collectively, our findings highlight the potential of PAD2 as an indicative marker and therapeutic target for sepsis.
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http://dx.doi.org/10.1172/jci.insight.138873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605547PMC
October 2020

Peptidylarginine Deiminases 2 Mediates Caspase-1-Associated Lethality in Pseudomonas aeruginosa Pneumonia-Induced Sepsis.

J Infect Dis 2021 Mar;223(6):1093-1102

Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan, USA.

Background: Pseudomonas aeruginosa (PA) is a pathogenic bacterium that causes severe pneumonia in critically ill and immunocompromised patients. Peptidylarginine deiminase (PAD) 2, PAD4, and caspase-1 are important enzymes in mediating host response to infection. The goal of this study was to determine the interplay between PAD2, PAD4, and caspase-1 in PA pneumonia-induced sepsis.

Methods: Pneumonia was produced in wild-type, Pad2-/-, and Pad4-/- mice by intranasal inoculation of PA (2.5 × 106 colony-forming units per mouse), and survival (n = 15/group) was monitored for 10 days. Bone marrow-derived macrophages (BMDMs) were isolated for in vitro studies. Samples were collected at specific timepoints for Western blot, bacterial load determination, and flow cytometry analysis.

Results: Caspase-1-dependent inflammation was diminished in PA-inoculated Pad2-/- mice, contributing to reduced macrophage death and enhanced bacterial clearance. In addition, Pad2-/- mice exhibited improved survival and attenuated acute lung injury after PA infection. In contrast, Pad4-/- mice did not display diminished caspase-1 activation, altered bacterial loads, or improved survival.

Conclusions: Peptidylarginine deiminase 2 plays an essential role in the pathogenesis of pulmonary sepsis by mediating caspase-1 activation. This goes against previous findings of PAD4 in sepsis. Our study suggests that PAD2 is a potential therapeutic target of PA pneumonia-induced sepsis.
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http://dx.doi.org/10.1093/infdis/jiaa475DOI Listing
March 2021

MG53 suppresses interferon-β and inflammation via regulation of ryanodine receptor-mediated intracellular calcium signaling.

Nat Commun 2020 07 17;11(1):3624. Epub 2020 Jul 17.

Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

TRIM family proteins play integral roles in the innate immune response to virus infection. MG53 (TRIM72) is essential for cell membrane repair and is believed to be a muscle-specific TRIM protein. Here we show human macrophages express MG53, and MG53 protein expression is reduced following virus infection. Knockdown of MG53 in macrophages leads to increases in type I interferon (IFN) upon infection. MG53 knockout mice infected with influenza virus show comparable influenza virus titres to wild type mice, but display increased morbidity accompanied by more accumulation of CD45+ cells and elevation of IFNβ in the lung. We find that MG53 knockdown results in activation of NFκB signalling, which is linked to an increase in intracellular calcium oscillation mediated by ryanodine receptor (RyR). MG53 inhibits IFNβ induction in an RyR-dependent manner. This study establishes MG53 as a new target for control of virus-induced morbidity and tissue injury.
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http://dx.doi.org/10.1038/s41467-020-17177-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368064PMC
July 2020

Corrigendum to "A systematic comparison of exercise training protocols on animal models of cardiovascular capacity" [Life Sci. 217 (2019) 128-140].

Life Sci 2020 Aug 4;254:117757. Epub 2020 Jun 4.

National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China/CGDB, Shaanxi Normal University College of Life Sciences, Xi'an 710119, China. Electronic address:

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http://dx.doi.org/10.1016/j.lfs.2020.117757DOI Listing
August 2020

Correction to: A novel organ preservation solution with efficient clearance of red blood cells improves kidney transplantation in a canine model.

Cell Biosci 2020 9;10:62. Epub 2020 May 9.

1Institute of Organ Transplantation, Key Laboratory of the Ministry of Health and the Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China.

[This corrects the article DOI: 10.1186/s13578-018-0226-2.].
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http://dx.doi.org/10.1186/s13578-020-00421-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211332PMC
May 2020

Nonalcoholic fatty liver disease experiences accumulation of hepatic liquid crystal associated with increasing lipophagy.

Cell Biosci 2020 6;10:55. Epub 2020 Apr 6.

Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, Xi'an, 710062 China.

Background: In the past 30 years, incidences of non-alcoholic fatty liver disease (NAFLD) has risen by 30%. However, there is still no clear mechanism or accurate method of anticipating liver failure. Here we reveal the phase transitions of liquid crystalline qualities in hepatic lipid droplets (HLDs) as a novel method of anticipating prognosis.

Methods: NAFLD was induced by feeding C57BL/6J mice on a high-fat (HiF) diet. These NAFLD livers were then evaluated under polarized microscopy, X-ray diffraction and small-angle scattering, lipid component chromatography analysis and protein expression analysis. Optically active HLDs from mouse model and patient samples were both then confirmed to have liquid crystal characteristics. Liver MAP1LC3A expression was then evaluated to determine the role of autophagy in liquid crystal HLD (LC-HLD) formation.

Results: Unlike the normal diet cohort, HiF diet mice developed NAFLD livers containing HLDs exhibiting Maltese cross birefringence, phase transition, and fluidity signature to liquid crystals. These LC-HLDs transitioned to anisotropic crystal at 0 °C and remain crystalline. Temperature increase to 42 °C causes both liquid crystal and crystal HLDs to convert to isotropic droplet form. These isotropic HLDs successfully transition to anisotropic LC with fast temperature decrease and anisotropic crystal with slow temperature decrease. These findings were duplicated in patient liver. Patient LC-HLDs with no inner optical activity were discovered, hinting at lipid saturation as the mechanism through which HLD acquire LC characteristics. Downregulation of MAP1LC3A in conjunction with increased LC-HLD also implicated autophagy in NAFLD LC-HLD formation.

Conclusions: Increasing concentrations of amphiphilic lipids in HLDs favors organization into alternating hydrophilic and hydrophobic layers, which present as LC-HLDs. Thus, evaluating the extent of liquid crystallization with phase transition in HLDs of NAFLD patients may reveal disease severity and predict impending liver damage.
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http://dx.doi.org/10.1186/s13578-020-00414-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137450PMC
April 2020

Calcium-dependent Protein Kinases in Malaria Parasite Development and Infection.

Cell Transplant 2020 Jan-Dec;29:963689719884888

National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, Shaanxi Normal University College of Life Sciences, Xi'an, China.

Apicomplexan parasites have challenged researchers for nearly a century. A major challenge to developing efficient treatments and vaccines is the parasite's ability to change its cellular and molecular makeup to develop intracellular and extracellular niches in its hosts. Ca signaling is an important messenger for the egress of the malaria parasite from the infected erythrocyte, gametogenesis, ookinete motility in the mosquito, and sporozoite invasion of mammalian hepatocytes. Calcium-dependent protein kinases (CDPKs) have crucial functions in calcium signaling at various stages of the parasite's life cycle; this therefore makes them attractive drug targets against malaria. Here, we summarize the functions of the various CDPK isoforms in relation to the malaria life cycle by emphasizing the molecular mechanism of developmental progression within host tissues. We also discuss the current development of anti-malarial drugs, such as how specific bumped kinase inhibitors (BKIs) for parasite CDPKs have been shown to reduce infection in , , and . Our suggested combinations of BKIs, artemisinin derivatives with peroxide bridge, and inhibitors on the Ca(2+)-ATPase PfATP6 as a potential target should be inspected further as a treatment against malaria.
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http://dx.doi.org/10.1177/0963689719884888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444236PMC
February 2021

MG53 Does Not Manifest the Development of Diabetes in Mice.

Diabetes 2020 05 5;69(5):1052-1064. Epub 2020 Mar 5.

Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH

MG53 is a member of the TRIM protein family that is predominantly expressed in striated muscles and participates in cell membrane repair. Controversy exists regarding MG53's role in insulin signaling and manifestation of diabetes. We generated mice with either whole-body ablation or sustained elevation of MG53 in the bloodstream in order to evaluate the physiological function of MG53 in diabetes. To quantify the amount of MG53 protein in circulation, we developed a monoclonal antibody against MG53 with high specificity. Western blot using this antibody revealed lower or no change of serum MG53 levels in mice or patients with diabetes compared with control subjects. Neither whole-body ablation of MG53 nor sustained elevation of MG53 in circulation altered insulin signaling and glucose handling in mice. Instead, mice with ablation of MG53 were more susceptible to streptozotocin-induced dysfunctional handling of glucose compared with the wild-type littermates. Alkaline-induced corneal injury demonstrated delayed healing in mice, which was restored by topical administration of recombinant human (rh)MG53. Daily intravenous administration of rhMG53 in rats at concentrations up to 10 mg/kg did not produce adverse effects on glucose handling. These findings challenge the hypothetical function of MG53 as a causative factor for the development of diabetes. Our data suggest that rhMG53 is a potentially safe and effective biologic to treat diabetic oculopathy in rodents.
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http://dx.doi.org/10.2337/db19-0807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171965PMC
May 2020

TRIC-A Channel Maintains Store Calcium Handling by Interacting With Type 2 Ryanodine Receptor in Cardiac Muscle.

Circ Res 2020 02 6;126(4):417-435. Epub 2019 Dec 6.

From the Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus (X. Zhou, K.H.P., P.-h.L., J.M.).

Rationale: Trimeric intracellular cation (TRIC)-A and B are distributed to endoplasmic reticulum/sarcoplasmic reticulum intracellular Ca stores. The crystal structure of TRIC has been determined, confirming the homotrimeric structure of a potassium channel. While the pore architectures of TRIC-A and TRIC-B are conserved, the carboxyl-terminal tail (CTT) domains of TRIC-A and TRIC-B are different from each other. Aside from its recognized role as a counterion channel that participates in excitation-contraction coupling of striated muscles, the physiological function of TRIC-A in heart physiology and disease has remained largely unexplored.

Objective: In cardiomyocytes, spontaneous Ca waves, triggered by store overload-induced Ca release mediated by the RyR (type 2 ryanodine receptor), develop extrasystolic contractions often associated with arrhythmic events. Here, we test the hypothesis that TRIC-A is a physiological component of RyR-mediated Ca release machinery that directly modulates store overload-induced Ca release activity via CTT.

Methods And Results: We show that cardiomyocytes derived from the TRIC-A (TRIC-A knockout) mice display dysregulated Ca movement across sarcoplasmic reticulum. Biochemical studies demonstrate a direct interaction between CTT-A and RyR. Modeling and docking studies reveal potential sites on RyR that show differential interactions with CTT-A and CTT-B. In HEK293 (human embryonic kidney) cells with stable expression of RyR, transient expression of TRIC-A, but not TRIC-B, leads to apparent suppression of spontaneous Ca oscillations. Ca measurements using the cytosolic indicator Fura-2 and the endoplasmic reticulum luminal store indicator D1ER suggest that TRIC-A enhances Ca leak across the endoplasmic reticulum by directly targeting RyR to modulate store overload-induced Ca release. Moreover, synthetic CTT-A peptide facilitates RyR activity in lipid bilayer reconstitution system, enhances Ca sparks in permeabilized TRIC-A cardiomyocytes, and induces intracellular Ca release after microinjection into isolated cardiomyocytes, whereas such effects were not observed with the CTT-B peptide. In response to isoproterenol stimulation, the TRIC-A mice display irregular ECG and develop more fibrosis than the WT (wild type) littermates.

Conclusions: In addition to the ion-conducting function, TRIC-A functions as an accessory protein of RyR to modulate sarcoplasmic reticulum Ca handling in cardiac muscle.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.316241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035183PMC
February 2020

The TRIM protein Mitsugumin 53 enhances survival and therapeutic efficacy of stem cells in murine traumatic brain injury.

Stem Cell Res Ther 2019 11 28;10(1):352. Epub 2019 Nov 28.

School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China.

Background: Traumatic brain injury (TBI) is a common neurotrauma leading to brain dysfunction and death. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) hold promise in the treatment of TBI. However, their efficacy is modest due to low survival and differentiation under the harsh microenvironment of the injured brain. MG53, a member of TRIM family protein, plays a vital role in cell and tissue damage repair. The present study aims to test whether MG53 preserves hUC-MSCs against oxidative stress and enhances stem cell survival and efficacy in TBI treatment.

Methods: In this study, we performed a series of in vitro and in vivo experiments in hUC-MSCs and mice to define the function of MG53 enhancing survival, neurogenesis, and therapeutic efficacy of stem cells in murine traumatic brain injury.

Results: We found that recombinant human MG53 (rhMG53) protein protected hUC-MSCs against HO-induced oxidative damage and stimulated hUC-MSC proliferation and migration. In a mouse model of contusion-induced TBI, intravenous administration of MG53 protein preserved the survival of transplanted hUC-MSCs, mitigated brain edema, reduced neurological deficits, and relieved anxiety and depressive-like behaviors. Co-treatment of MG53 and hUC-MSCs enhanced neurogenesis by reducing apoptosis and improving PI3K/Akt-GSK3β signaling.

Conclusion: MG53 enhances the efficacy of hUC-MSCs in the recovery of TBI, indicating that such adjunctive therapy may provide a novel strategy to lessen damage and optimize recovery for brain injury.
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http://dx.doi.org/10.1186/s13287-019-1433-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883632PMC
November 2019

N-acetylcysteine prevents oxidized low-density lipoprotein-induced reduction of MG53 and enhances MG53 protective effect on bone marrow stem cells.

J Cell Mol Med 2020 01 19;24(1):886-898. Epub 2019 Nov 19.

Center for Precision Medicine and Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, Missouri, USA.

MG53 is an important membrane repair protein and partially protects bone marrow multipotent adult progenitor cells (MAPCs) against oxidized low-density lipoprotein (ox-LDL). The present study was to test the hypothesis that the limited protective effect of MG53 on MAPCs was due to ox-LDL-induced reduction of MG53. MAPCs were cultured with and without ox-LDL (0-20 μg/mL) for up to 48 hours with or without MG53 and antioxidant N-acetylcysteine (NAC). Serum MG53 level was measured in ox-LDL-treated mice with or without NAC treatment. Ox-LDL induced significant membrane damage and substantially impaired MAPC survival with selective inhibition of Akt phosphorylation. NAC treatment effectively prevented ox-LDL-induced reduction of Akt phosphorylation without protecting MAPCs against ox-LDL. While having no effect on Akt phosphorylation, MG53 significantly decreased ox-LDL-induced membrane damage and partially improved the survival, proliferation and apoptosis of MAPCs in vitro. Ox-LDL significantly decreased MG53 level in vitro and serum MG53 level in vivo without changing MG53 clearance. NAC treatment prevented ox-LDL-induced MG53 reduction both in vitro and in vivo. Combined NAC and MG53 treatment significantly improved MAPC survival against ox-LDL. These data suggested that NAC enhanced the protective effect of MG53 on MAPCs against ox-LDL through preventing ox-LDL-induced reduction of MG53.
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http://dx.doi.org/10.1111/jcmm.14798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933383PMC
January 2020

Sustained elevation of MG53 in the bloodstream increases tissue regenerative capacity without compromising metabolic function.

Nat Commun 2019 10 11;10(1):4659. Epub 2019 Oct 11.

Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, 43210, USA.

MG53 is a muscle-specific TRIM-family protein that presides over the cell membrane repair response. Here, we show that MG53 present in blood circulation acts as a myokine to facilitate tissue injury-repair and regeneration. Transgenic mice with sustained elevation of MG53 in the bloodstream (tPA-MG53) have a healthier and longer life-span when compared with littermate wild type mice. The tPA-MG53 mice show normal glucose handling and insulin signaling in skeletal muscle, and sustained elevation of MG53 in the bloodstream does not have a deleterious impact on db/db mice. More importantly, the tPA-MG53 mice display remarkable dermal wound healing capacity, enhanced muscle performance, and improved injury-repair and regeneration. Recombinant human MG53 protein protects against eccentric contraction-induced acute and chronic muscle injury in mice. Our findings highlight the myokine function of MG53 in tissue protection and present MG53 as an attractive biological reagent for regenerative medicine without interference with glucose handling in the body.
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http://dx.doi.org/10.1038/s41467-019-12483-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789113PMC
October 2019

Spatiotemporal delivery of basic fibroblast growth factor to directly and simultaneously attenuate cardiac fibrosis and promote cardiac tissue vascularization following myocardial infarction.

J Control Release 2019 10 12;311-312:233-244. Epub 2019 Sep 12.

Department of Materials Science and Engineering, The Ohio State University, Columbus, OH 43210, United States of America; Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO 63130, USA. Electronic address:

Following myocardial infarction (MI), the destruction of vasculature in the infarcted heart muscle and progression of cardiac fibrosis lead to cardiac function deterioration. Vascularization of the damaged tissue and prevention of cardiac fibrosis represent promising strategies to improve cardiac function. Herein we have developed a bFGF release system with suitable release kinetics to simultaneously achieve the two goals. The release system was based on an injectable, thermosensitive, and fast gelation hydrogel and bFGF. The hydrogel had gelation time <7 s. It can quickly solidify upon injection into tissue so as to increase drug retention in the tissue. Hydrogel complex modulus can be tuned by hydrogel solution concentration. The complex modulus of 176.6 Pa and lower allowed cardiac fibroblast to maintain its phenotype. Bioactive bFGF was able to gradually release from the hydrogel for 4 weeks. The released bFGF promoted cardiac fibroblast survival under ischemic conditions mimicking those of the infarcted hearts. It also attenuated cardiac fibroblasts from differentiating into myofibroblasts in the presence of TGFβ when tested in 3D collagen model mimicking the scenario when the bFGF release system was injected into hearts. Furthermore, the released bFGF stimulated human umbilical endothelial cells to form endothelial lumen. After 4 weeks of implantation into infarcted hearts, the bFGF release system significantly increased blood vessel density, decreased myofibroblast density and collagen content, augmented cardiac cell survival/proliferation, and reduced macrophage density. In addition, the bFGF release system significantly increased cardiac function. These results demonstrate that delivery of bFGF with appropriate release kinetics alone may represent an efficient approach to control cardiac remodeling after MI.
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http://dx.doi.org/10.1016/j.jconrel.2019.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874903PMC
October 2019

Physical exercise: bulking up neurogenesis in human adults.

Cell Biosci 2019 3;9:74. Epub 2019 Sep 3.

1National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China/CGDB, Shaanxi Normal University College of Life Sciences, Xi'an, 710119 China.

Whether neurogenesis occurs in the adult human brain has been a long-debated topic fueled by conflicting data both for and against neurogenesis in the mature brain. Recent reports from two independent teams may have indubitably proven that adult, hippocampal neurogenesis persists throughout the human lifespan. Llorens-Martín et al. found that thousands of immature, neurogenesis related, doublecortin-positive (DCX) labelled neurons can be detected in the human dentate gyrus (DG) up to the eighth decade of life. While the presence of these DCX neurons decrease with age, they are significantly decrease in patient with Alzheimer's disease. Another group have also found mammalian embryonic Hopx precursors to persist beyond the early development stage as quiescent Hopx radial glial-like neural progenitors during early postnatal period, then as Hopx adult dentate neural progenitors. Together, the findings from these two groups suggest that unlike the previously thought, neurogenesis and neuroplasticity can occur well into adulthood in some capacity, at least in the hippocampus. These recent findings that neurogenesis can occur beyond development have brought into questions whether physical exercise can be shown to promote neurogenesis and brain health, as it has been shown to promote the function of other organ systems. Some data has already shown physical exercise to induce adult hippocampal neurogenesis (AHN) as demonstrated by restoration of cognitive functions, improvement of synaptic plasticity, and enhancement of angiogenesis. A large-scale meta-analysis has also demonstrated that 45-60 min of moderate-intensity physical exercise to dramatically improve cognitive functions in human subjects over the age of 50. Given these convergent developments in our understanding of neurogenesis and exercise induced improvement in cognitive function, we speculate that hippocampal neurogenesis can be promoted by physical exercise and discuss the current molecular evidence supporting the likely molecular pathways involved.
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http://dx.doi.org/10.1186/s13578-019-0337-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724373PMC
September 2019

MG53 attenuates lipopolysaccharide-induced neurotoxicity and neuroinflammation via inhibiting TLR4/NF-κB pathway in vitro and in vivo.

Prog Neuropsychopharmacol Biol Psychiatry 2019 12 29;95:109684. Epub 2019 Jun 29.

School of Life Sciences, Zhengzhou University, Zhengzhou 450001, Henan, China. Electronic address:

Neuroinflammation plays important roles in the pathogenesis and development of neurodegenerative disorders. Lipopolysaccharide (LPS) induces neuroinflammation and causes neurotoxicity, which results in cell damage or memory impairment in different cells and animals. In the present study, we investigated the neuroprotective effects of MG53, a member of the TRIM family proteins, against LPS-induced neuroinflammation and neurotoxicity in vitro and in vivo. MG53 significantly protected HT22 cells against LPS-induced cell apoptosis and cell cycle arrest by inhibiting TNF-α, IL-6 and IL-1β expression. In addition, MG53 ameliorated LPS-induced memory impairment and neuronal cell death in mice. Interestingly, MG53 significantly promoted newborn cell survival, improved neurogenesis, and mitigated neuroinflammation evidenced by lower production of IL-1β and IL-6, less activation of microglia in the hippocampus of LPS treated mice. Further studies demonstrated that MG53 significantly inhibited TLR4 expression and nuclear factor-κB (NF-κB) phosphorylation in LPS treated HT22 cells and mice. Taken together, our results suggested that MG53 attenuated LPS-induced neurotoxicity and neuroinflammation partly by inhibiting TLR4/NF-κB pathway in vitro and in vivo.
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http://dx.doi.org/10.1016/j.pnpbp.2019.109684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708450PMC
December 2019

Extraocular muscle function is impaired in mice.

J Gen Physiol 2019 07 13;151(7):929-943. Epub 2019 May 13.

Department of Anesthesia, Basel University Hospital, Basel, Switzerland

Calcium is an ubiquitous second messenger mediating numerous physiological processes, including muscle contraction and neuronal excitability. Ca is stored in the ER/SR and is released into the cytoplasm via the opening of intracellular inositol trisphosphate receptor and ryanodine receptor calcium channels. Whereas in skeletal muscle, isoform 1 of the RYR is the main channel mediating calcium release from the SR leading to muscle contraction, the function of ubiquitously expressed ryanodine receptor 3 (RYR3) is far from clear; it is not known whether RYR3 plays a role in excitation-contraction coupling. We recently reported that human extraocular muscles express high levels of RYR3, suggesting that such muscles may be useful to study the function of this isoform of the Ca channel. In the present investigation, we characterize the visual function of mice. We observe that ablation of RYR3 affects both mechanical properties and calcium homeostasis in extraocular muscles. These changes significantly impact vision. Our results reveal for the first time an important role for RYR3 in extraocular muscle function.
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http://dx.doi.org/10.1085/jgp.201912333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605690PMC
July 2019
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