Direct conversion of cardiac fibroblasts into endothelial-like cells using Sox17 and Erg.

Endothelial cells are a heterogeneous population with various organ-specific and conserved functions that are critical to organ development, function, and regeneration. Here we report a Sox17-Erg direct reprogramming approach that uses cardiac fibroblasts to create differentiated endothelial cells that demonstrate endothelial-like molecular and physiological functions in vitro and in vivo. Injection of these induced endothelial cells into myocardial infarct sites after injury results in improved vascular perfusion of the scar region. Furthermore, we use genomic analyses to illustrate that Sox17-Erg reprogramming instructs cardiac fibroblasts toward an arterial-like identity. This results in a more efficient direct conversion of fibroblasts into endothelial-like cells when compared to traditional Etv2-based reprogramming. Overall, this Sox17-Erg direct reprogramming strategy offers a robust tool to generate endothelial cells both in vitro and in vivo, and has the potential to be used in repairing injured tissue.

HMG-B transcription factors of unicellular opisthokonts and their relatedness to the Sox-Tcf/Lef-Mata proteins of Metazoa and fungi.

A phylogenetic analysis of transcription factors of the Sox-Tcf/Lef-Mata (STM) family of the HMG-B superfamily was carried out in order to clarify the evolutionary roots of the Wnt signaling pathway in unicellular organisms. The data set for analysis included protein sequences of metazoans, fungi, unicellular opisthokonts, apusomonads and amoebozoans. The topology of the phylogenetic tree suggests that STM-related proteins arose in the common ancestor of Opisthokonta and Amoebozoa, two of amoebozoan STM proteins are sister-related to opisthokont ones and the three known lineages of STM transcription factors (STM family in narrow sence) are found in Opisthokonta only. Of these, the holozoan Sox protein branch is the result of either the first or second branching, that originated in the common ancestor of Opisthokonta. The lineage containing Tcf/Lef proteins (holozoan) and the lineage containing Mata proteins (holomycotan) are sister. They derived either at the time of the Holozoa and Holomycota divergence or originate from two paralogs of the common ancestor of Opisthokonta, which arose after the separation of the Sox lineage. Interaction with Armadillo-like proteins may be an original feature of the STM protein family and existed in the unicellular ancestors of multicellular animals; a connection is possible between the presence of Mata-related proteins in Aphelidium protococcorum and specific genome feature of this species.

Deubiquitinase UCHL1 promotes angiogenesis and blood-spinal cord barrier function recovery after spinal cord injury by stabilizing Sox17.

Improving the function of the blood-spinal cord barrier (BSCB) benefits the functional recovery of mice following spinal cord injury (SCI). The death of endothelial cells and disruption of the BSCB at the injury site contribute to secondary damage, and the ubiquitin-proteasome system is involved in regulating protein function. However, little is known about the regulation of deubiquitinated enzymes in endothelial cells and their effect on BSCB function after SCI. We observed that Sox17 is predominantly localized in endothelial cells and is significantly upregulated after SCI and in LPS-treated brain microvascular endothelial cells. In vitro Sox17 knockdown attenuated endothelial cell proliferation, migration, and tube formation, while in vivo Sox17 knockdown inhibited endothelial regeneration and barrier recovery, leading to poor functional recovery after SCI. Conversely, in vivo overexpression of Sox17 promoted angiogenesis and functional recovery after injury. Additionally, immunoprecipitation-mass spectrometry revealed the interaction between the deubiquitinase UCHL1 and Sox17, which stabilized Sox17 and influenced angiogenesis and BSCB repair following injury. By generating UCHL1 conditional knockout mice and conducting rescue experiments, we further validated that the deubiquitinase UCHL1 promotes angiogenesis and restoration of BSCB function after injury by stabilizing Sox17. Collectively, our findings present a novel therapeutic target for treating SCI by revealing a potential mechanism for endothelial cell regeneration and BSCB repair after SCI.

Repeated co-option of HMG-box genes for sex determination in brown algae and animals.

In many eukaryotes, genetic sex determination is not governed by XX/XY or ZW/ZZ systems but by a specialized region on the poorly studied U (female) or V (male) sex chromosomes. Previous studies have hinted at the existence of a dominant male-sex factor on the V chromosome in brown algae, a group of multicellular eukaryotes distantly related to animals and plants. The nature of this factor has remained elusive. Here, we demonstrate that an HMG-box gene acts as the male-determining factor in brown algae, mirroring the role HMG-box genes play in sex determination in animals. Over a billion-year evolutionary timeline, these lineages have independently co-opted the HMG box for male determination, representing a paradigm for evolution's ability to recurrently use the same genetic "toolkit" to accomplish similar tasks.

LCP1-mediated cytoskeleton alterations involve in arsenite-triggered malignant phenotype of human immortalized prostate stromal cells.

The connection between continuous arsenic exposure and prostate cancer is already established. However, the exact mechanisms of arsenic tumorigenesis are far from clear. Here, we employed human prostate stromal immortalized cells (WPMY-1) continuous exposure to 1 and 2 µM arsenite for 29 weeks to identify the malignant phenotype and explore the underlying molecular mechanism. As expected, continuous low-dose arsenite exposure led to the malignant phenotype of WPMY-1 cells. Quantitative proteomics identified 517 differentially expressed proteins (DEPs), of which the most remarkably changed proteins (such as LCP1 and DDX58, etc.) and the bioinformatic analysis were focused on the regulation of cytoskeleton, cell adhesion, and migration. Further, cell experiments showed that continuous arsenite exposure altered cytoskeleton structure, enhanced cell adhesive capability, and raised the levels of reactive oxygen species (ROS), ATM, p-ATM, p-ERK1/2, and LCP1 proteins. N-acetylcysteine (NAC) treatment antagonized the increase of LCP1 proteins, and LCP1 knockdown partially restored F-actin organization caused by arsenic. Overall, the results demonstrated that ROS-ATM-ERK1/2 signaling pathway was involved in the activation of LCP1, leading to cytoskeleton alterations. These alterations are believed to play a significant role in arsenite-triggered tumor microenvironment cell-acquired malignant phenotype, which could provide potential biomarkers with therapeutic implications for prostate cancer.

Increased serum levels of high-mobility group box 1 protein and the location characteristics in the patients of intracranial aneurysms.

OBJECTIVE: Inflammation-related factors play a crucial role in intracranial aneurysms (IA) initiation, progression, and rupture. High mobility group box 1 (HMGB-1) serves as an alarm to drive the pathogenesis of the inflammatory disease. This study aimed to evaluate the role of HMGB-1 in IA and explore the correlation with other inflammatory-related factors. METHODS: A total of twenty-eight adult male Japanese white rabbits were included in with elastase-induced aneurysms, n = 18) and the control group (normal rabbits, n = 10). To assess the expression of HMGB-1, both reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) was performed on serum samples obtained from human subjects (10 patients with IA and 10 healthy donors) as well as from rabbits (aneurysm group and control group). Immunohistochemistry and immunofluorescence were employed to evaluate the expression levels of elastic fibers, HMGB-1, tumor necrosis factor-alpha (TNF-α), and triggering receptor expressed on myeloid cells-1 (TREM-1). RESULTS: The expression of HMGB-1 was found to be significantly higher in the IA group compared to the control group, both at the mRNA and protein levels (P < 0.0001). Similar findings were observed in the rabbit aneurysm model group compared to the control group (P < 0.0001). HMGB-1 expression was observed to be more abundant in the inner wall of the aneurysm compared to the external wall, whereas in the control group, it was rarely scattered. Additionally, the localization patterns of TNF-α and TREM-1 exhibited similar characteristics to HMGB-1. CONCLUSION: Our findings demonstrate that HMGB-1 is highly expressed in both IA patients and rabbit aneurysm models. Furthermore, the similar localization patterns of HMGB-1, TNF-α, and TREM-1 suggest their potential involvement in the inflammatory processes associated with IA. These results highlight the potential of HMGB-1 as a novel therapeutic target for IA.

Expression of Tissue Factor and Platelet/Leukocyte Markers on Extracellular Vesicles Reflect Platelet-Leukocyte Interaction in Severe COVID-19.

Severe COVID-19 is frequently associated with thromboembolic complications. Increased platelet activation and platelet-leukocyte aggregate formation can amplify thrombotic responses by inducing tissue factor (TF) expression on leukocytes. Here, we characterized TF-positive extracellular vesicles (EVs) and their cellular origin in 12 patients suffering from severe COVID-19 (time course, 134 samples overall) and 25 healthy controls. EVs exposing phosphatidylserine (PS) were characterized by flow cytometry. Their cellular origin was determined by staining with anti-CD41, anti-CD45, anti-CD235a, and anti-CD105 as platelet, leukocyte, red blood cell, and endothelial markers. We further investigated the association of EVs with TF, platelet factor 4 (PF4), C-reactive protein (CRP), and high mobility group box-1 protein (HMGB-1). COVID-19 patients showed higher levels of PS-exposing EVs compared to controls. The majority of these EVs originated from platelets. A higher amount of EVs in patient samples was associated with CRP, HMGB-1, PF4, and TF as compared to EVs from healthy donors. In COVID-19 samples, 16.5% of all CD41+ EVs displayed the leukocyte marker CD45, and 55.5% of all EV aggregates (CD41+CD45+) co-expressed TF, which reflects the interaction of platelets and leukocytes in COVID-19 on an EV level.

Combined extract (Curcuma longa-Glycyrrhiza glabra) alleviates the inflammations of Achilles tendinopathy in Wistar rats.

OBJECTIVE: Achilles tendinopathy is a frequent pathological condition in adults with overused ankles, causing microtrauma, inducing tenocyte apoptosis and inflammatory response. Common treatment involves oral prescription or injection of anti-inflammatory agents, surgery, or shock-wave therapy. However, prolonged administration is not advisable due to adverse effects. Therefore, a novel and safe regimen is needed. Curcuma longa and Glycyrrhiza glabra extracts are known for their anti-inflammatory effects owing to their active compounds (curcumin and glycyrrhizin, respectively). This study aimed to determine the effect of combined extracts of Curcuma longa and Glycyrrhiza glabra on tendon healing in an animal model of Achilles tendinopathy (Wistar rats). MATERIALS AND METHODS: This study took place from February to May 2022 and compared the regimens administered to 32 animal models of Wistar rats with 4 healthy rats as a control group to determine the most effective therapeutic regimen: immobilization, immobilization with ibuprofen, or immobilization with the combined extract. The outcomes were measured to find which intervention provided the lowest inflammatory markers [High Mobility Group Box-1 (HMGB-1), Tumor Necrosis Factor-α (TNF-α), Chemokin motif ligand 12 (CXCL-12)], and improved tissue morphology represented by the BONAR score, decreased cross-sectional area (CSA), and increased Macrophage 2 (M2) differentiation. RESULTS: After Achilles tendinopathy was induced, total immobilization (I1) was proven to be the most effective with the lowest CSA, whereas immobilization+175 mg/kg Curcuma longa+110 mg/kg Glycyrrhiza glabra extract (I5) was the most effective with the lowest HMGB-1 levels and the lowest CXCL-12 levels. Immobilization+131 mg/kg Curcuma longa+82.5 mg/kg Glycyrrhiza glabra extract (I6) was the most effective with the lowest Bonar score, while immobilization+87.5 mg/kg Curcuma longa+55 mg/kg Glycyrrhiza glabra extract (I7) was proven to be the most effective with the highest M2 coverage area and the lowest TNF-α levels. CONCLUSIONS: We found that combined extract therapy was the most effective intervention for treating Achilles tendinopathy due to its ability to provide the lowest inflammatory markers.

Evaluating the protective role of trimetazidine versus nano-trimetazidine in amelioration of bilateral renal ischemia/reperfusion induced neuro-degeneration: Implications of ERK1/2, JNK and Galectin-3 /NF-κB/TNF-α/HMGB-1 signaling.

BACKGROUND: Renal ischemia/reperfusion (I/R) is a primary culprit of acute kidney injury. Neurodegeneration can result from I/R, but the mechanisms are still challenging. We studied the implications of bilateral renal I/R on brain and potential involvement of the oxidative stress (OS) driven extracellular signal-regulated kinase1/2, c-Jun N-terminal kinase (ERK1/2, JNK) and Galectin-3 (Gal-3)/nuclear factor Kappa B (NF-қB)/tumor necrosis factor-alpha (TNF-α), high mobility group box-1 (HMGB-1), and caspase-3 paths upregulation. We tested the impact of Nano-trimetazidine (Nano-TMZ) on these pathways being a target of its neuroprotective effects. METHODS: Study groups; Sham, I/R, TMZ+I/R, and Nano-TMZ+I/R. Kidney functions, cognition, hippocampal OS markers, Gal-3, NF-қB, p65 and HMGB-1 gene expression, TNF-α level, t-JNK/p-JNK and t-ERK/p-ERK proteins, caspase-3, glial fibrillary acidic protein (GFAP) and ionized calcium binding protein-1 (Iba-1) were assessed. RESULTS: Nano-TMZ averted renal I/R-induced hippocampal impairment by virtue of its anti: oxidative, inflammatory, and apoptotic properties. CONCLUSION: Nano-TMZ is more than anti-ischemic.

Two mitochondrial HMG-box proteins, Cim1 and Abf2, antagonistically regulate mtDNA copy number in Saccharomyces cerevisiae.

The mitochondrial genome, mtDNA, is present in multiple copies in cells and encodes essential subunits of oxidative phosphorylation complexes. mtDNA levels have to change in response to metabolic demands and copy number alterations are implicated in various diseases. The mitochondrial HMG-box proteins Abf2 in yeast and TFAM in mammals are critical for mtDNA maintenance and packaging and have been linked to mtDNA copy number control. Here, we discover the previously unrecognized mitochondrial HMG-box protein Cim1 (copy number influence on mtDNA) in Saccharomyces cerevisiae, which exhibits metabolic state dependent mtDNA association. Surprisingly, in contrast to Abf2's supportive role in mtDNA maintenance, Cim1 negatively regulates mtDNA copy number. Cells lacking Cim1 display increased mtDNA levels and enhanced mitochondrial function, while Cim1 overexpression results in mtDNA loss. Intriguingly, Cim1 deletion alleviates mtDNA maintenance defects associated with loss of Abf2, while defects caused by Cim1 overexpression are mitigated by simultaneous overexpression of Abf2. Moreover, we find that the conserved LON protease Pim1 is essential to maintain low Cim1 levels, thereby preventing its accumulation and concomitant repressive effects on mtDNA. We propose a model in which the protein ratio of antagonistically acting Cim1 and Abf2 determines mtDNA copy number.

RNA helicase DHX33 regulates HMGB family genes in human cancer cells.

RNA helicase DHX33 has been shown to be aberrantly expressed in various human cancers, however, its role in tumorigenesis remains incompletely understood. In this report, we uncovered that a family of DNA architecture proteins, HMGBs, can be regulated by DHX33 in cancer cells but not in normal cells. Specifically, DHX33 knockdown caused the downregulation of HMGBs at the levels of both gene transcription and protein expression. Notably, in RAS driven lung tumorigenesis, nuclear HMGBs proteins can be induced via DHX33. When DHX33 was knocked out, HMGBs overexpression was debilitated. Mechanistically, DHX33 was found to bind to the promoters of HMGB family genes and regulated their transcription through demethylation on gene promoters. Our study reveals a novel mechanism for DHX33 to promote tumorigenesis and highlights its therapeutic value in human cancers.

Early and Dose-Dependent Xenogeneic Mesenchymal Stem Cell Therapy Improved Outcomes in Acute Respiratory Distress Syndrome Rodent Through Ameliorating Inflammation, Oxidative Stress, and Immune Reaction.

This study tested whether human umbilical cord-derived mesenchymal stem cells (HUCDMSCs) treatment effectively protected the rat lung against acute respiratory distress syndrome (ARDS) injury, and benefits of early and dose-dependent treatment. Rat pulmonary epithelial cell line L2 (PECL2) were categorized into G1 (PECL2), G2 (PECL2 + healthy rat lung-derived extraction/50 mg/ml co-cultured for 24 h), G3 (PECL2 + ARDS rat lung-derived extraction/50 mg/ml co-cultured for 24 h), and G4 (condition as G3 + HUCDMSCs/1 × 105/co-cultured for 24 h). The result showed that the protein expressions of inflammatory (HMGB-1/TLR-2/TLR-4/MAL/TRAM/MyD88/TRIF/TRAF6/IkB/NF-κB/IL-1ß/TNF-α), oxidative-stress/mitochondrial-damaged (NOX-1/NOX-2/ASK1/p-MKK4/p-MKK7/JNKs/JUN/cytosolic-cytochrome-C/cyclophilin-D/DRP1), and cell-apoptotic/fibrotic (cleaved-caspase 3/cleaved-PARP/TGF-ß/p-Smad3) biomarkers were significantly increased in G3 than in G1/G2 and were significantly reversed in G4 (all P < 0.001), but they were similar between G1/G2. Adult male rats (n = 42) were equally categorized into group 1 (normal control), group 2 (ARDS only), group 3 [ARDS + HUCDMSCs/1.2 × 106 cells intravenous administration at 3 h after 48 h ARDS induction (i.e., early treatment)], group 4 [ARDS + HUCDMSCs/1.2 × 106 cells intravenous administration at 24 h after 48 h ARDS induction (late treatment)], and group 5 [ARDS + HUCDMSCs/1.2 × 106 cells intravenous administration at 3 h/24 h after-48 h ARDS induction (dose-dependent treatment)]. By day 5 after ARDS induction, the SaO2%/immune regulatory T cells were highest in group 1, lowest in group 2, significantly lower in group 4 than in groups 3/5, and significantly lower in group 3 than in group 5, whereas the circulatory/bronchioalveolar lavage fluid inflammatory cells (CD11b-c+/LyG6+/MPO+)/circulatory immune cells (CD3-C4+/CD3-CD8+)/lung-leakage-albumin level/lung injury score/lung protein expressions of inflammatory (HMGB-1/TLR-2/TLR-4/MAL/TRAM/MyD88/TRIF/TRAF6/IκB-ß/p-NF-κB/IL-1ß/TNF-α)/fibrotic (p-SMad3/TGF-ß), apoptosis (mitochondrial-Bax/cleaved-caspase-3)/oxidative-cell-stress (NOX-1/NOX-2/ASK1/p-MKK4/p-MKK7/p-JNKs/p-cJUN)/mitochondrial damaged (cyclophilin-D/DRP1/cytosolic-cytochrome-C) biomarkers displayed an opposite pattern of SaO2% among the groups (all P < 0.0001). Early administration was superior to and two-dose counterpart was even more superior to late HUCDMSCs treatment for protecting the lung against ARDS injury.

An engineered Sox17 induces somatic to neural stem cell fate transitions independently from pluripotency reprogramming.

Advanced strategies to interconvert cell types provide promising avenues to model cellular pathologies and to develop therapies for neurological disorders. Yet, methods to directly transdifferentiate somatic cells into multipotent induced neural stem cells (iNSCs) are slow and inefficient, and it is unclear whether cells pass through a pluripotent state with full epigenetic reset. We report iNSC reprogramming from embryonic and aged mouse fibroblasts as well as from human blood using an engineered Sox17 (eSox17FNV). eSox17FNV efficiently drives iNSC reprogramming while Sox2 or Sox17 fail. eSox17FNV acquires the capacity to bind different protein partners on regulatory DNA to scan the genome more efficiently and has a more potent transactivation domain than Sox2. Lineage tracing and time-resolved transcriptomics show that emerging iNSCs do not transit through a pluripotent state. Our work distinguishes lineage from pluripotency reprogramming with the potential to generate more authentic cell models for aging-associated neurodegenerative diseases.

Glycyrrhizic Acid Inhibits High-Mobility Group Box-1 and Homocysteine-Induced Vascular Dysfunction.

Hyperhomocysteinemia (HHcy) worsens cardiovascular outcomes by impairing vascular function and promoting chronic inflammation via release of danger-associated molecular patterns, such as high-mobility group box-1 (HMGB-1). Elevated levels of HMGB-1 have recently been reported in patients with HHcy. Therefore, targeting HMGB-1 may be a potential therapy to improve HHcy-induced cardiovascular pathologies. This study aimed to further elucidate HMGB-1's role during acute HHcy and HHcy-induced atherogenesis and to determine if inhibiting HMGB-1 with glycyrrhizic acid (Glyz) improved vascular function. Male New Zealand White rabbits (n = 25) were placed on either a standard control chow (CD; n = 15) or atherogenic diet (AD; n = 10) for 4 weeks. Rabbit serum and Krebs taken from organ bath studies were collected to quantify HMGB-1 levels. Isometric tension analysis was performed on abdominal aorta (AA) rings from CD and AD rabbits. Rings were incubated with homocysteine (Hcy) [3 mM] for 60 min to induce acute HHcy or rhHMGB-1 [100 nM]. Vascular function was assessed by relaxation to cumulative doses of acetylcholine. Markers of vascular dysfunction and inflammation were quantified in the endothelium, media, and adventitia of AA rings. HMGB-1 was significantly upregulated in serum (p < 0.0001) and Krebs (p < 0.0001) after Hcy exposure or an AD. Incubation with Hcy (p < 0.0001) or rhHMGB-1 (p < 0.0001) and an AD (p < 0.0001) significantly reduced relaxation to acetylcholine, which was markedly improved by Glyz. HMGB-1 expression was elevated (p < 0.0001) after Hcy exposure and AD (p < 0.0001) and was normalized after Glyz treatment. Moreover, markers of vascular function, cell stress and inflammation were also reduced after Glyz. These results demonstrate that HMGB-1 has a central role during HHcy-induced vascular dysfunction and inhibiting it with Glyz could be a potential treatment option for cardiovascular diseases.

HMGB family proteins: Potential biomarkers and mechanistic factors in cardiovascular diseases.

Cardiovascular disease (CVD) is the most fatal disease that causes sudden death, and inflammation contributes substantially to its occurrence and progression. The prevalence of CVD increases as the population ages, and the pathophysiology is complex. Anti-inflammatory and immunological modulation are the potential methods for CVD prevention and treatment. High-Mobility Group (HMG) chromosomal proteins are one of the most abundant nuclear nonhistone proteins which act as inflammatory mediators in DNA replication, transcription, and repair by producing cytokines and serving as damage-associated molecular patterns in inflammatory responses. The most common and well-studied HMG proteins are those with an HMGB domain, which participate in a variety of biological processes. HMGB1 and HMGB2 were the first members of the HMGB family to be identified and are present in all investigated eukaryotes. Our review is primarily concerned with the involvement of HMGB1 and HMGB2 in CVD. The purpose of this review is to provide a theoretical framework for diagnosing and treating CVD by discussing the structure and function of HMGB1 and HMGB2.

Artemisinin attenuates type 2 diabetic cardiomyopathy in rats through modulation of AGE-RAGE/HMGB-1 signaling pathway.

Diabetes mellitus is a common metabolic disorder. About two-thirds of diabetic patients develop diabetic cardiomyopathy (DCM), which becomes a challenging issue as it severely threatens the patient's life. Hyperglycemia and the resulting advanced glycated end products (AGE) and their receptor (RAGE)/High Mobility Group Box-1 (HMGB-1) molecular pathway are thought to be key players. Recently, artemisinin (ART) has gained more attention owing to its potent biological activities beyond its antimalarial effect. Herein, we aim to evaluate the effect of ART on DCM and the possible underlying mechanisms. Twenty-four male Sprague-Dawley rats were divided into: control, ART, type 2 diabetic and type 2 diabetic treated with ART groups. At the end of the research, the ECG was recorded, then the heart weight to body weight (HW/BW) ratio, fasting blood glucose, serum insulin and HOMA-IR were evaluated. Cardiac biomarkers (CK-MB and LDH), oxidative stress markers, IL-1ß, AGE, RAGE and HMGB-1 expression were also measured. The heart specimens were stained for H&E as well as Masson's trichrome. DCM induced disturbances in all studied parameters; contrary to this, ART improved these insults. Our study concluded that ART could improve DCM through modulation of the AGE-RAGE/HMGB-1 signaling pathway, with subsequent impacts on oxidative stress, inflammation and fibrosis. ART could therefore be a promising therapy for the management of DCM.

Inhibition of BRD4 expression attenuates the inflammatory response and apoptosis by downregulating the HMGB-1/NF-κB signaling pathway following traumatic brain injury in rats.

Neuroinflammation plays an important part in secondary traumatic brain injury (TBI). Bromodomain-4 (BRD4) exerts specific proinflammatory effects in various neuropathological conditions. However, the underlying mechanism of action of BRD4 after TBI is not known. We measured BRD4 expression after TBI and investigated its possible mechanism of action. We established a model of craniocerebral injury in rats. After different intervention measures, we used western blotting, immunofluorescence, real-time reverse transcription-quantitative polymerase chain reaction, neuronal apoptosis, and behavioral tests to evaluate the effect of BRD4 on brain injury. At 72 h after brain injury, BRD4 overexpression aggravated the neuroinflammatory response, neuronal apoptosis, neurological dysfunction, and blood-brain-barrier damage, whereas upregulating expression of HMGB-1 and NF-κB had the opposite effect. Glycyrrhizic acid could reverse the proinflammatory effect of BRD4 overexpression upon TBI. Our results suggest that: (i) BRD4 may have a proinflammatory role in secondary brain injury through the HMGB-1/NF-κB signaling pathway; (ii) inhibition of BRD4 expression may play a part in secondary brain injury. BRD4 could be targeted therapy strategy for brain injury.

Sesquiterpene nootkatone counteracted the melamine-induced neurotoxicity via repressing of oxidative stress, inflammatory, and apoptotic trajectories.

Melamine (ML), a chemical substance of high nitrogen content, is used as a food adulterant. Former evidences implied that ML could induce a variety of toxic effects including neurotoxicity and cognitive impairment. Therefore, the aim of this study was to delineate the protective effect of the nootkatone (NK) against ML-induced neural adverse effects. Rats were orally pretreated with NK (5 and 10 mg/kg) prior to the oral administration of ML (700 mg/kg) for a period of 28 days. Our findings unveiled remarkable alleviating effect of NK on MK-induced neurobehavioral disturbance in open field test. Furthermore, NK lessened ML-caused increases in the acetylcholine esterase level in the brain tissue of exposed rats. NK also decreased the neural oxidative stress as represented by elevated levels of SOD, CAT, and GSH along with decreased MDA and NO levels. Upregulated mRNA expression levels of neural NRF-2 and HO-1 were noticed after NK administration. Remarkable anti-inflammatory impact was prominent by decreased neural IL-1ß, and TNF-α along with downregulated NF-κB and TLR-4 gene expression levels in NK-treated rats. Noteworthily, pre-treatment with NK decreased the immune reaction of RAGE and HMGB-1 induced by oral ML exposure. Brain histological examination validated the obtained biochemical and molecular results. To sum up, these outcomes reveal that NK successfully alleviated the neural damage induced by ML via blocking of oxidative stress, and inflammatory signaling pathways. Consequently, our study may suggest NK as a new effective therapeutic supplement for treatment of ML-mediated neurotoxicity in rats via inhibition of HMGB-1-RAGE/TLR-4/NF-κB.

Structure and Functions of HMGB2 Protein.

High-Mobility Group (HMG) chromosomal proteins are the most numerous nuclear non-histone proteins. HMGB domain proteins are the most abundant and well-studied HMG proteins. They are involved in variety of biological processes. HMGB1 and HMGB2 were the first members of HMGB-family to be discovered and are found in all studied eukaryotes. Despite the high degree of homology, HMGB1 and HMGB2 proteins differ from each other both in structure and functions. In contrast to HMGB2, there is a large pool of works devoted to the HMGB1 protein whose structure-function properties have been described in detail in our previous review in 2020. In this review, we attempted to bring together diverse data about the structure and functions of the HMGB2 protein. The review also describes post-translational modifications of the HMGB2 protein and its role in the development of a number of diseases. Particular attention is paid to its interaction with various targets, including DNA and protein partners. The influence of the level of HMGB2 expression on various processes associated with cell differentiation and aging and its ability to mediate the differentiation of embryonic and adult stem cells are also discussed.

Stem cells therapeutic effect in a reserpine-induced fibromyalgia rat model: A possible NLRP3 inflammasome modulation with neurogenesis promotion in the cerebral cortex.

Fibromyalgia is a chronic pain syndrome with a multifactorial pathophysiology affecting 2-8 % of the population. AIMS: To investigate the therapeutic effects of bone marrow mesenchymal stem cells (BMSCs) against fibromyalgia-related cerebral cortex damage and the possible underlying mechanisms of action. MATERIALS AND METHODS: Rats were randomly allocated into three groups; control, fibromyalgia and fibromyalgia treated with BMSCs groups. Physical and behavioural assessments were performed. Cerebral cortices were collected for biochemical and histological assessment. KEY FINDINGS: Fibromyalgia group showed behavioural changes indicating presence of pain, fatigue, depression, and sleep disturbances. Moreover, biochemical biomarkers alterations were demonstrated by a significant decrease in brain monoamines and GSH levels, but MDA, NO, TNF-alpha, HMGB-1, NLRP3, and caspase-1 levels significantly increased. Furthermore, histological assessment revealed structural and ultrastructural alterations indicating neuronal and neuroglial degeneration with microglia activation, an increase in mast cell number and IL-1ß immune-expression. Additionally, a significant decrease in Beclin-1 immune-expression, and blood brain barrier disruption were noticed. Interestingly, BMSCs administration significantly improved behavioural alterations, restored the reduced brain monoamines and oxidative stress markers, and reduced TNF-alpha, HMGB-1, NLRP3, and caspase-1 levels. Profoundly, cerebral cortices demonstrated improved histological structure, significant decrease in mast cell number and IL-1ß immune-expression, besides a significant increase in Beclin-1 and DCX immune-expression. SIGNIFICANCE: For the best of our knowledge, this is the first study showing ameliorative effects for BMSCs treatment in fibromyalgia-related cerebral cortical damage. The neurotherapeutic effects of BMSCs could be attributed to NLRP3 inflammasome signaling pathway inhibition, mast cell deactivation, and stimulation of neurogenesis and autophagy.