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This review examines the roles of HS–proteoglycans (HS–PGs) in general, and, in particular, perlecan and syndecan as representative examples and their interactive ligands, which regulate physiological processes and cellular behavior in health and disease. HS–PGs are essential for the functional properties of tissues both in development and in the extracellular matrix (ECM) remodeling that occurs in response to trauma or disease. HS–PGs interact with a biodiverse range of chemokines, chemokine receptors, protease inhibitors, and growth factors in immune regulation, inflammation, ECM stabilization, and tissue protection. Some cell regulatory proteoglycan receptors are dually modified hybrid HS/CS proteoglycans (betaglycan, CD47). Neurexins provide synaptic stabilization, plasticity, and specificity of interaction, promoting neurotransduction, neurogenesis, and differentiation. Ternary complexes of glypican-1 and Robbo–Slit neuroregulatory proteins direct axonogenesis and neural network formation. Specific neurexin–neuroligin complexes stabilize synaptic interactions and neural activity. Disruption in these interactions leads to neurological deficits in disorders of functional cognitive decline. Interactions with HS–PGs also promote or inhibit tumor development. Thus, HS–PGs have complex and diverse regulatory roles in the physiological processes that regulate cellular behavior and the functional properties of normal and pathological tissues. Specialized HS–PGs, such as the neurexins, pikachurin, and Eyes-shut, provide synaptic stabilization and specificity of neural transduction and also stabilize the axenome primary cilium of phototoreceptors and ribbon synapse interactions with bipolar neurons of retinal neural networks, which are essential in ocular vision. Pikachurin and Eyes–Shut interactions with an α-dystroglycan stabilize the photoreceptor synapse. Novel regulatory roles for HS–PGs controlling cell behavior and tissue function are expected to continue to be uncovered in this fascinating class of proteoglycan. [ABSTRACT FROM AUTHOR]

Pentosan polysulfate (PPS), a small semi-synthetic highly sulfated heparan sulfate (HS)-like molecule, shares many of the interactive properties of HS. The aim of this review was to outline the potential of PPS as an interventional therapeutic protective agent in physiological processes affecting pathological tissues. PPS is a multifunctional molecule with diverse therapeutic actions against many disease processes. PPS has been used for decades in the treatment of interstitial cystitis and painful bowel disease, it has tissue-protective properties as a protease inhibitor in cartilage, tendon and IVD, and it has been used as a cell-directive component in bioscaffolds in tissue engineering applications. PPS regulates complement activation, coagulation, fibrinolysis and thrombocytopenia, and it promotes the synthesis of hyaluronan. Nerve growth factor production in osteocytes is inhibited by PPS, reducing bone pain in osteoarthritis and rheumatoid arthritis (OA/RA). PPS also removes fatty compounds from lipid-engorged subchondral blood vessels in OA/RA cartilage, reducing joint pain. PPS regulates cytokine and inflammatory mediator production and is also an anti-tumor agent that promotes the proliferation and differentiation of mesenchymal stem cells and the development of progenitor cell lineages that have proven to be useful in strategies designed to effect repair of the degenerate intervertebral disc (IVD) and OA cartilage. PPS stimulates proteoglycan synthesis by chondrocytes in the presence or absence of interleukin (IL)-1, and stimulates hyaluronan production by synoviocytes. PPS is thus a multifunctional tissue-protective molecule of potential therapeutic application for a diverse range of disease processes. [ABSTRACT FROM AUTHOR]

Sepsis is a life-threatening condition characterized by uncontrolled systemic inflammation and coagulation, leading to multiorgan failure. Therapeutic options to prevent sepsis-associated immunopathology remain scarce. Here, we established a mouse model of long-lasting disease tolerance during severe sepsis, manifested by diminished immunothrombosis and organ damage in spite of a high pathogen burden. We found that both neutrophils and B cells emerged as key regulators of tissue integrity. Enduring changes in the transcriptional profile of neutrophils include upregulated Cxcr4 expression in protected, tolerant hosts. Neutrophil Cxcr4 upregulation required the presence of B cells, suggesting that B cells promoted disease tolerance by improving tissue damage control via the suppression of neutrophils’ tissue-damaging properties. Finally, therapeutic administration of a Cxcr4 agonist successfully promoted tissue damage control and prevented liver damage during sepsis. Our findings highlight the importance of a critical B-cell/neutrophil interaction during sepsis and establish neutrophil Cxcr4 activation as a potential means to promote disease tolerance during sepsis.

Gaseous molecules have been increasingly explored for therapeutic development. Here, following an analytical background introduction, a systematic review of medical gas research is presented, focusing on tissue protections, mechanisms, data tangibility, and translational challenges. The pharmacological efficacies of carbon monoxide (CO) and xenon (Xe) are further examined with emphasis on intracellular messengers associated with cytoprotection and functional improvement for the CNS, heart, retina, liver, kidneys, lungs, etc. Overall, the outcome supports the hypothesis that readily deliverable "biological gas" (CO, H2, H2S, NO, O2, O3, and N2O) or "noble gas" (He, Ar, and Xe) treatment may preserve cells against common pathologies by regulating oxidative, inflammatory, apoptotic, survival, and/or repair processes. Specifically, CO, in safe dosages, elicits neurorestoration via igniting sGC/cGMP/MAPK signaling and crosstalk between HO‐CO, HIF‐1α/VEGF, and NOS pathways. Xe rescues neurons through NMDA antagonism and PI3K/Akt/HIF‐1α/ERK activation. Primary findings also reveal that the need to utilize cutting‐edge molecular and genetic tactics to validate mechanistic targets and optimize outcome consistency remains urgent; the number of neurotherapeutic investigations is limited, without published results from large in vivo models. Lastly, the broad‐spectrum, concurrent multimodal homeostatic actions of medical gases may represent a novel pharmaceutical approach to treating critical organ failure and neurotrauma. [ABSTRACT FROM AUTHOR]

The development of long lasting therapeutic agents is critically important for efficient treatment of chronic diseases. We herein report a rational strategy to develop a therapeutic thermogel featured with prolonged anti-inflammatory and corneal-protective effects. Specifically, a hyaluronic acid with different sulfation degrees and an amine-terminated poly(N-isopropylacrylamide) are conjugated to achieve the thermogels. In vitro studies reveal that the thermogels are highly biocompatible to statens seruminstitut rabbit cornea cells and their anti-inflammatory properties are strongly dependent on the sulfation degree. In a rabbit model of ocular inflammation, single-dose topical administration of a thermogel formulation could repair defects in corneal epithelium (∼99% thickness restored), prevent corneal cell apoptosis (∼68.3% cells recovered), and suppress ocular surface inflammation (∼4-fold decrease) for a follow-up period of 7 days. This high treatment efficacy of the thermogel can be attributed to its potent inhibition in selectin-mediated leukocyte infiltration as well as effective corneal protection. These findings show a great promise for topical treatment of ocular inflammation and advancement of ophthalmic formulations using the bioactive thermogel as a therapeutic component that is not rapidly cleared from the eye and thus considerably reduces administration times.

Erythropoietin (EPO) is used at present in clinical practice to stimulate red cell production. However, a number of reports have emerged suggesting the presence of nonerythropoietic properties for EPO. Chief among them is its ability to confer protection against acute tissue injury. In this report, we briefly review the role of EPO in tissue protection and provide examples of tissue protection using cisplatin-induced kidney injury model. Also provided is a brief description of potential pathways through which EPO may be mediating this effect.

As the second wave of coronavirus disease 2019 (COVID-19) is well under way around the world, the optimal therapeutic approach that addresses virus replication and hyperinflammation leading to tissue injury remains elusive. This issue of Clinical Kidney Journal provides further evidence of complement activation involvement in COVID-19. Taking advantage of the unique repeat access to chronic haemodialysis patients, the differential time course of C3 and C5 activation in relation to inflammation and severity of disease have been characterized. This further points to complement as a therapeutic target. Indeed, clinical trials targeting diverse components of complement are ongoing. However, a unique case of COVID-19 in a patient with pre-existent atypical haemolytic syndrome on chronic eculizumab therapy suggests that even early eculizumab may fail to prevent disease progression to a severe stage. Finally, preclinical studies in endotoxaemia, another hyperinflammation syndrome characterized by lung and kidney injury, suggest that cilastatin, an inexpensive drug already in clinical use, may provide tissue protection against hyperinflammation in COVID-19. [ABSTRACT FROM AUTHOR]

Annexin-A1 (ANXA1) was first discovered in the early 1980's as a protein, which mediates (some of the) anti-inflammatory effects of glucocorticoids. Subsequently, the role of ANXA1 in inflammation has been extensively studied. The biology of ANXA1 is complex and it has many different roles in both health and disease. Its effects as a potent endogenous anti-inflammatory mediator are well-described in both acute and chronic inflammation and its role in activating the pro-resolution phase receptor, FPR2, has been described and is now being exploited for therapeutic benefit. In the present mini review, we will endeavor to give an overview of ANXA1 biology in relation to inflammation and functions that mediate pro-resolution that are independent of glucocorticoid induction. We will focus on the role of ANXA1 in diseases with a large inflammatory component focusing on diabetes and microvascular disease. Finally, we will explore the possibility of exploiting ANXA1 as a novel therapeutic target in diabetes and the treatment of microvascular disease.

Introduction: Knowledge of thermally induced skin injury has increased, but its pathophysiology remains unclear. Although it is assumed that local cooling may protect tissue, little is known about the impact of local heating on human skin. This study aimed to evaluate acute skin perfusion dynamics following thermal stimuli in healthy human volunteers.Material and Methods: In 54 subjects, a TSA-II-NeuroSensory Analyzer was used to induce local hypothermia (15 °C and 5 °C) and local hyperthermia (40 °C and 45 °C) at the palmar forearm of healthy volunteers. Changes in tissue microcirculation were assessed using an O2C device before and after each temperature change.Results: Blood flow and velocity values showed a continuous decrease with decreasing skin temperature, whereas haemoglobin oxygen saturation (SO2) showed a continuous increase in superficial (2 mm) and deep layers (8 mm). With increasing skin temperature, flow, SO2 and velocity increased in the superficial and deep layers. The relative amount of haemoglobin (rHB) did not show a continuous alteration.Discussion: Local cooling may protect damaged tissue due to increased SO2 (lower oxygen consumption). However, reduced blood flow and velocity in response to local cooling limit nutrient requirements and the transport of metabolites. Despite higher oxygen consumption of tissue at higher temperatures, both blood flow and SO2 increase. Thus, we hypothesize that not only hypothermia but also hyperthermia may provide tissue protection. [ABSTRACT FROM AUTHOR]

Highlights • Late treadmill training caused better functional activity. • Late locomotor training preserved motoneurons in the spinal cord. • Early treadmill training did not facilitate functional recovery. • Early locomotor training increased the spinal lesion volume. Abstract Locomotor training (LT) has been exhaustively investigated as a treatment for the spinal cord injury (SCI), however the literature reports both positive and negative effects over the functional recovery. The initiation period of LT following SCI is one of the major variables that needs attention. To investigate the better period, three different starting times were investigated after SCI in rats. Methods: Wistar rats were randomly divided into groups: control, SCI (rats with spinal cord contusion), and SCI groups exposed to LT starting 7, 14 or 28 days after the injury (SCI-T7, SCI-T14 and SCI-T28). LT was performed on a treadmill, five days a week, 20 minutes per day, for ten weeks. Basso, Breattie and Bresnahan (BBB) scale and Horizontal Ladder walking test were used to evaluate the motor function; at the end, morphological and biochemical analyses of the spinal cords, tibialis anterior and soleus muscles were performed. Results: SCI-T14 and SCI-T28 groups had an improvement in both behavioral tests, while SCI-T7 presented a worsening in the functional performance. Late training groups preserved motoneurons in the spinal cord, showed larger muscle fiber areas and higher BDNF expression in tibialis anterior muscle. SCI-T7 group had higher lesion volume after LT in comparison with the SCI group. Late onset of LT promoted an increment of the hindlimb function, while early onset of training worsened the functional recovery of the SCI animals. These results demonstrate a critical LT starting time after the injury, contributing to define the best therapeutic window for rehabilitation. [ABSTRACT FROM AUTHOR]

A number of remote robotic catheter systems have been developed to protect physicians from X-ray exposure in endovascular surgery. However, the teleoperation prevents the physicians sensing the force directly which may easily result in healthy vessels injured. To realize the safe operation, a tissue protection-based VR training system has been developed in this paper to prevent collateral damage by collision. The integrated VR simulator cannot only remind the novice possible collisions by visual signs, but also cooperate with the newly designed tissue protection mechanism to remit collision trauma beforehand. Such mechanism exploits the diameter variable pulley in order to implement the safe interaction between catheter and vasculature. To testify the effectiveness of the tissue protection in training system, we invited four non-medical students to participate the successive 5 days training session. The evaluation results show that the average impingement distance (representing tissue damage) to vascular wall has been reduced to 0.6 mm, and the collision frequency is greatly decreased which implies the realization of relative safe catheterization. [ABSTRACT FROM AUTHOR]

The current study was designed to investigate the potential effect of Spirulina platensis, Arthrospira platensis, (SP) on tissue protection of Nile tilapia (Oreochromis niloticus) through estimation of P53 level. Five isonitrogenous and isocaloric rations containing graded levels of dried SP 5, 7.5,10, 15, and 20 g/kg diet were fed separately to five equal groups of O. niloticus fingerlings, additional control group was assigned for 3 months. Liver samples were separately collected from each group by the end of each month. The expression level of P53 showed a substantial decrease among the treated groups in a time-dependent manner. It is therefore advisable to incorporate SP in diets for tissue protection and antioxidant effects in cultured O. niloticus.

Stem cells from human exfoliated deciduous teeth (SHED) transplants have been investigated as a possible treatment strategy for spinal cord injuries (SCI) due to their potential for promoting functional recovery. The aim of present study was to investigate the effects of SHED on neuronal death after an experimental model of SCI. Methods: Wistar rats were spinalized using NYU impactor®. Animals were randomly distributed into 4 groups: Control (Naive) or Surgical control, Sham (laminectomy with no SCI); SCI (laminectomy followed by SCI, treated with vehicle); SHED (SCI treated with intraspinal transplantation of 3 × 10 5 SHED, 1 h after SCI). Functional evaluations and morphological analysis were performed to confirm the spinal injury and the benefit of SHED transplantation on behavior, tissue protection and motor neuron survival. Flow cytometry of neurons, astrocytes, macrophages/microglia and T cells of spinal cord tissue were run at six, twenty-four, forty-eight and seventy-two hours after lesion. Six hours after SCI, ELISA and Western Blot were run to assess pro- and anti-apoptotic factors. The SHED group showed a significant functional improvement in comparison to the SCI animals, as from the first week until the end of the experiment. This behavioral protection was associated with less tissue impairment and greater motor neuron preservation. SHED reduced neuronal loss over time, as well as the overexpression of pro-apoptotic factor TNF-α, while maintained basal levels of the anti-apoptotic BCL-XL six hours after lesion. Data here presented show that SHED transplantation one hour after SCI interferes with the balance between pro- and anti-apoptotic factors and reduces early neuronal apoptosis, what contributes to tissue and motor neuron preservation and hind limbs functional recovery. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-22 is a cytokine displaying tissue protective and pro-regenerative functions in various preclinical disease models. Anti-bacterial, pro-proliferative, and anti-apoptotic properties mediated by activation of the transcription factor signal transducer and activator of transcription (STAT)-3 are key to biological functions of this IL-10 family member. Herein, we introduce RINm5F insulinoma cells as rat ß-cell line that, under the influence of IL-22, displays activation of STAT3 with induction of its downstream gene targets Socs3, Bcl3, and Reg3ß. In addition, IL-22 also activates STAT1 in this cell type. To refine those observations, IL-22 biological activity was evaluated using ex vivo cultivated murine pancreatic islets. In accord with data on RINm5F cells, islet exposure to IL-22 activated STAT3 and upregulation of STAT3-inducible Socs3, Bcl3, and STEAP4 was evident under those conditions. As these observations supported the hypothesis that IL-22 may exert protective functions in toxic ß-cell injury, application of IL-22 was investigated in murine multiple-low-dose streptozotocin (STZ)-induced diabetes. For that purpose, recombinant IL-22 was administered thrice either immediately before and at disease onset (at d4, d6, d8) or closely thereafter (at d8, d10, d12). These two IL-22-treatment periods coincide with two early peaks of ß-cell injury detectable in this model. Notably, none of the two IL-22-treatment strategies affected diabetes incidence or blood glucose levels in STZ-treated mice. Moreover, pathological changes in islet morphology analyzed 28 days after disease induction were not ameliorated by IL-22 administration. Taken together, despite being active on rat RINm5F insulinoma cells and murine pancreatic islets, recombinant IL-22 fails to protect pancreatic ß-cells in the tested protocols from toxic effects of STZ and thus is unable to ameliorate disease in the widely used model of STZ-induced diabetes.

Background: Erythropoiesis stimulating agents (ESAs) were proposed to enhance survival of renal tissues through direct effects via activation of EPO receptors on renal cells resulting in reduced cell apoptosis, or indirect effects via increased oxygen delivery due to increased numbers of Hb containing red blood cells. Thus through several mechanisms there may be benefit of ESA administration on kidney disease progression and kidney function in renal patients. However conflicting ESA reno-protection outcomes have been reported in both pre-clinical animal studies and human clinical trials. To better understand the potential beneficial effects of ESAs on renal-patients, meta-analyses of clinical trials is needed.Methods: Literature searches and manual searches of references lists from published studies were performed. Controlled trials that included ESA treatment on renal patients with relevant renal endpoints were selected.Results: Thirty two ESA controlled trials in 3 categories of intervention were identified. These included 7 trials with patients who had a high likelihood of AKI, 7 trials with kidney transplant patients and 18 anemia correction trials with chronic kidney disease (predialysis) patients. There was a trend toward improvement in renal outcomes in the ESA treated arm of AKI and transplant trials, but none reached statistical significance. In 12 of the anemia correction trials, meta-analyses showed no difference in renal outcomes with the anemia correction but both arms received some ESA treatment making it difficult to assess effects of ESA treatment alone. However, in 6 trials the low Hb arm received no ESAs and meta-analysis also showed no difference in renal outcomes, consistent with no benefit of ESA/ Hb increase.Conclusions: Most ESA trials were small with modest event rates. While trends tended to favor the ESA treatment arm, these meta-analyses showed no reduction of incidence of AKI, no reduction in DGF or improvement in 1-year graft survival after renal transplantation and no significant delay in progression of CKD. These results do not support significant clinical reno-protection by ESAs. [ABSTRACT FROM AUTHOR]

The main function of erythropoietin (EPO) is to maintain red blood cell mass, but in recent years, increasing evidence has suggested a wider biological role not solely related to erythropoiesis, e.g. angiogenesis and tissue protection. EPO is produced in the liver during fetal life, but the main production shifts to the kidney after birth. The liver maintains a production capacity of up to 10% of the total EPO synthesis in healthy controls, but can be up-regulated to 90–100%. However, the hepatic EPO synthesis has been shown not to be adequate for correction of anemia in the absence of renal-derived EPO. Elevated circulating EPO has been reported in a number of diseases, but data from cirrhotic patients are sparse and the level of plasma EPO in patients with cirrhosis is controversial. Cirrhosis is characterized by liver fibrosis, hepatic dysfunction and the release of proinflammatory cytokines, which lead to arterial hypotension, hepatic nephropathy and anemia. An increase in EPO due to renal hypoperfusion, hypoxia and anemia or an EPO-mediated hepato-protective and regenerative mechanism is plausible. However, poor hepatic synthesis capacity, a decreasing co-factor level and inflammatory feedback mechanisms may explain a potential insufficient EPO response in end-stage cirrhosis. Finally, the question remains as to whether a potential increase in EPO production in certain stages of cirrhosis originates from the kidney or liver. This paper aims to review contemporary aspects of EPO relating to chronic liver disease. [ABSTRACT FROM PUBLISHER]

Interleukin (IL)-22 is a cytokine displaying tissue protective and pro-regenerative functions in various preclinical disease models. Anti-bacterial, pro-proliferative, and antiapoptotic properties mediated by activation of the transcription factor signal transducer and activator of transcription (STAT)-3 are key to biological functions of this IL-10 family member. Herein, we introduce RINm5F insulinoma cells as rat β-cell line that, under the influence of IL-22, displays activation of STAT3 with induction of its downstream gene targets Socs3, Bcl3, and Reg3b. In addition, IL-22 also activates STAT1 in this cell type. To refine those observations, IL-22 biological activity was evaluated using ex vivo cultivated murine pancreatic islets. In accord with data on RINm5F cells, islet exposure to IL-22 activated STAT3 and upregulation of STAT3-inducible Socs3, Bcl3, and Steap4 was evident under those conditions. As these observations supported the hypothesis that IL-22 may exert protective functions in toxic β-cell injury, application of IL-22 was investigated in murine multiple-low-dose streptozotocin (STZ)-induced diabetes. For that purpose, recombinant IL-22 was administered thrice either immediately before and at disease onset (at d4, d6, d8) or closely thereafter (at d8, d10, d12). These two IL-22-treatment periods coincide with two early peaks of β-cell injury detectable in this model. Notably, none of the two IL-22-treatment strategies affected diabetes incidence or blood glucose levels in STZ-treated mice. Moreover, pathological changes in islet morphology analyzed 28 days after disease induction were not ameliorated by IL-22 administration. Taken together, despite being active on rat RINm5F insulinoma cells and murine pancreatic islets, recombinant IL-22 fails to protect pancreatic β-cells in the tested protocols from toxic effects of STZ and thus is unable to ameliorate disease in the widely used model of STZ-induced diabetes. [ABSTRACT FROM AUTHOR]

Nociceptive pain is a hallmark of many chronic inflammatory conditions including inflammatory bowel diseases (IBDs); however, whether pain-sensing neurons influence intestinal inflammation remains poorly defined. Employing chemogenetic silencing, adenoviral-mediated colon-specific silencing, and pharmacological ablation of TRPV1+ nociceptors, we observed more severe inflammation and defective tissue-protective reparative processes in a murine model of intestinal damage and inflammation. Disrupted nociception led to significant alterations in the intestinal microbiota and a transmissible dysbiosis, while mono-colonization of germ-free mice with Gram+ Clostridium spp. promoted intestinal tissue protection through a nociceptor-dependent pathway. Mechanistically, disruption of nociception resulted in decreased levels of substance P, and therapeutic delivery of substance P promoted tissue-protective effects exerted by TRPV1+ nociceptors in a microbiota-dependent manner. Finally, dysregulated nociceptor gene expression was observed in intestinal biopsies from IBD patients. Collectively, these findings indicate an evolutionarily conserved functional link between nociception, the intestinal microbiota, and the restoration of intestinal homeostasis. [Display omitted] • TRPV1+ nociceptors are protective in a murine model of intestinal inflammation • Ablation of TRPV1+ nociceptors leads to a transmissible microbial dysbiosis • Clostridium spp. colonization drives nociceptor-mediated tissue protection in mice • TRPV1+ nociceptor-derived substance P promotes intestinal tissue protection Gut-innervating TRPV1+ nociceptors influence the composition of the intestinal microbiota to limit inflammation and promote intestinal tissue protection. [ABSTRACT FROM AUTHOR]

Background: Patients with mesenteric ischemia frequently suffer from bowel necrosis even after revascularization. Hydrogen gas has showed promising effects for ischemia-reperfusion injury by reducing reactive oxygen species in various animal and clinical studies. We examined intestinal tissue injury by ischemia and reperfusion under continuous initiation of 3% hydrogen gas., Aim: To clarify the treatment effects and target cells of hydrogen gas for mesenteric ischemia., Methods: Three rat groups underwent 60-min mesenteric artery occlusion (ischemia), 60-min reperfusion following 60-min occlusion (reperfusion), or ischemia-reperfusion with the same duration under continuous 3% hydrogen gas inhalation (hydrogen). The distal ileum was harvested. Immunofluorescence staining with caspase-3 and leucine-rich repeat-containing G-protein-coupled 5 (LGR5), a specific marker of intestinal stem cell, was conducted to evaluate the injury location and cell types protected by hydrogen. mRNA expressions of LGR5, olfactomedin 4 (OLFM4), hairy and enhancer of split 1, Jagged 2, and Neurogenic locus notch homolog protein 1 were measured by quantitative polymerase chain reaction. Tissue oxidative stress was analyzed with immunostaining for 8-hydroxy-2'-deoxyguanosine (8-OHdG). Systemic oxidative stress was evaluated by plasma 8-OHdG., Results: Ischemia damaged the epithelial layer at the tip of the villi, whereas reperfusion induced extensive apoptosis of the cells at the crypt base, which were identified as intestinal stem cells with double immunofluorescence stain. Hydrogen mitigated such apoptosis at the crypt base, and the LGR5 expression of the tissues was higher in the hydrogen group than in the reperfusion group. OLFM4 was also relatively higher in the hydrogen group, whereas other measured RNAs were comparable between the groups. 8-OHdG concentration was high in the reperfusion group, which was reduced by hydrogen, particularly at the crypt base. Serum 8-OHdG concentrations were relatively higher in both reperfusion and hydrogen groups without significance., Conclusion: This study demonstrated that hydrogen gas inhalation preserves intestinal stem cells and mitigates oxidative stress caused by mesenteric ischemia and reperfusion., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Abstract: The current study was designed to investigate the potential effect of Spirulina platensis, Arthrospira platensis, (SP) on tissue protection of Nile tilapia (Oreochromis niloticus) through estimation of P53 level. Five isonitrogenous and isocaloric rations containing graded levels of dried SP 5, 7.5,10, 15, and 20g/kg diet were fed separately to five equal groups of O. niloticus fingerlings, additional control group was assigned for 3months. Liver samples were separately collected from each group by the end of each month. The expression level of P53 showed a substantial decrease among the treated groups in a time-dependent manner. It is therefore advisable to incorporate SP in diets for tissue protection and antioxidant effects in cultured O. niloticus. [Copyright &y& Elsevier]

Mesenchymal stromal cells (MSC) can promote tissue protection following injury, in part by modulating inflammatory cell responses. The aim of this study was to investigate the potential tissue protective properties of encapsulated MSCs (eMSC) in an organotypic injury model induced by fibronectin culture. MSC were encapsulated in alginate beads containing a network of nanopores, which segregate the cells from the extracapsular milieu, while still permitting diffusion into and out of the capsule. An increase in blood brain barrier permeability during pathological conditions permits the influx of blood plasma constituents that can be quite harmful to surrounding tissues. In particular, increased concentrations of fibronectin have been shown in a number of diseases and CNS traumas, co-localizing in areas of activated microglia. We observed over a 14-day period, a consistent increase in OHC degradation in the presence of fibronectin measured by a significant decrease in slice area, the breakdown in OHC pyramidal layers, and consistent cell death over the culture period. Microglial ionized calcium-binding adapter molecule 1 (IBA-1) expression remained elevated throughout the culture period with the majority found within the pyramidal layers. When eMSC were added to the cultures, a significant decrease in OHC degradation was observed as reflected by a reduction in OHC area shrinkage and in the amount of cell death. In the presence of eMSC, pyramidal layer structure was maintained and axonal extension from the periphery of the OHCs was observed. Therefore, MSC, delivered in a nanoporous alginate matrix, can modulate responses to injury by reversing fibronectin-induced OHC degradation. [ABSTRACT FROM AUTHOR]

Mefenamic acid (MA) spherical agglomerates (SAs) were prepared with various polymethacrylates having different permeability characteristics (Eudragit RS 100, Eudragit RL 100 and Eudragit L 100) and also with combination of Eudragit RS 100 and Eudragit L 100 in different ratios. SAs were prepared by spherical crystallization method using ethanol/dichloromethane solvent (crystallization) system. The influence of various formulation factors on the encapsulation efficiency, as in vitro drug release, and micromeritic properties was investigated. Target release profile of MA was also drawn. The yields of preparation and the encapsulation efficiencies were high for all formulations. The shape and surface characteristics of SAs were observed by a scanning electron microscope. The particle sizes are in the range of 0.219 ± 0.1 to 0.482 ± 0.25 mm (mean ± confidence interval t95%). In addition, histological studies showed that the administration of MA in SAs containing Eudragit RS/L provided a distinct tissue protection in the stomach and duodenum. Differential scanning calorimetry and X-ray diffraction of powder studies showed that MA particles crystallized in the presence of polymethacrylates did not undergo structural modifications. [ABSTRACT FROM AUTHOR]

Background Erythropoiesis-stimulating agents (ESAs) stimulate formation of red blood cells by binding to and activating Epo receptors (EpoR) on erythroid progenitor cells. Beyond successful treatment of anemia, ESAs have been reported to reduce damage following insult to organs, including the kidney, possibly via direct activation of EpoR. However, data on ESA effects outside hematopoietic functions are conflicting. Furthermore, limited use of appropriate EpoR-positive and EpoR-negative controls and lack of specific anti-EpoR antibodies make interpretation of data difficult. Recently positive and negative control cell types were validated and a sensitive and specific anti-EpoR antibody (A82) that detects low levels of EpoR protein was described. Methods A82 was used to measure EpoR protein levels in tissues, human renal cells and human cell lines by western blot analysis. Surface EpoR was examined on renal cells by measuring binding of [125I]-rHuEpo or antibodies. Renal cells and cell lines were treated with rHuEpo to see if phosphorylation of signaling proteins or proliferation/survival could be induced. Small inhibitory RNA (siRNA) were used to determine if EpoR knockdown affected cell viability. Results Total EpoR protein was low to undetectable in tissues and renal cells with no detectable EpoR on cell surfaces. EpoR knockdown had no effect on viability of renal cell lines. RHuEpo had no detectable effect on intracellular signaling on renal cell lines with no growth-promoting or survival effect on primary human renal cells. Conclusions These results suggest that functional EpoR protein is absent on renal cells and that non-EpoR mechanisms should be explored to explain non-hematopoietic effects of ESAs. [ABSTRACT FROM PUBLISHER]

Abstract: The immune system has been shown to be involved in not only the host defense against infectious pathogens but also in tissue repair processes continuously occurring in the body. Our review presents the hypothesis about the mechanism of TLR-mediated regulation of adaptive immune responses linked to the tissue destruction. In our opinion following injury to a tissue, the expression of tissue-specific determinant/MHC class II complexes on dendritic cells and macrophages are upregulated significantly due to the increased uptake of tissue debris. Consequently, T-cells become activated as a result of low affinity, but high avidity interactions between self-reactive CD4+T cells and antigen-presenting cells (APCs). The type of self antigen-induced immune responses depends on the multiple downstream signals generated by intracellular toll-like receptors (TLRs) 3, 7, 8, and 9, that discriminate “self” and “non-self” nucleic acids. Accumulating data suggest that ligation of intracellular TLRs by endogenous DNA/RNA released from necrotic cells may result in developing Th2-like responses, as well as in the alternative activation of macrophages (M2), that favor local tissue protection and compensatory cell growth. In contrast, ligation of intracellular TLRs by exogenous pathogen-derived DNA/RNA may promote Th1-driven responses, as well as classical activation of macrophages (M1), that contribute to local tissue destruction and suppress cell growth. We suggest here that the balance between the host- and pathogen-derived nucleic acids interacting with intracellular TLRs contributes to the balance between immune-mediated tissue-protective and tissue-destructive events occurring in the body. [Copyright &y& Elsevier]

The present study was carried out to elucidate the potential of petroleum ether and methanolic extract of Clerodendron inerme (L.) Gaertn leaves on genomic stability and tissue protection using F1 hybrid mice (C57BL male and Swiss albino female). The dried powdered leaves of C. inerme were extracted successively with petroleum ether and methanol in soxhlet apparatus. The methanolic extract yielded 15.7% w/w and petroleum ether extract yielded 3.0% w/w, respectively. Results revealed that when the C. inerme methanolic extract (CIME) was given alone and with radiation therapy (4 Gy), it was noticed that the intestinal tissues were protected better by methanolic extract 500 mg/kg BW orally in mice as compared to other test groups and radiation control groups. Methanolic extract showed good results in intestinal tissue protection but the percentage chromosomal aberration was not well appreciated in comparison to petroleum ether extract which showed good activity in percentage chromosomal aberration and the total removal of aberrated chromosome. [ABSTRACT FROM AUTHOR]

Abstract: Insulin-like growth factor I (IGF-I) is an important growth factor for embryonic development, postnatal growth, tissue repair and maintenance of homeostasis. IGF-I functions and regulations are complex and tissue-specific. IGF-I mediates growth hormone signaling to target tissues during growth, but many IGF-I variants have been discovered, resulting in complex models to describe IGF-I function and regulation. Mechano-growth factor (MGF) is an alternative splicing variant of IGF-I and serves as a local tissue repair factor that responds to changes in physiological conditions or environmental stimuli. MGF expression is significantly increased in muscle, bone and tendon following damage resulting from mechanical stimuli and in the brain and heart following ischemia. MGF has been shown to activate satellite cells in muscle resulting in hypertrophy or regeneration, and functions as a neuroprotectant in brain ischemia. Both expression and processing of this IGF-I variant are tissue specific, but the functional mechanism is poorly understood. MGF and its short derivative have been examined as a potential therapy for muscular dystrophy and cerebral hypoxia–ischemia using experimental animals. Although the unique mode of action of MGF has been identified, the details remain elusive. Here we review the expression and regulation of MGF and the function of this IGF-I isoform in tissue protection. [ABSTRACT FROM AUTHOR]

Published studies have described a number of physiological properties and cellular functions of thymosin β4 (Tβ4), the major G-actin-sequestering molecule in mammalian cells. Those activities include the promotion of cell migration, blood vessel formation, cell survival, stem cell differentiation, the modulation of cytokines, chemokines, and specific proteases, the upregulation of matrix molecules and gene expression, and the downregulation of a major nuclear transcription factor. Such properties have provided the scientific rationale for a number of ongoing and planned dermal, corneal, cardiac clinical trials evaluating the tissue protective, regenerative and repair potential of Tβ4, and direction for future clinical applications in the treatment of diseases of the central nervous system, lung inflammatory disease, and sepsis. A special emphasis is placed on the development of Tβ4 in the treatment of patients with ST elevation myocardial infarction in combination with percutaneous coronary intervention. [ABSTRACT FROM AUTHOR]

The amino acid taurine has an established role in attenuating lung fibrosis secondary to bleomycin-induced injury. This study evaluates taurine’s effect on TGF-β1 expression and the development of lung fibrosis after single-dose thoracic radiotherapy. Four groups of C57/Bl6 mice received 14 Gy thoracic radiation. Mice were treated with taurine or saline supplementation by gavage. After 10 days and 14 weeks of treatment, TGF-β1 levels were measured in serum and bronchoalveolar lavage fluid (BALF). Lung collagen content was determined using hydroxyproline analysis. Ten days post radiotherapy, serum TGF-β1 levels were significantly lower after gavage with taurine rather than saline ( P = 0.033). BALF TGF-β1 at 10 days was also significantly lower in mice treated with taurine ( P = 0.031). Hydroxyproline content was also significantly lower at 14 weeks in mice treated with taurine ( P = 0.020). This study presents novel findings of taurine’s role in protecting from TGF-β1-associated development of lung fibrosis after thoracic radiation. [ABSTRACT FROM AUTHOR]

Background There is considerable interest in tissue-protective treatments for multiple sclerosis (MS). Methods and Objectives We convened a group of MS clinical trialists and related researchers to discuss designs for proof of concept studies utilizing currently available data and assessment methods. Results Our favored design was a randomized, double-blind, parallel-group study of active treatment versus placebo focusing on changes in brain volume from a post-baseline scan (3-6 months after starting treatment) to the final visit 1 year later. Study designs aimed at reducing residual deficits following acute exacerbations are less straightforward, depending greatly on the anticipated rapidity of treatment effect onset. Conclusions The next step would be to perform one or more studies of potential tissue-protective agents with these designs in mind, creating the longitudinal data necessary to refine endpoint selection, eligibility criteria, and sample size estimates for future trials. [ABSTRACT FROM AUTHOR]

The prolyl-4-hydroxylase domain (PHD) 1–3 enzymes have been identified based on their ability to regulate the stability of hypoxia-inducible factor α subunits and thus to modify hypoxia-inducible gene expression. Transgenic mouse models provided insights into the isoform-specific functions of these oxygen sensors with physiological implications for angiogenesis, erythropoiesis/oxygen transport, cardiovascular function, metabolism and tissue homeostasis. This knowledge is important for the ongoing development of small molecule PHD inhibitors that are currently tested in preclinical and clinical trials for the treatment of anaemia and for cytoprotection. This review aims at summarizing the insights obtained from key mouse knock-out models as well as first experiences in the therapeutic application of PHD inhibitors. [ABSTRACT FROM AUTHOR]

Hypoxia induces in most arterial and venous smooth muscle tissues a rapid vasorelaxation. One mechanism for this vasorelaxation is reported as a hyperpolarization, induced by the opening of AlP-sensitive potassium channels [Beech and Bolton 1989, Ibbotson et al. 1993, Noack et al. 1992a, b]. These channels are believed to link metabolism and cell activity like in insulin secreting cells [Noack et al. 2003]. Insulin secretagogues (sulfonylureas and glinides) increase insulin secretion by closing the ATP-sensitive K+ channel (KATP channel) in the pancreatic β-cell membrane. KATP channels also subserve important functions in the heart. First, KATP channels in coronary myocytes contribute to the control of coronary blood flow at rest and in hypoxia [Ibbotson et al. 1993]. In vascular tissues, potassium and calcium channels play an important role in nitrergic and non-nitrergic relaxation processes in smooth muscle. ATP-sensitive potassium channels (KATP) may play an important role in the regulation of vascular tone, especially under hypoxic conditions, and exert a protective effect when energy supply is low [Noack et al. 1992b]. The link between oxygen tension and the opening of KATP (which occurs as the intracellular ATP concentration, [ATP]1, falls) is oxidative glycolysis. However, other mechanisms of hypoxia-induced vasorelaxation are also reported in the literature [Hourand et al. 2006, Noack et al. 2003, Park et al. 2007, Wardle et al. 2006, 2007]. In this study we investigated hypoxia-induced relaxation in the coronary vascular bed and portal veins from WKY rats. The amount of relaxation and excitability of coronary arteries during graded hypoxia was determined in contraction measurements. The mechanism for the increase of vasorelaxation during hypoxia was investigated using single cell voltage clamp and the Fura-2 technique in combination with contraction measurements in isolated vessels. Coronary arteries relaxed during stepwise reduction of pO2 but showed no reaction to application of glibenclamide (10-6 M). Portal veins were gradually relaxed by hypoxia; glibenclamide reduced the relaxation at a PO2 below 40 mmHg. Calcium-levels in coronary arteries showed no significant change under hypoxia. It is concluded that both, opening of KATP channels and calcium-independent mechanisms are involved in hypoxia-induced vasorelaxation. In different vascular beds, the importance of both mechanisms is more or less expressed. [ABSTRACT FROM AUTHOR]

Recombinant human erythropoietin (rHuEPO) has become the standard therapy for treatment of the anaemia of chronic kidney disease (CKD) during the past two decades. In addition, rHuEPO can be indicated for the treatment of cancer patients on chemotherapy and surgical patients to avoid allogeneic red blood cell transfusion. This review first describes recent attempts in developing rHuEPO congeners (mutated and pegylated rHuEPOs) and mimetics with prolonged half-lives and improved application requirements. Secondly, the pathophysiological background of the regulatory guideline, that blood haemoglobin levels in anaemic CKD or cancer patients on chemotherapy should not be raised above the target value of 120 g/l, is discussed. Finally, potential novel indications are considered for the use of rHuEPO and its analogues as pleiotropic cytoprotectant agents for cardio-, nephro-, hepato- and neuroprotection. [ABSTRACT FROM AUTHOR]