Tissue-protective Properties Research Articles

Bioactive Compounds in Osteoarthritis: Molecular Mechanisms and Therapeutic Roles

Osteoarthritis (OA) is the most common and debilitating form of arthritis. Current therapies focus on pain relief and efforts to slow disease progression through a combination of drug and non-drug treatments. Bioactive compounds derived from plants show significant promise due to their anti-inflammatory, antioxidant, and tissue-protective properties. These natural compounds can help regulate the inflammatory processes and metabolic pathways involved in OA, thereby alleviating symptoms and potentially slowing disease progression. Investigating the efficacy of these natural agents in treating osteoarthritis addresses a growing demand for natural health solutions and creates new opportunities for managing this increasingly prevalent age-related condition. The aim of this review is to provide an overview of the use of some bioactive compounds from plants in modulating the progression of osteoarthritis and alleviating associated pain.

Enhancing radioprotection: exploring the impact of L-carnitine supplementation on the oxidative stress in the liver.

The adverse effects of radiotherapy (RT) primarily occur through oxidative stress, and attempts are being made to mitigate these effects. L-Carnitine (L-Car) involved in physiological functions, possesses antioxidant and tissue-protective properties. The goal of this investigation is to appraise the radioprotective efficacy of L-Car supplementation. The groups were established by dividing thirty-two rats as: control, RT (10Gy), RT + L-Car (200mg/kg/d), L-Car. Upon completion of the experiment, the livers were harvested for histopathological, immunostaining [tumor necrosis factor-alpha (TNF-α), Caspase-3], spectrophotometric [total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI)], and mRNA expression [(Nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein 1 (Keap-1), Heme Oxygenase (HO-1), Transforming growth factor beta 1 (TGF-β1)] analyses. In the damage group, decreased Keap-1, Nrf2, HO-1, and TAS values, along with increased histopathological findings, alanine transferase, aspartate transferase, TNF-α, Caspase-3, TOS, OSI, TGF-β1 levels were found. All findings were improved with L-Car treatment. Considering these findings, it can be inferred that L-Car exhibits tissue-protective effects against organ damage predominantly induced by RT-related oxidative stress. Additionally, it has prevented the development of inflammation, apoptosis, and fibrosis. Therefore, L-Car may be considered as a supplement to reduce complications associated with RT.

Photothermal Catalytic Reduction and Bone Tissue Engineering Towards a Three-in-One Therapy Strategy for Osteosarcoma.

Osteosarcoma is one of the most dreadful bone neoplasms in young people, necessitating the development of innovative therapies that can effectively eliminate tumors while minimizing damage to limb function. An ideal therapeutic strategy should possess three essential capabilities: antitumor effects, tissue-protective properties, and the ability to enhance osteogenesis. In this study, self-assembled Ce-substituted molybdenum blue (CMB) nanowheel crystals are synthesized and loaded onto 3D-printed bioactive glass (CMB@BG) scaffolds to develop a unique three-in-one treatment approach for osteosarcoma. The CMB@BG scaffolds exhibit outstanding photothermally derived tumor ablation within the near-infrared-II window due to the surface plasmon resonance properties of the CMB nanowheel crystals. Furthermore, the photothermally synergistic catalytic effect of CMB promotes the rapid scavenging of reactive oxygen species caused by excessive heat, thereby suppressing inflammation and protecting surrounding tissues. The CMB@BG scaffolds possess pro-proliferation and pro-differentiation capabilities that efficiently accelerate bone regeneration within bone defects. Altogether, the CMB@BG scaffolds that combine highly efficient tumor ablation, tissue protection based on anti-inflammatory mechanisms, and enhanced osteogenic ability are likely to be a point-to-point solution for the comprehensive therapeutic needs of osteosarcoma.

The prophylactic and therapeutic effects of cannabidiol on lung injury secondary to cardiac ischemia model in rats via PERK/NRF2/CHOP/BCL2 pathway

Background Inflammation and oxidative stress are key players in lung injury stemming from cardiac ischemia (LISCI). Cannabidiol (CBD) demonstrates tissue-protective properties through its antioxidant, anti-inflammatory, and anti-apoptotic characteristics. This study aims to assess the preventive (p-CBD) and therapeutic (t-CBD) effects of CBD on LISCI. Methods Forty male Wistar Albino rats were divided into four groups: control (CON), LISCI, p-CBD, and t-CBD. The left anterior descending coronary artery was ligated for 30 min of ischemia followed by 30 min of reperfusion. Lung tissues were then extracted for histopathological, immunohistochemical, genetic, and biochemical analyses. Results Histopathologically, marked hyperemia, increased septal tissue thickness, and inflammatory cell infiltrations were observed in the lung tissues of the LISCI group. Spectrophotometrically, total oxidant status and oxidative stress index levels were elevated, while total antioxidant status levels were decreased. Immunohistochemically, expressions of cyclooxygenase-1 (COX1), granulocyte colony-stimulating factor (GCSF), interleukin-6 (IL6) were increased. In genetic analyses, PERK and CHOP expressions were increased, whereas Nuclear factor erythroid 2-related factor 2 (NRF2) and B-cell leukemia/lymphoma 2 protein (BCL2) expressions were decreased. These parameters were alleviated by both prophylactic and therapeutic CBD treatment protocols. Conclusion In LISCI-induced damage, both endoplasmic reticulum and mitochondrial stress, along with oxidative and inflammatory markers, were triggered, resulting in lung cell damage. However, both p-CBD and t-CBD treatments effectively reversed these mechanisms, normalizing all histopathological, biochemical, and PCR parameters.

Integrated In Vivo and In Vitro Evaluation of a Powder-to-Hydrogel, Film-Forming Polymer Complex Base with Tissue-Protective and Microbiome-Supportive Properties.

The study aimed to perform a comprehensive in vitro and in vivo evaluation of a newly developed, patent-pending, powder-to-hydrogel, film-forming polymer complex base, which possesses tissue-protective and microbiome-supportive properties, and to compare its characteristics with poloxamer 407. The study used a combination of in vitro assays, including tissue viability and cell migration, and in vivo wound healing evaluations in male diabetic mice. Microbiome dynamics at wound sites were also analyzed. The in vitro assays demonstrated that the polymer complex base was non-cytotoxic and that it enhanced cell migration over poloxamer 407. In vivo, the polymer complex base demonstrated superior wound healing capabilities, particularly in combination with misoprostol and phenytoin, as evidenced by the reduced wound area and inflammation scores. Microbiome analysis revealed favorable shifts in bacterial populations associated with the polymer complex base-treated wounds. The polymer complex base demonstrates clinical significance in wound care, potentially offering improved healing, safety and microbiome support. Its transformative properties and efficacy in drug delivery make it a promising candidate for advanced wound care applications, particularly in chronic wound management.

Unlocking Cardioprotective Potential of Gut Microbiome: Exploring Therapeutic Strategies.

The microbial community inhabiting the human gut resembles a bustling metropolis, wherein beneficial bacteria play pivotal roles in regulating our bodily functions. These microorganisms adeptly break down resilient dietary fibers to fuel our energy, synthesize essential vitamins crucial for our well-being, and maintain the delicate balance of our immune system. Recent research indicates a potential correlation between alterations in the composition and activities of these gut microbes and the development of coronary artery disease (CAD). Consequently, scientists are delving into the intriguing realm of manipulating these gut inhabitants to potentially mitigate disease risks. Various promising strategies have emerged in this endeavor. Studies have evidenced that probiotics can mitigate inflammation and enhance the endothelial health of our blood vessels. Notably, strains such as Lactobacilli and Bifidobacteria have garnered substantial attention in both laboratory settings and clinical trials. Conversely, prebiotics exhibit anti-inflammatory properties and hold potential in managing conditions like hypertension and hypercholesterolemia. Synbiotics, which synergistically combine probiotics and prebiotics, show promise in regulating glucose metabolism and abnormal lipid profiles. However, uncertainties persist regarding postbiotics, while antibiotics are deemed unsuitable due to their potential adverse effects. On the other hand, TMAO blockers, such as 3,3-dimethyl-1-butanol, demonstrate encouraging outcomes in laboratory experiments owing to their anti-inflammatory and tissue-protective properties. Moreover, fecal transplantation, despite yielding mixed results, warrants further exploration and refinement. In this comprehensive review, we delve into the intricate interplay between the gut microbiota and CAD, shedding light on the multifaceted approaches researchers are employing to leverage this understanding for therapeutic advancements.

Cyclosporine-induced kidney damage was halted by sitagliptin and hesperidin via increasing Nrf2 and suppressing TNF-α, NF-κB, and Bax

Cyclosporine A (CsA) is employed for organ transplantation and autoimmune disorders. Nephrotoxicity is a serious side effect that hampers the therapeutic use of CsA. Hesperidin and sitagliptin were investigated for their antioxidant, anti-inflammatory, and tissue-protective properties. We aimed to investigate and compare the possible nephroprotective effects of hesperidin and sitagliptin. Male Wistar rats were utilized for induction of CsA nephrotoxicity (20 mg/kg/day, intraperitoneally for 7 days). Animals were treated with sitagliptin (10 mg/kg/day, orally for 14 days) or hesperidin (200 mg/kg/day, orally for 14 days). Blood urea, serum creatinine, albumin, cystatin-C (CYS-C), myeloperoxidase (MPO), and glucose were measured. The renal malondialdehyde (MDA), glutathione (GSH), catalase, and SOD were estimated. Renal TNF-α protein expression was evaluated. Histopathological examination and immunostaining study of Bax, Nrf-2, and NF-κB were performed. Sitagliptin or hesperidin attenuated CsA-mediated elevations of blood urea, serum creatinine, CYS-C, glucose, renal MDA, and MPO, and preserved the serum albumin, renal catalase, SOD, and GSH. They reduced the expressions of TNF-α, Bax, NF-κB, and pathological kidney damage. Nrf2 expression in the kidney was raised. Hesperidin or sitagliptin could protect the kidney against CsA through the mitigation of oxidative stress, apoptosis, and inflammation. Sitagliptin proved to be more beneficial than hesperidin.

Microfluidic Preparation of pH-Responsive Microsphere Fibers and Their Controlled Drug Release Properties.

In this study, a capillary microfluidic device was constructed, and sodium alginate solution and a pH-sensitive hydrophobic polymer (p(BMA-co-DAMA-co-MMA)) solution were introduced into the device for the preparation of hydrogel fibers loaded with polymer microspheres. The structure of the microsphere fiber, including the size and spacing of the microspheres, could be controlled by flow rate, and the microspheres were able to degrade and release cargo responding to acidic pH conditions. By modification with carboxymethylcellulose (CMC), alginate hydrogel exhibited enhanced pH sensitivity (shrunk in acidic while swollen in basic condition). This led to an impact on the diffusion rate of the molecules released from the inner microspheres. The microsphere fiber showed dramatic and negligible degradation and drug release in tumor cell (i.e., A431 and A549 cells) and normal cell environments, respectively. These results indicated that the microsphere fiber prepared in this study showed selective drug release in acidic environments, such as tumor and inflammation sites, which could be applied as a smart surgical dressing with normal tissue protective properties.

DIA-Based Proteomics Reveals the Protective Effect of Quercetin against Cyclophosphamide-Induced Testicular Toxicity in Mice

Cyclophosphamide (CP) is a common employed immunosuppressive and anti-neoplastic alkylating antineoplastic drug with documented male reproductive harm. Quercetin, a widely distributed anti-oxidant flavonoid, has been demonstrated to have a variety of biological roles, including tissue-protective properties. Here, administration of quercetin alleviated the CP-induced damage to the testicles, as evidenced by improvements in body weight, testis and epididymis index, serum testosterone concentration, the pathomorphological of testis, and reduced apoptosis in testicular cells. Moreover, Proteomic data indicated that all DEPs were classified into five categories, Cluster 1 (C1) and C4 were regulated by cyclophosphamide and quercetin. KEGG pathway analyses showed that mTOR signaling pathways and Proteasome were the most abundant pathways in C1 and C4, respectively. In the protein-protein interaction (PPI) network analysis, quercetin inhibits the expression of GSK3B, EIF4E, and RPS6KA2 proteins in CP-induced spermatogenesis failure in mice via the mTOR signaling pathway, protecting against spermatogonia injury. On the other hand, quercetin alleviates spermatogonia injury by stimulating the production of Rps23, Rpl8, Rps11, and Mrps17 proteins in CP-induced testis injury in mice via the pathways of Proteasome. Our results have showed that quercetin has a putative protective effect via modulating the pathways of mTOR and Proteasome in CP induced testis injury

Epigallocatechin-3-gallate improves the quality of maternally aged oocytes.

The decline in female fertility as age advances is intricately linked to the diminished developmental potential of oocytes. Despite this challenge, the strategies available to enhance the quality of aged oocytes remain limited. Epigallocatechin-3-gallate (EGCG), characterised by its anti-inflammatory, antioxidant and tissue protective properties, holds promise as a candidate for improving the quality of maternally aged oocytes. In this study, we explored the precise impact and underlying mechanisms of EGCG on aged oocytes. EGCG exhibited the capacity to enhance the quality of aged oocytes both in vitro and in vivo. Specifically, the application of EGCG in vitro resulted in noteworthy improvements, including an increased rate of first polar body extrusion, enhanced mitochondrial function, refined spindle morphology and a reduction in oxidative stress. These beneficial effects were further validated by the improved fertility observed among aged mice. In addition, our findings propose that EGCG might augment the expression of Arf6. This augmentation, in turn, contributes to the assembly of spindle-associated F-actin, which can contribute to mitigate the aneuploidy induced by the disruption of spindle F-actin within aged oocytes. This work thus contributes not only to understanding the role of EGCG in bolstering oocyte health, but also underscores its potential as a therapeutic intervention to address fertility challenges associated with advanced age.

Antihyperglycemic and Histological Effect of Aloe vera on Alloxan-Induced Diabetes in Wistar Rats

Introduction: Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycemia and is associated with various complications if not properly managed. Aloe vera, a medicinal plant with diverse pharmacological properties, has shown promise as a potential therapeutic intervention for diabetes. This study aimed to investigate the antihyperglycemic and histological effects of Aloe vera in an alloxan-induced diabetic Wistar rat model. Method: Forty-eight Wistar rats were divided into six groups and treated with different regimens of Aloe vera and metformin, a standard antidiabetic drug. The effects of the treatments on blood glucose levels and histology of the pancreas, liver, and kidney were evaluated. Result: The results of the study revealed that alloxan injection induced hyperglycemia and pathological changes in the pancreas, liver and kidney of Wistar rats. The treatment with 100mg/kg, 200mg/kg and 400mg/kg of Aloe vera significantly reduced blood glucose levels in a dose-dependent manner. Additionally, Aloe vera administration preserved the histological integrity of the pancreas, liver, and kidney in diabetic rats. This preservation of organ histology can be attributed to the antioxidant, anti-inflammatory, and tissue-protective properties of Aloe vera. Conclusion: Aloe vera demonstrated antihyperglycemic effects and preserved organ histology in an alloxan-induced diabetic Wistar rat model. The bioactive compounds present in Aloe vera are believed to contribute to these effects. Aloe vera holds potential as an alternative or adjunctive therapy for diabetes management, but its clinical efficacy and safety need to be further explored.

Drug exporter expression correlates with group 3 innate lymphoid cell resistance to immunosuppressive agents

Allogeneic hematopoietic cell transplantation (HCT) is often complicated by graft versus host disease (GvHD), an alloreactive immune response triggered by tissue damage. Interleukin (IL)-22 producing type 3 innate lymphoid cells (ILC3) protect epithelial tissues against chemo(radio)therapy-induced damage, suppress alloreactive T cells and mitigate acute GvHD symptoms after allogeneic HCT. Relatively high numbers of ILC before and after allogeneic HCT has been associated with significantly reduced tissue damage and less acute GvHD. While most transplantation conditioning and GvHD prophylaxis regimens are aimed at eliminating host and alloreactive donor lymphocytes, the effect of these regimens on ILC remain elusive. Here, we studied the effect of conditioning chemotherapy and immunosuppressive agents on the survival, proliferation, activation and function of human ILC3 in vitro. Tonsil-derived ILC3 were activated and incubated with agents commonly used to prevent and treat GvHD. While fludarabine, rapamycin, mycophenolic acid and prednisolone suppressed ILC3 to a similar degree as T cells, the effect of other agents, including cyclosporine A, methotrexate, imatinib, ibrutinib and ruxolitinib, was milder on ILC3 than on T cells. ILC3 are less sensitive to immunosuppressants potentially because of their expression of functionally active ATP Binding Cassette Subfamily B Member 1 (ABCB1) drug exporter proteins. This suggests less intracellular accumulation of immunosuppressive agents, which renders ILC3 resistant to these compounds. The present findings may help to develop strategies to simultaneously maintain the tissue protective properties of ILC3 and at the same time suppress alloreactive lymphocytes, which is important in the prevention and treatment of acute GvHD.

Protective Efficiency of Pterocarpus erinaceus Leaves Extract in Carbon-tetrachloride-induced Hepatic and Hematological Injuries in Rats

Aims: Chemical toxicity is one of the major leading causes of tissues injuries, which impair the tissue’s ability to maintain normal physiological functions. Pterocarpus erinaceus is a medicinal plant use as traditional remedy for the treatment of several disorders associated with tissues injuries. This study therefore aimed at investigating tissues protective efficiency of Pterocarpus erinaceus leaves extract in carbon-tetrachloride-induced hepatic and hematological injuries in rats.
 Materials and Methods: Leaves of Pterocarpus erinaceous after collection were air-dried and pulverized. It was extracted with methanol and the methanolic extracts were used. Acute toxicity and hepatoprotective studies against CCl4 toxicity were conducted. Rats were grouped into; Group 1: Normal control (liquid paraffin, vehicle 1ml.kg), Group 2: Negative control (received 1ml/kg CCl4), Group 3: Positive control (received 1ml/kg CCl4 +100ml/kg Silymarin), Group 4-6: Extract treated rats (received 1ml/kg CCl4 + varied doses of Extracts at 100, 200, and 400mg/kg body weight of rats). The treatment was done daily via oral means for 14 days.
 Results: The results of the acute toxicity study showed Pterocarpus erinaceus extract safe with LD50 greater than 5000mg/kg body weight. This study reveals Pterocarpus erinaceus able to ameliorate CCl4 toxicity by minimizing damage to hepatic and hematological tissues. Histological study of the rats’ hepatic cells further unveils the protective ability of the plant extract against severity of CCl4-mediate hepatic architectural damage.
 Conclusion: Pterocarpus erinaceus leaves possess components with tissue-protective properties hence the need to harness it for utilization.

858-P: Recruitment Strategies for a Cellular Therapy Study for Type 1 Diabetes

Mesenchymal stem cells may be a novel T1D treatment based on immunoregulatory and tissue-protective properties. Therefore, an NIDDK sponsored prospective, single center, double blind study of MSCs for new onset T1D (NCT04061746) has generated significant social media interest. This trial is hard to enroll because of a narrow age range (18-30 years) and requirement of a new onset diagnosis (6 months). We evaluated the impact of social media tools, clinicaltrials.gov advertisement, and medical record review (EPIC) to define the optimal screening process for this and future trials. Through clinicaltrials.gov the study piqued the interest of 173 participants. Additionally, the study team has pre-screened 346 patients from an EPIC generated report. Among the 22 patients consented, referrals were received from physicians (N=5), clinicaltrials.gov (N=13), and EPIC reports (N=4). Among those discovered via EPIC list, we depicted the main reasons for study ineligibility (Fig. 1). The study recently launched a social media campaign in December 2022, initially reaching a total of 16,593 viewers. 4,475 viewers (26.97%) interacted with the campaign, and 2 (0.012%) were potentially interested in follow up from the research team. We conclude that clinicaltrials.gov, medical record review, and physician referrals are all critical to screening for new-onset diabetes studies. Other T1D studies might benefit from utilizing these strategies. Disclosure L.Benn: None. W.Gou: None. P.J.Nietert: None. M.Cornier: Consultant; Novo Nordisk, Alnylum, Letsgetchecked, Research Support; Novartis Pharmaceuticals Corporation, Amgen Inc., Kaneka. S.Norton: None. C.Strange: None. H.Wang: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK118529, DK120394, DK105183, DK125454); U.S. Department of Veterans Affairs (I01BX004536)

The Effects of N-acetylcysteine on Transient Receptor Potential Melastatin 2 Channels Activation and Expression in Testicular Tissue of Diabetic Rats.

Diabetes mellitus (DM) is a common, chronic metabolic disease that has harmful effects on many diverse tissues, including the testis. One of the ways of tissue damage is the modification of transient receptor potential melastatin 2 (TRPM2) channels by increased reactive oxygen species (ROS). In our study for the first time, it was aimed to investigate TRPM2 channel activation in testicular tissues of diabetic rats induced by streptozotosin (STZ) and to examine the efficacy of N-acetylcysteine (NAC) treatment, which is an antioxidant. In our study, 28 Wistar albino male rats aged 8-10 weeks were used, and animals were divided into four groups: control group, NAC group, DM group, and DM + NAC group. The experimental phase was designed as eight weeks. The malondialdehyde(MDA)level, which is an indicator for lipid peroxidation due to oxidative stress, was measured by the spectrophotometric method. The Tunel assay was used to determine apoptosis on testicular tissue. TRPM2 immunoreactivity was determined by the avidin-biotin-peroxidase complex method, and quantitative polymerase chain reaction (QPCR) was used to determine TRPM2 expression levels. It was seen that MDA levels were significantly increased in the DM group and decreased after NAC treatment. Similarly, it was observed that apoptosis levels, which increased significantly in diabetic rats, decreased to the levels of the control group after treatment. It was seen that TRPM2 activation and expression levels were significantly decreased in the DM group. The results of this study show that NAC regulates TRPM2 activation in the testicular tissue of patients with diabetes and has tissue-protective properties.

Effect of mesenchymal stromal cell transplantation on long-term survival in amyotrophic lateral sclerosis

Background aimsThanks to their immunomodulatory, tissue-protective and regenerative properties, mesenchymal stromal cells (MSCs) are a promising approach for amyotrophic lateral sclerosis (ALS); however, trials are limited and few follow-up studies have been published. This post-hoc analysis aims to describe the potential long-term effects of MSCs in ALS, analyzing data from two phase 1 clinical trials in ALS patients conducted by our group in 2002 and 2006. MethodsWe conducted two consecutive phase 1 prospective, open, pilot clinical trials, enrolling a total of 19 ALS patients. We followed patients for the duration of the disease. For each patient, we used the European Network to Cure ALS (ENCALS) survival prediction model to retrospectively calculate the expected survival at diagnosis. We then compared the predicted disease duration with the observed survival, analyzing patients at a single-patient level. ResultsUsing the ENCALS model, we predicted short survival in one patient, intermediate survival in three patients, long survival in three patients and very long survival in 12 patients. The difference between predicted and observed survival for the whole group was significant and demonstrated a mean predicted survival of 70.79 months (standard deviation [SD], 27.53) and a mean observed survival of 118.8 months (SD, 89.26) (P = 0.016). Based on the monthly ALS Functional Rating Scale–Revised progression rate (median, 0.64/month), we considered 10 of 19 patients slow progressors and nine of 19 patients fast progressors. Of the slow progressors, eight of 10 (80%) had significantly increased disease duration compared with predicted, and only two (20%) had decreased estimated disease duration. By contrast, five of nine (55%) fast progressors had increased disease duration, whereas four (45%) had decreased disease duration. To date, four patients are still alive. ConclusionsThe current study represents the first very long-term analysis of survival as an effect of MSC focal transplantation in the central nervous system of ALS patients, demonstrating that MSC transplantation could potentially slow down ALS progression and improve survival. Due to the interindividual variability in clinical course, at the current state of our knowledge, we cannot generalize the results, but these data provide new insights for planning the next generation of efficacy MSC clinical trials in ALS.

Pentosan Polysulfate Affords Pleotropic Protection to Multiple Cells and Tissues.

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.

Recombinant Alpha-1-Microglobulin (RMC-035) to Prevent Acute Kidney Injury in Cardiac Surgery Patients: Phase 1b Evaluation of Safety and Pharmacokinetics

Acute kidney injury (AKI) is a common complication in cardiac surgery patients and prevention is needed to improve clinical outcomes. Alpha-1-microglobulin (A1M) is a physiological antioxidant with strong tissue-protective and cell-protective properties that has demonstrated renoprotective effects. RMC-035, a recombinant variant of endogenous human A1M, is being developed for the prevention of AKI in cardiac surgery patients. In this phase 1b, randomized, double-blind, and parallel group clinical study, 12 cardiac surgery patients undergoing elective, open-chest, on-pump coronary artery bypass graft and/or valve surgery with additional predisposing AKI risk factors were enrolled to receive in total 5 intravenous doses of either RMC-035 or placebo. The primary objective was to evaluate the safety and tolerability of RMC-035. The secondary objective was to evaluate its pharmacokinetic properties. RMC-035 was well tolerated. The nature and frequency of adverse events (AEs) were consistent with the expected background rates in the underlying patient population with no AEs reported as related to study drug. No clinically relevant changes were observed for vital signs or laboratory parameters except for renal biomarkers. Several established AKI urine biomarkers were reduced at 4 hours after first dose administration in the treatment group, indicating a reduced perioperative tubular cell injury following RMC-035 treatment. Multiple intravenous doses of RMC-035 were well tolerated in patients undergoing cardiac surgery. Observed RMC-035 plasma exposures were safe and in the range of expected pharmacological activity. Furthermore, urine biomarkers suggest reduced perioperative kidney cell injury, warranting further investigation of RMC-035 as a potential renoprotective treatment.

Mechanically Robust and Transparent Organohydrogel‐Based E‐Skin Nanoengineered from Natural Skin

AbstractElectronic skins (e‐skins), which are mechanically compliant with human skin, are regarded as ideal electronic devices for noninvasive human–machine interaction and wearable devices. In order to fully mimic human skin, e‐skins should possess reliable mechanical properties and be able to resist external environmental factors like heat, cold, desiccation, and bacteria, while perceiving multiple external stimuli, such as temperature, humidity, and strain. Here, a transparent, mechanically robust, environmentally stable, versatile natural skin‐derived organohydrogel (NSD‐Gel) is nanoengineered through the integration of betaine, silver nanoparticles, and sodium chloride in a glycerol/water binary solvent. The transparent NSD‐Gel e‐skin exhibits outstanding tensile strength (7.33 MPa), puncture resistance, moisture retention, self‐regeneration, and antibacterial properties. Additionally, the NSD‐Gel e‐skin possesses enhanced cold/heat resistance and stimuli‐responsive characteristics that effectively sense environmental temperature and humidity changes, as well as physiological human body motion signals. In vitro and in vivo experiments show that the NSD‐Gel e‐skin confers desired biocompatibility and tissue protective properties even in extremely harsh environments (−196 °C to 100 °C). The NSD‐Gel e‐skin has great potential for applications in multidimensional wearable electronic devices, human‐machine interfaces, and artificial intelligence, generating a versatile platform for the development of high‐performance e‐skins with on‐demand properties.

TSG-6 inhibits IL-1β-induced inflammatory responses and extracellular matrix degradation in nucleus pulposus cells by activating the PI3K/Akt signaling pathway

PurposeTumor necrosis factor (TNF)-stimulated gene-6 (TSG-6), a secreted protein associated with inflammation, is believed to possess momentous and multiple anti-inflammatory and tissue-protective properties. However, the role and potential mechanism of TSG-6 in cervical disk degeneration (CDD) are still not clear. Hence, we aimed to explore the effect of TSG-6 on CDD.MethodsQuantitative reverse transcriptase polymerase chain reaction (qRT-PCR) or enzyme-linked immunosorbent assay was applied to detect the expression level of TSG-6 and IL-1β in normal and degenerated nucleus pulposus (NP) tissues. Then, qRT-PCR and western blot were adopted to test the TSG-6 protein expression after IL-1β treatment (10 ng/mL) in human NP cells (HNPCs). After over-expressing TSG-6, qRT-PCR was also utilized to evaluate the expression of TNF-α, IL-8, and IL-6 and the synthesis of sulfated glycosaminoglycans (sGAGs), western blot to check the expression of extracellular matrix (ECM) proteins [collagen II, aggrecan, and matrix metalloproteinase-3 (MMP-3)], pain-related molecules (CGRP, calcitonin gene-related peptide; NGF, nerve growth factor; SP, substance P), and PI3K/Akt signaling pathway-related proteins.ResultsBriefly speaking, TSG-6 and IL-1β expression levels were significantly increased in CDD patient tissues; and IL-1β treatment could significantly increase TSG-6 expression in HNPCs. Further research revealed that, in addition to greatly promoting sGAGs synthesis, TSG-6 over-expression also inhibited TNF-α, IL-8, and IL-6 expression and ECM degradation in IL-1β-induced HNPCs. (The collagen II and aggrecan expression was up-regulated and MMP-3 expression was down-regulated.) Furthermore, over-expression of TSG-6 could decrease the levels of CGRP, NGF, and SP protein expression and activate the PI3K/Akt signaling pathway in IL-1β-treated HNPCs.ConclusionTSG-6 inhibits inflammatory responses, ECM degradation, and expression of pain-related molecules in IL-1β-induced HNPCs by activating the PI3K/Akt signaling pathway.