Pleiotrophin-Neuregulin1 promote axon regeneration and sorting in conduit repair of critical nerve gap injuries.

Significant challenges remain in the treatment of critical nerve gap injuries using artificial nerve conduits. We previously reported successful axon regeneration across a 40 mm nerve gap using a biosynthetic nerve implant (BNI) with multi-luminal synergistic growth factor release. However, axon sorting, remyelination, and functional recovery were limited. Neuregulin1 (NRG1) plays a significant role in regulating the proliferation and differentiation of Schwann cells (SCs) during development and after injury. We hypothesize that the release of NRG1 type III combined with pleiotrophin (PTN) in the BNI will enhance axon growth, remyelination, and function of regenerated nerves across a critical gap. A rabbit 40 mm peroneal gap injury model was used to investigate the therapeutic efficacy of BNIs containing either NRG1, PTN, or PTN+NRG1 growth factor release. We found that NRG1 treatment doubled the number of regenerated axons (1276±895) compared to empty controls (633±666) and PTN tripled this number (2270±989). NRG1 also significantly increased the number of SOX10+ Schwann cells in mid-conduit (20.42%±11.78%) and reduced the number of abnormal Remak axon bundles. The combination of PTN+NRG1 increased axon diameter (1.70±1.06) vs control (1.21±0.77) (p<0.01), with 15.35% of axons above 3 µm, comparable to autograft. However, the total number of remyelinated axons was not increased by the added NRG1 release, which correlated with absence of axonal NRG1 type III expression in the regenerated axons. Electrophysiological evaluation showed higher muscle force recruitment (23.8±16.0 mN vs 17.4±1.4 mN) and maximum evoked compound motor action potential (353 µV vs 37 µV) in PTN-NRG1 group versus control, which correlated with the improvement in the toe spread recovery observed in PTN-NRG1 treated animals (0.64±0.02) vs control (0.50±0.01). These results revealed the need of a combination of pro-regenerative and remyelinating growth factor combination therapy for the repair of critical nerve gaps.

Biomaterials and Regenerative Medicine in Pain Management.

PURPOSE OF REVIEW: Pain presents a unique challenge due to the complexity of the biological pathways involved in the pain perception, the growing concern regarding the use of opioid analgesics, and the limited availability of optimal treatment options. The use of biomaterials and regenerative medicine in pain management is being actively explored and showing exciting progress in improving the efficacy of conventional pharmacotherapy and as novel non-pharmacological therapy for chronic pain caused by degenerative diseases. In this paper we review current clinical applications, and promising research in the use of biomaterials and regenerative medicine in pain management. RECENT FINDINGS: Regenerative therapies have been developed to repair damaged tissues in back, joint, and shoulder that lead to chronic and inflammatory pain. Novel regenerative biomaterials have been designed to incorporate biochemical and physical pro-regenerative cues that augment the efficacy of regenerative therapies. New biomaterials improve target localization with improved tunability for controlled drug delivery, and injectable scaffolds enhance the efficacy of regenerative therapies through improving cellular migration. Advanced biomaterial carrier systems have been developed for sustained and targeted delivery of analgesic agents to specific tissues and organs, showing improved treatment efficacy, extended duration of action, and reduced dosage. Targeting endosomal receptors by nanoparticles has shown promising anti-nociception effects. Biomaterial scavengers are designed to remove proinflammatory reactive oxygen species that trigger nociceptors and cause pain hypersensitivity, providing a proactive approach for pain management. Pharmacotherapy remains the method of choice for pain management; however, conventional analgesic agents are associated with adverse effects. The relatively short duration of action when applied as free drug limited their efficacy in postoperative and chronic pain treatment. The application of biomaterials in pain management is a promising strategy to improve the efficacy of current pharmacotherapy through sustained and targeted delivery of analgesic agents. Regenerative medicine strategies target the damaged tissue and provide non-pharmacological alternatives to manage chronic and inflammatory pain. In the future, the successful development of regenerative therapies that completely repair damaged tissues will provide a more optimal alternative for the treatment of chronic pain caused. Future studies will leverage on the increasing understanding of the molecular mechanisms governing pain perception and transmission, injury response and tissue regeneration, and the development of new biomaterials and tissue regenerative methods.

A Review of the Role of the Antiplatelet Drug Ticagrelor in the Management of Acute Coronary Syndrome, Acute Thrombotic Disease, and Other Diseases.

P2Y12 inhibitors, including aspirin, are key components of dual-antiplatelet therapy (DAPT), which is the optimal therapeutic strategy for preventing arterial thrombosis in patients with acute coronary syndromes (ACS) who underwent stent implantation. Ticagrelor is a cyclopentyl-triazole pyrimidine antiplatelet drug that was the first reversible oral P2Y12 receptor antagonist. Compared with clopidogrel, ticagrelor exerts a faster onset and offset of function by reversible and selective inhibition of platelet aggregation in ACS patients, including those with coronary artery blood revascularization. Despite improvement in stent materials, stent thrombosis (ST) due to high on-treatment platelet reactivity (HPR) to clopidogrel continues to occur. In addition to antiplatelet aggregation, ticagrelor displays pleiotropic cardioprotective effects, including improving coronary blood flow, reducing myocardial necrosis after an ischemic event, and anti-inflammatory effects. The benefits of ticagrelor over clopidogrel were consistent in the PLATO results, with lower incidence of the primary endpoint. Also, in 2020, the findings from the phase 3 THALES trial (NCT03354429) showed that aspirin combined with 90 mg of ticagrelor significantly reduced the rates of stroke and death compared with aspirin alone in patients with AIS or TIA. Here, we review recent research on the superiority of ticagrelor over clopidogrel, discuss the pharmacological mechanism, and present future perspectives. This review aims to present the roles of ticagrelor in the management of acute coronary syndrome, acute thrombotic disease, and other diseases.

AM1241 alleviates myocardial ischemia-reperfusion injury in rats by enhancing Pink1/Parkin-mediated autophagy.

AIMS: The purpose of this study was to reveal the therapeutic efficacy and underlying mechanism of cannabinoid type 2 receptor agonist (AM1241) on myocardial ischemia-reperfusion injury (MIRI) in rats. MAIN METHODS: We established a rat myocardial ischemia/reperfusion (I/R) model and H9c2 hypoxia/reoxygenation (H/R) model. ELISA was used to determine the concentrations of cardiac troponin I (cTnI), creatine kinase-MB (CK-MB), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) in plasma. EB/TTC staining was performed to observe the myocardial infarct size. Besides, the pathological changes of myocardial tissue were identified via H&E staining and Masson's trichrome staining. TUNEL assay was performed to examine myocardial apoptosis. Then, the protein expression of Pink1, Parkin and autophagy-related markers (Beclin-1, P62 and LC3) were detected by Western blot, and autophagy was evaluated by Mitotracker staining. KEY FINDINGS: The results of EB/TTC staining, H&E staining, Masson's trichrome staining and cardiac enzymes measuring showed that AM1241 treatment significantly diminished infarct size, the structural abnormalities and the activities of cardiac enzymes (cTnI, CK-MB, AST and LDH). AM1241 also significantly reduced the number of TUNEL-positive cells induced by I/R in a dose-dependent manner. Furthermore, AM1241 activated Pink1/Parkin signaling pathway and upregulated autophagy level. SIGNIFICANCE: AM1241 exerts a protective effect against MIRI in rats by inducing autophagy through the activation of Pink1/Parkin pathway.

Reduced glutathione does not further reduce contrast-induced nephropathy in elderly patients with diabetes receiving percutaneous coronary intervention.

OBJECTIVE: To investigate the preventive effect of hydration combined with reduced glutathione on contrast-induced nephropathy (CIN) after coronary intervention therapy in elderly Chinese patients with diabetes. METHODS: Patients with diabetes aged ≥65 years, who received percutaneous coronary intervention (PCI) between 1 August 2016 and 31 December 2018, were enrolled and randomized into two groups: patients treated with hydration combined with reduced glutathione (treatment group) and patients who received hydration alone (controls). Serum creatinine and creatinine clearance levels were measured in all patients before PCI and then daily for 3 days after PCI. Occurrence of CIN (the primary endpoint) was defined as serum creatinine value 25% or 44.2 mmol/l (0.5 mg/dl) above baseline at 72 h after an exposure to contrast medium. RESULTS: A total of 396 patients were included (treatment group, n = 204; and controls, n = 192). The CIN occurrence rate in the treatment and control group was 5.88% and 6.77%, respectively, with no statistically significant between-group difference. CONCLUSION: In elderly patients with diabetes receiving PCI, the risk of CIN was not effectively lowered by hydration combined with reduced glutathione.

Retinol palmitate protects against myocardial ischemia/reperfusion injury via reducing oxidative stress and inhibiting apoptosis.

The purpose of this study was to determine whether retinol palmitate could protect against myocardial ischemia/reperfusion (I/R) injury and explore the underlying mechanism. Retinol palmitate reduced the level of reactive oxygen species and prevented cellular apoptosis. In vivo, retinol palmitate increased superoxide dismutase (SOD) activity and reduced the level of malondialdehyde in I/R mice. Retinol palmitate also decreased myocardial infarct size and reduced cellular apoptosis by suppressing the expression of proapoptotic-related proteins and increasing that of SOD-related proteins. Our results suggest that retinol palmitate pretreatment has a protective effect against myocardial I/R injury by maintaining the balance between intracellular oxidants and antioxidants.

Acute myocardial infarction in pregnancy: spasm caused by hyperthyroidism?

We present a 26-year-old woman with ST-segment elevation myocardial infarction in the 14th week of pregnancy. Coronary angiography revealed no abnormalities in the coronary arteries. She had no history of coronary risk factors such as smoking, diabetes mellitus, hypertension, or dyslipidemia. Although we do not have direct evidence of coronary spasm in this patient, several factors suggest that coronary spasm is the most likely cause of myocardial infarction. We suspect that hyperthyroidism may have played an important role in coronary spasm in this patient. Early use of coronary angiography is helpful to identify the types of coronary artery lesions.

Osthole protects against Ang II-induced endotheliocyte death by targeting NF-κB pathway and Keap-1/Nrf2 pathway.

Osthole, the main active constituents in traditional Chinese medicine fructus cnidii, has anti-inflammatory and anti-oxidant activities. Apoptosis of vascular endothelial cells is an important cause of cardiovascular disease. Inflammation and oxidative stress are two key factors in injury of endotheliocyte. In this study, we investigated the effect of osthole on Ang II-induced apoptosis of rat aortic endothelial cells (RAECs) and explored the underlying mechanisms. In the present study, the protective effects of osthole on RAECs induced by Ang II in vitro were tested. Additionally, molecular docking and molecular dynamics (MD) simulations were utilized to investigate the potential binding mode of osthole to NF-κB and Keap1. Our results showed osthole remarkably attenuates Ang II-induced apoptosis of RAECs via alleviating inflammation and oxidative stress. Molecular docking and MD simulations revealed the potential interaction of osthole bind to the P65 subunit of NF-κB and the Keap1 protein, an adaptor for the degradation of Nrf2. We further found that osthole decreased Ang II-induced inflammation and oxidative stress through respectively modulating NF-κB and Nrf2 pathways in RAECs. These studies provide evidence that osthole may represent a potential therapeutic agent for the treatment of vascular injury.

Development of Inducible CD19-CAR T Cells with a Tet-On System for Controlled Activity and Enhanced Clinical Safety.

The tetracycline regulatory system has been widely used to control the transgene expression. With this powerful tool, it might be possible to effectively control the functional activity of chimeric antigen receptor (CAR) T cells and manage the severe side effects after infusion. In this study, we developed novel inducible CD19CAR (iCAR19) T cells by incorporating a one-vector Tet-on system into the CD19CAR construct. The iCAR19 T cells showed dox-dependent cell proliferation, cytokine production, CAR expression, and strong CD19-specific cytotoxicity. After 48 h of dox induction, the relative CAR expression of induced cells was five times greater than that of uninduced cells. Twenty-four hours after dox removal, CAR expression significantly decreased by more than 60%. In cytotoxicity assays, dox-treated cells induced significantly higher specific lysis against target cells. These results suggested that the activity of iCAR19 T cells was successfully controlled by our Tet-on system, offering an enhanced safety profile while maintaining a robust anti-tumor effect. Besides, all manufacture processes of the lentiviral vectors and the T cells were conducted according to the Good Manufacturing Practice (GMP) standards for subsequent clinical translation.

Adipose-derived stem cells in articular cartilage regeneration: current concepts and optimization strategies.

Knee osteoarthritis (KOA) is the most common progressive joint disorder associated with disability in the world. As a chronic disease, KOA has multifactorial etiology. However, the poor self-healing ability of the articular cartilage due to its intrinsic tissue hypovascularity and hypocellularity seems to be directly incriminated in the physio-pathological mechanism of KOA. While conventional therapies result in unfavorable clinical outcomes, regenerative cell therapies have shown great promise in articular cartilage regeneration. Adipose-derived stem cells (ASCs) appear to be an ideal alternative to bone-marrow derived stem cells (BMSCs) and autologous chondrocytes, due to their lower immunogenicity, richer source and easier acquisition. Since the first case report in 2011, ASCs have demonstrated safety and efficacy for articular cartilage regeneration in several phase I/II clinical trials. However, different levels of abnormality were found in the regenerated cartilage for most of the patients. A large portion of recent publications investigated different optimization strategies to improve the therapeutic function of ASCs, including cell source selection, preconditioning and co-delivery. Herein, we give an update on the latest research progress on ASCs, with a focus on the most promising optimization strategies for ASC-based therapy.

Repair of Rat Sciatic Nerve Defects by Using Allogeneic Bone Marrow Mononuclear Cells Combined With Chitosan/Silk Fibroin Scaffold.

The therapeutic benefits of bone marrow mononuclear cells (BM-MNCs) in many diseases have been well established. To advance BM-MNC-based cell therapy into the clinic for peripheral nerve repair, in this study we developed a new design of tissue-engineered nerve grafts (TENGs), which consist of a chitosan/fibroin-based nerve scaffold and BM-MNCs serving as support cells. These TENGs were used for interpositional nerve grafting to bridge a 10-mm-long sciatic nerve defect in rats. Histological and functional assessments after nerve grafting showed that regenerative outcomes achieved by our developed TENGs were better than those achieved by chitosan/silk fibroin scaffolds and were close to those achieved by autologous nerve grafts. In addition, we used green fluorescent protein-labeled BM-MNCs to track the cell location within the chitosan/fibroin-based nerve scaffold and trace the cell fate at an early stage of sciatic nerve regeneration. The result suggested that BM-MNCs could survive at least 2 weeks after nerve grafting, thus helping to gain a preliminary mechanistic insight into the favorable effects of BM-MNCs on axonal regrowth.

Catheter ablation of cardiac fat pads attenuates Bezold-Jarisch reflex in dogs.

BACKGROUND: Bezold-Jarisch reflex (BJR) plays an important role in the pathophysiology of several cardiovascular disorders. Radiofrequency catheter ablation (RFCA) of the vagal ganglia in cardiac fat pads (FPs) may attenuate BJR. The purpose of this study was to examine the effects of RFCA of the cardiac FPs on veratridine-induced BJR in dogs. METHODS AND RESULTS: This study was performed in 30 pentobarbital-anesthetized and open-chest dogs: control group received no ablation (n = 15); and ablation group (n = 15) received epicardial ablation of the 3 FPs located near the right pulmonary vein, the inferior vena cava, and the aortic root. The BJR was induced by injection of veratridine (15 µg/kg) into the left ventricle. Before injection of veratridine, there were no significant differences in heart rate (HR), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), mean arterial pressure (MAP), left ventricular systolic pressure (LVSP), left ventricle end-diastolic pressure (LVEDP), left ventricular peak systolic and diastolic velocity (±dp/dt(max)) between these 2 groups (P > 0.05). However, the veratridine-induced decrease of HR in ablation group was significantly lower than that in control group (22.9 ± 8.5 bpm vs 93.3 ± 18.4 bpm, P < 0.01). There were no differences in the reduction of SAP, DAP, MAP, LVSP, LVEDP and dp/dt(max) between both groups (P > 0.05). CONCLUSIONS: RFCA of the cardiac FPs significantly attenuated veratridine-induced cardio-vagal component but not the vasodepressor component of the BJR. This might have therapeutic implications in BJR-related disorders such as cardio-inhibitory vasovagal syncope.