Lentivirus-modified hematopoietic stem cell gene therapy for advanced symptomatic juvenile metachromatic leukodystrophy: A long-term follow-up pilot study.

Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA). Lentivirus-modified autologous hematopoietic stem cell gene therapy (HSCGT) has recently been approved for clinical use in pre- and early-symptomatic children with MLD to increase ARSA activity. Unfortunately, this advanced therapy is not available for most patients with MLD who have progressed to more advanced symptomatic stages at diagnosis. Patients with late-onset juvenile MLD typically present with a slower neurological progression of symptoms and represent a significant burden to the economy and healthcare system, whereas those with early-onset infantile MLD die within a few years of symptom onset. We conducted a pilot study to determine the safety and benefit of HSCGT in patients with post-symptomatic juvenile MLD and report preliminary results. The safety profile of HSCGT was favorable in this long-term follow-up over nine years. The most common adverse events (AEs) within two months of HSCGT were related to busulfan conditioning, and all AEs resolved. No HSCGT-related AEs and no evidence of distorted hematopoietic differentiation during long-term follow-up for up to 9.6 years. Importantly, to date, patients have maintained remarkably improved ARSA activity with a stable disease state, including increased Functional Independence Measure (FIM) score and decreased magnetic resonance imaging (MRI) lesion score. This long-term follow-up pilot study suggests that HSCGT is safe and provides clinical benefit to patients with post-symptomatic juvenile MLD.

Noninvasive neuromodulation protects against doxorubicin-induced cardiotoxicity and inhibits tumor growth.

Doxorubicin (Dox) poses a considerable threat to patients owing to its cardiotoxicity, thus limiting its clinical utility. Optimal cardioprotective intervention strategies are needed to suppress tumor growth but also minimize cardiac side effects. Here, we showed that tragus vagus nerve stimulation (tVNS) improved the imbalanced autonomic tone, ameliorated impaired cardiac function and fibrosis, attenuated myocyte apoptosis, and mitochondrial dysfunction compared to those in the Dox group. The beneficial effects were attenuated by methyllycaconitine citrate (MLA). The transcript profile revealed that there were 312 differentially expressed genes and the protection of tVNS and retardation of MLA were related to inflammatory response and NADPH oxidase activity. In addition, tVNS synergizing with Dox inhibited tumor growth and lung metastasis and promoted apoptosis of tumor cells in an anti-tumor immunity manner. These results indicated that non-invasive neuromodulation can play a dual role in preventing Dox-induced cardiotoxicity and suppressing tumor growth through inflammation and oxidative stress.

Wireless Self-Powered Optogenetic System for Long-Term Cardiac Neuromodulation to Improve Post-MI Cardiac Remodeling and Malignant Arrhythmia.

Autonomic imbalance is an important characteristic of patients after myocardial infarction (MI) and adversely contributes to post-MI cardiac remodeling and ventricular arrhythmias (VAs). A previous study proved that optogenetic modulation could precisely inhibit cardiac sympathetic hyperactivity and prevent acute ischemia-induced VAs. Here, a wireless self-powered optogenetic modulation system is introduced, which achieves long-term precise cardiac neuromodulation in ambulatory canines. The wireless self-powered optical system based on a triboelectric nanogenerator is powered by energy harvested from body motion and realized the effective optical illumination that is required for optogenetic neuromodulation (ON). It is further demonstrated that long-term ON significantly mitigates MI-induced sympathetic remodeling and hyperactivity, and improves a variety of clinically relevant outcomes such as improves ventricular dysfunction, reduces infarct size, increases electrophysiological stability, and reduces susceptibility to VAs. These novel insights suggest that wireless ON holds translational potential for the clinical treatment of arrhythmia and other cardiovascular diseases related to sympathetic hyperactivity. Moreover, this innovative self-powered optical system may provide an opportunity to develop implantable/wearable and self-controllable devices for long-term optogenetic therapy.

Prediction of major adverse cardiovascular events in patients with acute coronary syndrome: Development and validation of a non-invasive nomogram model based on autonomic nervous system assessment.

Background: Disruption of the autonomic nervous system (ANS) can lead to acute coronary syndrome (ACS). We developed a nomogram model using heart rate variability (HRV) and other data to predict major adverse cardiovascular events (MACEs) following emergency coronary angiography in patients with ACS. Methods: ACS patients admitted from January 2018 to June 2020 were examined. Holter monitors were used to collect HRV data for 24 h. Coronary angiograms, clinical data, and MACEs were recorded. A nomogram was developed using the results of Cox regression analysis. Results: There were 439 patients in a development cohort and 241 in a validation cohort, and the mean follow-up time was 22.80 months. The nomogram considered low-frequency/high-frequency ratio, age, diabetes, previous myocardial infarction, and current smoking. The area-under-the-curve (AUC) values for 1-year MACE-free survival were 0.790 (95% CI: 0.702-0.877) in the development cohort and 0.894 (95% CI: 0.820-0.967) in the external validation cohort. The AUCs for 2-year MACE-free survival were 0.802 (95% CI: 0.739-0.866) in the development cohort and 0.798 (95% CI: 0.693-0.902) in the external validation cohort. Development and validation were adequately calibrated and their predictions correlated with the observed outcome. Decision curve analysis (DCA) showed the model had good discriminative ability in predicting MACEs. Conclusion: Our validated nomogram was based on non-invasive ANS assessment and traditional risk factors, and indicated reliable prediction of MACEs in patients with ACS. This approach has potential for use as a method for non-invasive monitoring of health that enables provision of individualized treatment strategies.

Topical and intravenous administration of human umbilical cord mesenchymal stem cells in patients with diabetic foot ulcer and peripheral arterial disease: a phase I pilot study with a 3-year follow-up.

BACKGROUND: Diabetic foot ulcer (DFU) is a serious chronic complication of diabetes mellitus that contributes to 85% of nontraumatic lower extremity amputations in diabetic patients. Preliminary clinical benefits have been shown in treatments based on mesenchymal stem cells for patients with DFU or peripheral arterial disease (PAD). However, the long-term safety and benefits are unclear for patients with both DFU and PAD who are not amenable to surgical revascularization. METHODS: In this phase I pilot study, 14 patients with PAD and incurable DFU were enrolled to assess the safety and efficacy of human umbilical cord mesenchymal stem cell (hUC-MSC) administration based on conservative treatments. All patients received topical and intravenous administrations of hUC-MSCs at a dosage of 2 × 105 cells/kg with an upper limit of 1 × 107 cells for each dose. The adverse events during treatment and follow-up were documented for safety assessments. The therapeutic efficacy was assessed by ulcer healing status, recurrence rate, and 3-year amputation-free rate in the follow-up phase. RESULTS: The safety profiles were favorable. Only 2 cases of transient fever were observed within 3 days after transfusion and considered possibly related to hUC-MSC administration intravenously. Ulcer disclosure was achieved for more than 95% of the lesion area for all patients within 1.5 months after treatment. The symptoms of chronic limb ischaemia were alleviated along with a decrease in Wagner scores, Rutherford grades, and visual analogue scale scores. No direct evidence was observed to indicate the alleviation of the obstruction in the main vessels of target limbs based on computed tomography angiography. The duration of rehospitalization for DFU was 2.0 ± 0.6 years. All of the patients survived without amputation due to the recurrence of DFU within 3 years after treatments. CONCLUSIONS: Based on the current pilot study, the preliminary clinical benefits of hUC-MSCs on DFU healing were shown, including good tolerance, a shortened healing time to 1.5 months and a favorable 3-year amputation-free survival rate. The clinical evidence in the current study suggested a further phase I/II study with a larger patient population and a more rigorous design to explore the efficacy and mechanism of hUC-MSCs on DFU healing. TRIAL REGISTRATION: The current study was registered retrospectively on 22 Jan 2022 with the Chinese Clinical Trial Registry (ChiCTR2200055885), http://www.chictr.org.cn/showproj.aspx?proj=135888.

Renal NF-κB activation impairs uric acid homeostasis to promote tumor-associated mortality independent of wasting.

Tumor-induced host wasting and mortality are general phenomena across species. Many groups have previously demonstrated endocrinal impacts of malignant tumors on host wasting in rodents and Drosophila. Whether and how environmental factors and host immune response contribute to tumor-associated host wasting and survival, however, are largely unknown. Here, we report that flies bearing malignant yki3SA-gut tumors exhibited the exponential increase of commensal bacteria, which were mostly acquired from the environment, and systemic IMD-NF-κB activation due to suppression of a gut antibacterial amidase PGRP-SC2. Either gut microbial elimination or specific IMD-NF-κB blockade in the renal-like Malpighian tubules potently improved mortality of yki3SA-tumor-bearing flies in a manner independent of host wasting. We further indicate that renal IMD-NF-κB activation caused uric acid (UA) overload to reduce survival of tumor-bearing flies. Therefore, our results uncover a fundamental mechanism whereby gut commensal dysbiosis, renal immune activation, and UA imbalance potentiate tumor-associated host death.

Mesenchymal stem cell-derived extracellular vesicles for immunomodulation and regeneration: a next generation therapeutic tool?

Mesenchymal stem cells (MSCs) can be widely isolated from various tissues including bone marrow, umbilical cord, and adipose tissue, with the potential for self-renewal and multipotent differentiation. There is compelling evidence that the therapeutic effect of MSCs mainly depends on their paracrine action. Extracellular vesicles (EVs) are fundamental paracrine effectors of MSCs and play a crucial role in intercellular communication, existing in various body fluids and cell supernatants. Since MSC-derived EVs retain the function of protocells and have lower immunogenicity, they have a wide range of prospective therapeutic applications with advantages over cell therapy. We describe some characteristics of MSC-EVs, and discuss their role in immune regulation and regeneration, with emphasis on the molecular mechanism and application of MSC-EVs in the treatment of fibrosis and support tissue repair. We also highlight current challenges in the clinical application of MSC-EVs and potential ways to overcome the problem of quality heterogeneity.

Differential effects of macrophage subtypes on SARS-CoV-2 infection in a human pluripotent stem cell-derived model.

Dysfunctional immune responses contribute critically to the progression of Coronavirus Disease-2019 (COVID-19), with macrophages as one of the main cell types involved. It is urgent to understand the interactions among permissive cells, macrophages, and the SARS-CoV-2 virus, thereby offering important insights into effective therapeutic strategies. Here, we establish a lung and macrophage co-culture system derived from human pluripotent stem cells (hPSCs), modeling the host-pathogen interaction in SARS-CoV-2 infection. We find that both classically polarized macrophages (M1) and alternatively polarized macrophages (M2) have inhibitory effects on SARS-CoV-2 infection. However, M1 and non-activated (M0) macrophages, but not M2 macrophages, significantly up-regulate inflammatory factors upon viral infection. Moreover, M1 macrophages suppress the growth and enhance apoptosis of lung cells. Inhibition of viral entry using an ACE2 blocking antibody substantially enhances the activity of M2 macrophages. Our studies indicate differential immune response patterns in distinct macrophage phenotypes, which could lead to a range of COVID-19 disease severity.

Impaired bone marrow microenvironment and stem cells in transfusion-dependent beta-thalassemia.

Beta-thalassemia (BT) is a hereditary disease caused by abnormal hemoglobin synthesis with consequent ineffective erythropoiesis. Patients with thalassemia major are dependent on long-term blood transfusions with associated long-term complications such as iron overload (IO). This excess iron can result in tissue damage, impaired organ function, and increased morbidity. Growing evidence has demonstrated that IO contributes to impairment of the bone marrow (BM) microenvironment that largely impacts the function of BM mesenchymal stem cells, hematopoietic stem cells, and endothelial cells. In this article, we review recent progress in the understanding of iron metabolism and the perniciousness induced by IO. We highlight the importance of understanding the cross-talk between BM stem cells and the BM microenvironment, particularly the pathological effect of IO on BM stem cells and BT-associated complications. We also provide an update on recent novel therapies to cure transfusion-dependent beta-thalassemia and iron overload-induced complications for their future clinical application.

Non-invasive transcutaneous vagal nerve stimulation improves myocardial performance in doxorubicin-induced cardiotoxicity.

AIMS: The clinical use of antitumour agent doxorubicin (DOX) is hampered by its dose-dependent cardiotoxicity. Development of highly efficient and safe adjuvant intervention for preventing DOX-induced adverse cardiac events is urgently needed. We aimed to investigate whether transcutaneous vagal nerve stimulation (tVNS) plays a cardio-protective role in DOX-induced cardiotoxicity. METHODS AND RESULTS: Healthy male adult Sprague Dawley rats were used in the experiment and were randomly divided into four groups including control, DOX, tVNS, and DOX+tVNS groups. A cumulative dose of 15 mg/kg DOX was intraperitoneally injected into rats to generate cardiotoxicity. Non-invasive tVNS was conducted for 6 weeks (30 min/day). After 6-week intervention, the indices from the echocardiography revealed that tVNS significantly improved left ventricular function compared to the DOX group. The increased malondialdehyde and Interleukin-1ß, and decreased superoxide dismutase were observed in the DOX group, while tVNS significantly prevented these changes. From cardiac histopathological analysis, the DOX+tVNS group showed a mild myocardial damage, and decreases in cardiac fibrosis and myocardial apoptosis compared to the DOX group. Heart rate variability analysis showed that tVNS significantly inhibited DOX-induced sympathetic hyperactivity compared to the DOX group. Additionally, the results of RNA-sequencing analysis showed that there were 245 differentially expressed genes in the DOX group compared to the control group, among which 39 genes were down-regulated by tVNS and most of these genes were involved in immune system. Moreover, tVNS significantly down-regulated the relative mRNA expressions of chemokine-related genes and macrophages recruitment compared to the DOX group. CONCLUSION: These results suggest that tVNS prevented DOX-induced cardiotoxicity by rebalancing autonomic tone, ameliorating cardiac dysfunction and remodelling. Notably, crosstalk between autonomic neuromodulation and innate immune cells macrophages mediated by chemokines might be involved in the underlying mechanisms.

Management of adrenoleukodystrophy: From pre-clinical studies to the development of new therapies.

X-linked adrenoleukodystrophy (X-ALD) is an inherited neurodegenerative disorder associated with mutations of the ABCD1 gene that encodes a peroxisomal transmembrane protein. It results in accumulation of very long chain fatty acids in tissues and body fluid. Along with other factors such as epigenetic and environmental involvement, ABCD1 mutation-provoked disorders can present different phenotypes including cerebral adrenoleukodystrophy (cALD), adrenomyeloneuropathy (AMN), and peripheral neuropathy. cALD is the most severe form that causes death in young childhood. Bone marrow transplantation and hematopoietic stem cell gene therapy are only effective when performed at an early stage of onsets in cALD. Nonetheless, current research and development of novel therapies are hampered by a lack of in-depth understanding disease pathophysiology and a lack of reliable cALD models. The Abcd1 and Abcd1/Abcd2 knock-out mouse models as well as the deficiency of Abcd1 rabbit models created in our lab, do not develop cALD phenotypes observed in human beings. In this review, we summarize the clinical and biochemical features of X-ALD, the progress of pre-clinical and clinical studies. Challenges and perspectives for future X-ALD studies are also discussed.

Bioremediation of Petroleum Hydrocarbons Using Acinetobacter sp. SCYY-5 Isolated from Contaminated Oil Sludge: Strategy and Effectiveness Study.

Biodegradation has been considered as an ideal technique for total petroleum hydrocarbon (TPH) contamination, but its efficiency is limited by its application in the field. Herein, an original TPH-degrading strain, SCYY-5, was isolated from contaminated oil sludge and identified as Acinetobacter sp. by 16S rDNA sequence analysis. The biological function of the isolate was investigated by heavy metal tolerance, carbon, and nitrogen source and degradation tests. To enhance its biodegradation efficiency, the response surface methodology (RSM) based on a function model was adopted to investigate and optimize the strategy of microbial and environmental variables for TPH removal. Furthermore, the performance of the system increased to 79.94% with the further addition of extra nutrients, suggesting that the RSM and added nutrients increased the activity of bacteria to meet the needs of the co-metabolism matrix during growth or degradation. These results verified that it is feasible to adopt the optimal strategy of combining bioremediation with RSM to improve the biodegradation efficiency, for contaminated oil sludge.

Adult mesenchymal stem cell ageing interplays with depressed mitochondrial Ndufs6.

Mesenchymal stem cell (MSC)-based therapy has emerged as a novel strategy to treat many degenerative diseases. Accumulating evidence shows that the function of MSCs declines with age, thus limiting their regenerative capacity. Nonetheless, the underlying mechanisms that control MSC ageing are not well understood. We show that compared with bone marrow-MSCs (BM-MSCs) isolated from young and aged samples, NADH dehydrogenase (ubiquinone) iron-sulfur protein 6 (Ndufs6) is depressed in aged MSCs. Similar to that of Ndufs6 knockout (Ndufs6-/-) mice, MSCs exhibited a reduced self-renewal and differentiation capacity with a tendency to senescence in the presence of an increased p53/p21 level. Downregulation of Ndufs6 by siRNA also accelerated progression of wild-type BM-MSCs to an aged state. In contrast, replenishment of Ndufs6 in Ndufs6-/--BM-MSCs significantly rejuvenated senescent cells and restored their proliferative ability. Compared with BM-MSCs, Ndufs6-/--BM-MSCs displayed increased intracellular and mitochondrial reactive oxygen species (ROS), and decreased mitochondrial membrane potential. Treatment of Ndufs6-/--BM-MSCs with mitochondrial ROS inhibitor Mito-TEMPO notably reversed the cellular senescence and reduced the increased p53/p21 level. We provide direct evidence that impairment of mitochondrial Ndufs6 is a putative accelerator of adult stem cell ageing that is associated with excessive ROS accumulation and upregulation of p53/p21. It also indicates that manipulation of mitochondrial function is critical and can effectively protect adult stem cells against senescence.

Physiological and Pathological Regulation of Peripheral Metabolism by Gut-Peptide Hormones in Drosophila.

The gastrointestinal (GI) tract in both vertebrates and invertebrates is now recognized as a major source of signals modulating, via gut-peptide hormones, the metabolic activities of peripheral organs, and carbo-lipid balance. Key advances in the understanding of metabolic functions of gut-peptide hormones and their mediated interorgan communication have been made using Drosophila as a model organism, given its powerful genetic tools and conserved metabolic regulation. Here, we summarize recent studies exploring peptide hormones that are involved in the communication between the midgut and other peripheral organs/tissues during feeding conditions. We also highlight the emerging impacts of fly gut-peptide hormones on stress sensing and carbo-lipid metabolism in various disease models, such as energy overload, pathogen infection, and tumor progression. Due to the functional similarity of intestine and its derived peptide hormones between Drosophila and mammals, it can be anticipated that findings obtained in the fly system will have important implications for the understanding of human physiology and pathology.

The fabrication and arsenic removal performance of cellulose nanocrystal-containing absorbents based on the "bridge joint" effect of iron ions.

By using the "bridge joint" effect of iron ions, cellulose nanocrystal-containing high-performance adsorbents were synthesized via coprecipitation method, which enhanced the cross-linking action of cellulose nanocrystal and polyethyleneimine. The morphology, specific surface area, surface chemistry and chemical valence of the adsorbents were characterized by SEM, FTIR, BET and XPS. According to the results, the iron ions successfully connect the two dispersed polymers together, inducing a large number of O-Fe-O bonds and, providing more adsorption active sites for the removal of seriously polluted and high-toxicity As(III)/As(V). Furthermore, the arsenic removal performance of the adsorbents was studied, and the adsorption mechanism was revealed according to the spectral characteristics of the chemical components. Of note, the synthesized iron-containing adsorbents are suitable for a wide pH range, which may offer a new application for nanocellulose in the treatment of arsenic pollution.

Interactions between metabolism regulator adiponectin and intrinsic cardiac autonomic nervous system: A potential treatment target for atrial fibrillation.

BACKGROUND: Previous studies indicated that inhibiting the cardiac autonomic nervous system (CANS) suppressed atrial fibrillation (AF). Clinical research revealed serum adiponectin (APN) exerted a beneficial influence on sympathetic and vagal tone in patients with type 2 diabetes. However, the effects of APN on CANS is unknown. This study aims to investigate whether APN could regulate CANS and suppress rapid atrial pacing (RAP)-induced AF. METHODS: Eighteen beagles were divided into the control group (saline plus sham RAP, N = 6), the RAP group (saline plus RAP, N = 6) and the APN + RAP group (APN plus RAP, N = 6). APN (10 µg, 0.1 µg/µL) or saline was microinjected into 4 major ganglionated plexi (GP) prior to RAP. Atrial electrophysiological parameters, anterior right GP (ARGP) function, neural activity and GP tissues were detected. RESULTS: Compared with the control treatment, RAP shortened effective refractory period (ERP) values at all sites and increased cumulative window of vulnerability (ΣWOV), ARGP function and neural activity, whereas APN injection reversed these changes. Mechanistically, APN ameliorated RAP-induced inflammatory response and down-regulated the expression of c-fos protein and nerve growth factor. Moreover, the APN receptors 1 and APN receptors 2 were detected both in neurons and in non-neuronal cells. APN pretreatment activated downstream adenosine monophosphate-activated protein kinase (AMPK) signaling, inhibited nuclear factor-kappa B signaling and promoted macrophage phenotype switching from proinflammatory to anti-inflammatory state. CONCLUSIONS: This study demonstrates that administration of APN into GP can suppress RAP-induced AF by regulating the CANS. APN signaling may provide a potential therapeutic target to AF.

Interaction between Endothelin-1 and Left Stellate Ganglion Activation: A Potential Mechanism of Malignant Ventricular Arrhythmia during Myocardial Ischemia.

Endothelin-1 (ET-1) is synthesized primarily by endothelial cells. ET-1 administration in vivo enhances the cardiac sympathetic afferent reflex and sympathetic activity. Previous studies have shown that sympathetic hyperactivity promotes malignant ventricular arrhythmia (VA). The aim of this study was to investigate whether ET-1 could activate the left stellate ganglion (LSG) and promote malignant VA. Twelve male beagle dogs who received local microinjections of saline (control, n = 6) and ET-1 into the LSG (n = 6) were included. The ventricular effective refractory period (ERP), LSG function, and LSG activity were measured at different time points. VA was continuously recorded for 1 h after left anterior descending occlusion (LADO), and LSG tissues were then collected for molecular detection. Compared to that of the control group, local ET-1 microinjection significantly decreased the ERP and increased the occurrence of VA. In addition, local microinjection of ET-1 increased the function and activity of the LSG in the normal and ischemic hearts. The expression levels of proinflammatory cytokines and the protein expression of c-fos and nerve growth factor (NGF) in the LSG were also increased. More importantly, endothelin A receptor (ETA-R) expression was found in the LSG, and its signaling was significantly activated in the ET-1 group. LSG activation induced by local ET-1 microinjection aggravates LADO-induced VA. Activated ETA-R signaling and the upregulation of proinflammatory cytokines in the LSG may be responsible for these effects.

Vagus Nerve Stimulation Attenuates Hepatic Ischemia/Reperfusion Injury via the Nrf2/HO-1 Pathway.

It has been demonstrated that vagus nerve stimulation (VNS) plays a protective role in ischemia/reperfusion (I/R) injury of various organs. The present study investigates the protective effect of VNS on hepatic I/R injury and the potential mechanisms. Male Sprague-Dawley rats were randomly allocated into three groups: the sham operation group (Sham; n = 6, sham surgery with sham VNS); the I/R group (n = 6, hepatic I/R surgery with sham VNS); and the VNS group (n = 6, hepatic I/R surgery plus VNS). The I/R model was established by 1 hour of 70% hepatic ischemia. Tissue samples and blood samples were collected after 6 hours of reperfusion. The left cervical vagus nerve was separated and stimulated throughout the whole I/R process. The stimulus intensity was standardized to the voltage level that slowed the sinus rate by 10%. VNS significantly reduced the necrotic area and cell death in I/R tissues. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) were also decreased by VNS. In addition, VNS suppressed inflammation, oxidative stress, and apoptosis in I/R tissues. VNS significantly increased the protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) in the liver. These data indicated that VNS may attenuate hepatic I/R injury by inhibiting inflammation, oxidative stress, and apoptosis possibly via the Nrf2/HO-1 pathway.

Vagus nerve stimulation protects against acute liver injury induced by renal ischemia reperfusion via antioxidant stress and anti-inflammation.

OBJECTIVE: Renal ischemia reperfusion (I/R) is not an isolated event; however, it results in remote organ dysfunction. Vagus nerve stimulation (VNS) has shown protective effects against renal I/R injury via an anti-inflammatory mechanism. This study aimed to investigate whether VNS could attenuate liver injury induced by renal I/R and identify the underlying mechanisms. METHODS: Eighteen healthy male Sprague-Dawley rats (200-250 g) were equally divided into three groups: sham group (sham surgery without I/R or VNS), I/R group (renal I/R) and VNS group (renal I/R plus VNS). The I/R model was established by excising the right kidney and then clamping the left renal pedicle with an occlusive nontraumatic microaneurysm clamp for 45 min followed by a 6-h reperfusion. The rats in the VNS group received spontaneous left cervical VNS with renal ischemia and reperfusion. At the end of the experiment, blood and liver tissues were collected to detect liver function, oxidative stress and inflammatory parameters. Additionally, TUNEL staining, real-time PCR, western blotting and hematoxylin and eosin staining of liver tissues were performed to assess liver injury and the underlying mechanisms. RESULTS: Kidney and liver function was severely damaged in the I/R group compared to the sham group. However, VNS significantly protected kidney and liver function. Rats treated with VNS revealed decreases in oxidative enzymes, apoptosis and levels of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) in serum and liver compared with rats in the I/R group. Rats in the VNS group also showed increased antioxidant stress responses compared to rats in the I/R group. CONCLUSION: VNS exerts protective effects against liver injury from renal I/R via inhibiting oxidative stress and apoptosis, downregulating inflammatory cytokines and enhancing antioxidative capability in the liver, and may become a promising adjuvant therapeutic strategy for treating liver injury induced by acute renal injury.

Development and Investigation of Lanthanum Sulfadiazine with Calcium Stearate and Epoxidised Soyabean Oil as Complex Thermal Stabilizers for Stabilizing Poly(vinyl chloride).

Lanthanum sulfadiazine (LaSD) was synthesized from sulfadiazine and lanthanum nitrate using water as solvent under alkaline conditions, and was used as a novel rare earth thermal stabilizer to stabilize poly(vinyl chloride) (PVC). The structure of LaSD was characterized by elemental analysis (EA), Fourier transform infrared spectroscopy (FTIR) and thermo- gravimetric analysis (TGA). The influence of lanthanum sulfadiazine with calcium stearate (CaSt2) and epoxidized soybean oil (ESBO) on stabilizing PVC was studied by using the Congo red test, oven discoloration test, UV-vis spectroscopy and thermal decomposition kinetics. The results showed that the addition of LaSD as a thermal stabilizer can significantly improve the initial whiteness and long-term stability of PVC. In addition, the synergies between LaSD, ESBO, and CaSt2 can provide outstanding improvement in the long-term thermal stability of PVC. When the ratio of LaSD/ESBO/CaSt2 is 1.8/0.6/0.6, its thermal stability time is 2193 s which is the best state for stabilizing PVC. Furthermore, comparing the reaction energy (Ea) and the variations in the conjugate double bond concentration in PVC samples, the order of thermal stability of PVC was PVC/LaSD/ESBO/CaSt2 > PVC/LaSD/ESBO > PVC/LaSD. The thermal stability mechanism of LaSD on PVC was studied by the AgCl precipitation method and FTIR spectrum. The results showed that the action of LaSD on PVC was achieved through replacing unstable chlorine atoms and absorbing hydrogen chloride.