Predictive Ability of Visit-to-Visit Variability of HbA1c Measurements for the Development of Diabetic Kidney Disease: A Retrospective Longitudinal Observational Study.

AIMS: This study is aimed at clarifying the relationship between visit-to-visit variability of glycated hemoglobin (HbA1c) and the risk of diabetic kidney disease (DKD) and to identifying the most useful index of visit-to-visit variability of HbA1c. METHODS: This clinic-based retrospective longitudinal study included 699 Japanese type 2 diabetes mellitus patients. Visit-to-visit variability of HbA1c was calculated as the internal standard deviation of HbA1c (HbA1c-SD), the coefficient of variation of HbA1c (HbA1c-CV), the HbA1c change score (HbA1c-HVS), and the area under the HbA1c curve (HbA1c-AUC) with 3-year serial HbA1c measurement data, and the associations between these indices and the development/progression of DKD were examined. RESULTS: Cox proportional hazards models showed that the HbA1c-SD and HbA1c-AUC were associated with the incidence of microalbuminuria, independently of the HbA1c level. These results were verified and replicated in propensity score (PS) matching and bootstrap analyses. Moreover, the HbA1c-SD and HbA1c-AUC were also associated with oxidized human serum albumin (HSA), an oxidative stress marker. CONCLUSIONS: Visit-to-visit variability of HbA1c was an independent risk factor of microalbuminuria in association with oxidative stress among type 2 diabetes mellitus patients. HbA1c-AUC, a novel index of HbA1c variability, may be a potent prognostic indicator in predicting the risk of microalbuminuria.

Protective Mechanism and Treatment of Neurogenesis in Cerebral Ischemia.

Stroke is the fifth leading cause of death worldwide and is a main cause of disability in adults. Neither currently marketed drugs nor commonly used treatments can promote nerve repair and neurogenesis after stroke, and the repair of neurons damaged by ischemia has become a research focus. This article reviews several possible mechanisms of stroke and neurogenesis and introduces novel neurogenic agents (fibroblast growth factors, brain-derived neurotrophic factor, purine nucleosides, resveratrol, S-nitrosoglutathione, osteopontin, etc.) as well as other treatments that have shown neuroprotective or neurogenesis-promoting effects.

The Therapeutic Potential of Chemokines in the Treatment of Chemotherapy- Induced Peripheral Neuropathy.

BACKGROUND: Some of the current challenges and complications of cancer therapy are chemotherapy- induced peripheral neuropathy (CIPN) and the neuropathic pain that are associated with this condition. Many major chemotherapeutic agents can cause neurotoxicity, significantly modulate the immune system and are always accompanied by various adverse effects. Recent evidence suggests that cross-talk occurs between the nervous system and the immune system during treatment with chemotherapeutic agents; thus, an emerging concept is that neuroinflammation is one of the major mechanisms underlying CIPN, as demonstrated by the upregulation of chemokines. Chemokines were originally identified as regulators of peripheral immune cell trafficking, and chemokines are also expressed on neurons and glial cells in the central nervous system. OBJECTIVE: In this review, we collected evidence demonstrating that chemokines are potential mediators and contributors to pain signalling in CIPN. The expression of chemokines and their receptors, such as CX3CL1/CX3CR1, CCL2/CCR2, CXCL1/CXCR2, CXCL12/CXCR4 and CCL3/CCR5, is altered in the pathological conditions of CIPN, and chemokine receptor antagonists attenuate neuropathic pain behaviour. CONCLUSION: By understanding the mechanisms of chemokine-mediated communication, we may reveal chemokine targets that can be used as novel therapeutic strategies for the treatment of CIPN.

Levo-corydalmine Attenuates Vincristine-Induced Neuropathic Pain in Mice by Upregulating the Nrf2/HO-1/CO Pathway to Inhibit Connexin 43 Expression.

Antimicrotubulin chemotherapeutic agents, including plant-derived vincaalkaloids such as vincristine, can cause peripheral neuropathic pain. Exogenously activated heme oxygenase 1 (HO-1) is a potential therapy for chemotherapy-induced neuroinflammation. In this study, we investigated a role for Nrf2/HO-1/CO in mediating vincristine-induced neuroinflammation by inhibiting connexin 43 (Cx43) production in the spinal cord following the intrathecal application of the HO-1 inducer protoporphyrin IX cobalt chloride (CoPP) or inhibitor protoporphyrin IX zinc (ZnPP), and we analyzed the underlying mechanisms by which levo-corydalmine (l-CDL, a tetrahydroprotoberberine) attenuates vincristine-induced pain. Treatment with levo-corydalmine or oxycodone hydrochloride (a semisynthetic opioid analgesic, used as a positive control) attenuated vincristine-induced persistent pain hypersensitivity and degeneration of the sciatic nerve. In addition, the increased prevalence of atypical mitochondria induced by vincristine was ameliorated by l-CDL in both A-fibers and C-fibers. Next, we evaluated whether nuclear factor E2-related factor 2 (Nrf2), an upstream activator of HO-1, directly bound to the HO-1 promoter sequence and degraded heme to produce carbon monoxide (CO) following stimulation with vincristine. Notably, l-CDL dose-dependently increased HO-1/CO expression by activating Nrf2 to inhibit Cx43 expression in both the spinal cord and in cultured astrocytes stimulated with TNF-α, corresponding to decreased Cx43-mediated hemichannel. Furthermore, l-CDL had no effect on Cx43 following the silencing of the HO-1 gene. Taken together, our findings reveal a novel mechanism by which Nrf2/HO-1/CO mediates Cx43 expression in vincristine-induced neuropathic pain. In addition, the present findings suggest that l-CDL likely protects against nerve damage and attenuates vincristine-induced neuroinflammation by upregulating Nrf2/HO-1/CO to inhibit Cx43 expression.

JLX001 Ameliorates Ischemia/Reperfusion Injury by Reducing Neuronal Apoptosis via Down-Regulating JNK Signaling Pathway.

JLX001, a novel compound with similar structure with cyclovirobuxine D (CVB-D), has been proved to exert therapeutical effects on permanent focal cerebral ischemia. However, the protective effects of JLX001 on cerebral ischemia/reperfusion (I/R) injury and its anti-apoptotic effects have not been reported. We investigated the efficacy of JLX001 in two pharmacodynamic tests (pre-treatment test and post-treatment) with rats subjected to middle cerebral artery occlusion/reperfusion (MCAO/R). The pharmacodynamic tests demonstrated that JLX001 ameliorated I/R injury by reducing infarct sizes and brain edema. The results of Morris water maze, neurological scores, cylinder test and posture reflex test implied that JLX001 improved the learning, memory and motor ability after MCAO/R in the long term. Anti-apoptotic effects of JLX001 and its regulation of cytosolic c-Jun N-terminal Kinases (JNKs) signal pathway were confirmed in vivo by co-immunofluorescence staining and western immunoblotting. Furthermore, primary cortical neuron cultures were prepared and exposed to oxygen glucose deprivation/reoxygenation (OGD/R) for in vitro studies. Cytotoxicity test and mitochondrial membrane potential (MMP) test showed that JLX001 enhanced cell survival rate and maintained MMP. Flow cytometry and TdT-mediated dUTP-X nick end labeling (TUNEL) staining demonstrated the anti-apoptotic effects of JLX001 in vitro. Likewise, JLX001 regulated JNK signal pathway in vivo, which was also confirmed by western immunoblotting. Collectively, this study presents the first evidence that JLX001 exerted protective effects against I/R injury by reducing neuronal apoptosis via down-regulating JNK signaling pathway.

Therapeutic effects of JLX-001 on ischemic stroke by inducing autophagy via AMPK-ULK1 signaling pathway in rats.

(3ß,5α,16α,20S)-4,4,14-trimethyl-3,20-bis(methylamino)-9,19-cyclopregnan-16-ol-dihydrochloride (JLX-001), a structural analogue of cyclovirobuxine D (CVB-D), is a novel compound from synthesis. This study aims to confirm the therapeutic effects of JLX001 on ischemic stroke (IS) and research its induction of autophagy function via 5'-AMP-activated protein kinase (AMPK)-Human Serine/threonine-protein kinase (ULK1) signaling pathway activation. The therapeutic effects of JLX001 were evaluated by infarct sizes, brain edema, neurological scores and proportion of apoptotic neurons in Sprague-Dawley (SD) rats with middle cerebral artery occlusion/reperfusion (MCAO/R). The number of autophagosomes was obtained by transmission electron microscopy. The expression of LC3-II was measured by immunofluorescence. p-AMPK and activated ULK1 were detected by western blots. Results showed that JLX001 treatment markedly alleviated cerebral infarcts, edema, neurological scores and proportion of apoptotic neurons in MCAO/R rats. The number of autophagosomes was increased, accompanying with the increased expressions of LC3-II, p-AMPK and ULK1. In summary, JLX001 attenuates cerebral ischemia injury and the underlying mechanisms may relate to inducing autophagy via AMPK-ULK1 signaling pathway activation.

O2O Method for Fast 2D Shape Retrieval.

A novel post-processing method, online to offline (O2O), to improve the efficiency of shape retrieval is proposed in this paper. The essence of this proposed method is to move more work that requires a lot of computation to offline. Based on this approach, the O2O rerank the retrieval result online with the help of the offline analysis. The result of offline analysis can be reused indefinitely, regardless of the query shape, as long as the database is unchanged. Therefore, O2O is very efficient and suitable for real-time applications. We evaluated our method for shape retrieval and recognition on five databases including MPEG-7 CE-1 Part B, Tari 1000, Animals, Kimia 99, and Swedish Plant Leaf. Our experimental results show that as a post-processing algorithm, O2O provides highly efficient and effective shape retrieval.

Correction: Anti-ulcerogenic effect of KFP-H008 against ethanol-induced gastric ulcer via p38 MAPK/NF-κB pathway.

[This corrects the article DOI: 10.1039/C7RA08879E.].

Immune Cells After Ischemic Stroke Onset: Roles, Migration, and Target Intervention.

Ischemic stroke is one of the leading health issues and the major cause of permanent disability in adults worldwide. Energy depletion and hypoxia occurring after ischemic stroke result in cell death, which activates resident glia cells and promotes the peripheral immune cells breaching into brain performing various functions even contradictory effects. The infiltration of immune cells may mediate neuron apoptosis and escalate ischemic damage, while it enhances neuron repair, differentiation, and neuroregeneration. The central nervous system (CNS) is immune-privileged site as it is separated from the peripheral immune system by the blood-brain barrier (BBB). Pathologically, the diapedesis of peripheral immune cells to CNS is controlled by BBB and regulated by immune cells/endothelial interactions. As immune responses play a key role in modulating the progression of ischemic injury development, understanding the characteristics and the contribution on regulating inflammatory responses of glia cells and peripheral immune cells may provide novel approaches for potential therapies. This review summarizes the multistep process of periphery immune cell extravasation into brain parenchyma during immunosurveillance and chronic inflammation after ischemic stroke onset. Furthermore, the review highlights promising target intervention, which may promote the development of future therapeutics for ischemic stroke.

Therapeutic effects of JLX001 on cerebral ischemia through inhibiting platelet activation and thrombus formation in rats.

(3ß,5α,16α,20S)-4,4,14-trimethyl-3,20-bis(methylamino)-9,19-cyclopregnan-16-ol-dihydrochloride (JLX001), a derivative of cyclovirobuxine D (CVB-D), is a novel compound from synthesis. This study aims to confirm the therapeutic effect of JLX001 on cerebral ischemia and researchits antiplatelet and antithrombosis activities via thromboxane (TXA2)/phospholipase C-ß-3(PLCß3)/protein kinase C (PKC) pathway suppression. The therapeutic effects of JLX001 was evaluated by infarct sizes, brain edema and neurological scores in Sprague-Dawley (SD) rats with middle cerebral artery occlusion (MCAO). Brain TXA2 and prostacyclin (PGI2) were measured by enzyme-linked immunosorbentassay (ELISA). P-PLCß3and activated PKC were detected by immunohistochemical method. Adenosine diphosphate (ADP) or 9, 11-dieoxy-11α, 9α-epoxymethanoeprostaglandin F2α (U46619) was used as platelet agonist in the in vivo and in vitro platelet aggregation experiments. Clotting time and bleeding time were determined. Besides, two whole-animal experiments including arteriovenous shunt thrombosis and pulmonary thromboembolism model were conducted. Results showed that JLX001 treatment markedly alleviated cerebral infarcts, edema, and neurological scores in permanent middle cerebral artery occlusion (pMCAO) rats. Brain TXA2 level, p-PLCß3and activated PKC were decreased, while PGI2level had no significant change. Besides, JLX001 inhibited platelet aggregation induced by ADP or U46619 and exhibited anti-coagulation effects with a minor bleeding risk. In the two whole-animal experiments, JLX001 inhibited thrombus formation. In summary, JLX001 attenuates cerebral ischemia injury and the underlying mechanisms relate to inhibiting platelet activation and thrombus formation via TXA2/PLCß3/PKC pathway suppression.

Levo-corydalmine alleviates vincristine-induced neuropathic pain in mice by inhibiting an NF-kappa B-dependent CXCL1/CXCR2 signaling pathway.

Vincristine is a commonly used chemotherapeutic drug that can produce painful peripheral neuropathy. The chemokine (C-X-C motif) ligand 1 (CXCL1) and its receptor chemokine (C-X-C motif) receptor 2 (CXCR2) may mediate the resolution of this inflammation. In this study, we investigated whether and how CXCL1 contributes to vincristine-induced pain and the underlying mechanisms of levo-corydalmine (l-CDL, a tetrahydroprotoberberine). Oxycodone hydrochloride (a semisynthetic opioid analgesic) was used as positive control in vivo experiments. The results revealed that both l-CDL and oxycodone attenuated vincristine-induced persistent pain hypersensitivity and proinflammatory factors release in mice. CXCL1 and CXCR2 were increased from 6 to 14 days after vincristine administration in the spinal cord. In addition, vincristine injection induced the phosphorylation of NFκB by activating p65/RelA. To confirm these results, we demonstrated that l-CDL controlled astrocytic-released CXCL1 by inhibiting p65/RelA activation, thus acting on the CXCR2 receptor in the spinal cord. In cultured astrocytes, TNF-α elicited marked release of the chemokine CXCL1; moreover, the release was blocked by NFκB p65 small interfering RNA, NFκB inhibitor, and was dose-dependently decreased by l-CDL. However, l-CDL had no effect on CXCL1 in response to NFκB p65-silenced. In primary neurons, l-CDL indirectly reduced an increase in CXCR2 by astrocyte-conditioned medium but did not act directly on the CXCR2 site. Taken together, our data first demonstrate that an NFκB-dependent CXCL1/CXCR2 signaling pathway is involved in vincristine-induced neuropathic pain. In addition, the present findings suggest that l-CDL likely attenuates this inflammation through down-regulation of this signaling pathway.

Research progress of mechanisms and drug therapy for neuropathic pain.

Neuropathic pain is maladaptive pain caused by injury or dysfunction in peripheral and central nervous system, and remains a worldwide thorny problem leading to decreases in physical and mental quality of people's life. Currently, drug therapy is the main treatment regimen for resolving pain, while effective drugs are still unmet in medical need, and commonly used drugs such as anticonvulsants and antidepressants often make patients experience adverse drug reactions like dizziness, somnolence, severe headache, and high blood pressure. Thus, in this review we overview the anatomical physiology, underlying mechanisms of neuropathic pain to provide a better understanding in the initiation, development, maintenance, and modulation of this pervasive disease, and inspire research in the unclear mechanisms as well as potential targets. Furthermore, we summarized the existing drug therapies and new compounds that have shown antalgic effects in laboratory studies to be helpful for rational regimens in clinical treatment and promotion in novel drug discovery.

KFP-H008 blocks gastric acid secretion through inhibiting H+-K+-ATPase.

1-(5-(1H-indol-5-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (KFP-H008)，a novel and potent potassium-competitive acid blocker for the treatment of acid secretion related diseases, has not been reported previously. In this study, we demonstrated that KFP-H008 inhibits basal acid secretion, 2-deoxy-D-glucose- (2DG-) stimulated gastric acid secretion in rats. KFP-H008 blocked histamine-stimulated acid secretion in rats and heidenhain pouch dogs and reversed acid output in isolated gastric perfusion under histamine stimulation. In all the animal experiments, KFP-H008 exerted a more effective, potent and longer-lasting inhibitory action in comparison with lansoprazole, a proton pump inhibitor (PPI) commonly used in clinic. KFP-H008 inhibited H+-K+-ATPase activity both at pH 6.5 and pH 7.5, and was unaffected by pH. The inhibitory action was reversible and was achieved in a K+-competitive manner. Furthermore, KFP-H008 did not affect Na+-K+-ATPase activity, thus exhibiting high selectivity, which is different from PPIs. In all, KFP-H008, a novel potassium-competitive acid blocker, may provide new option for the patients with acid-related diseases and provide longer-lasting inhibitory action than drugs commonly used in clinical treatment.