Neuroprotective strategies for neonatal hypoxic-ischemic brain damage: Current status and challenges.

Neonatal hypoxic-ischemic brain damage (HIBD) is a prominent contributor to both immediate mortality and long-term impairment in newborns. The elusive nature of the underlying mechanisms responsible for neonatal HIBD presents a significant obstacle in the effective clinical application of numerous pharmaceutical interventions. This comprehensive review aims to concentrate on the potential neuroprotective agents that have demonstrated efficacy in addressing various pathogenic factors associated with neonatal HIBD, encompassing oxidative stress, calcium overload, mitochondrial dysfunction, endoplasmic reticulum stress, inflammatory response, and apoptosis. In this review, we conducted an analysis of the precise molecular pathways by which these drugs elicit neuroprotective effects in animal models of neonatal hypoxic-ischemic brain injury (HIBD). Our objective was to provide a comprehensive overview of potential neuroprotective agents for the treatment of neonatal HIBD in animal experiments, with the ultimate goal of enhancing the feasibility of clinical translation and establishing a solid theoretical foundation for the clinical management of neonatal HIBD.

Targeting the chemokine ligand 2-chemokine receptor 2 axis provides the possibility of immunotherapy in chronic pain.

Chronic pain affects patients' physical and psychological health and quality of life, entailing a tremendous public health challenge. Currently, drugs for chronic pain are usually associated with a large number of side effects and poor efficacy. Chemokines in the neuroimmune interface combine with their receptors to regulate inflammation or mediate neuroinflammation in the peripheral and central nervous system. Targeting chemokines and their receptor-mediated neuroinflammation is an effective means to treat chronic pain. In recent years, growing evidence has shown that the expression of chemokine ligand 2 (CCL2) and its main chemokine receptor 2 (CCR2) is involved in its occurrence, development and maintenance of chronic pain. This paper summarises the relationship between the chemokine system, CCL2/CCR2 axis, and chronic pain, and the CCL2/CCR2 axis changes under different chronic pain conditions. Targeting chemokine CCL2 and its chemokine receptor CCR2 through siRNA, blocking antibodies, or small molecule antagonists may provide new therapeutic possibilities for managing chronic pain.

Neuroprotective effects of oxymatrine on hypoxic-ischemic brain damage in neonatal rats by activating the Wnt/ß-catenin pathway.

Neuronal apoptosis is a major pathological process associated with neurological dysfunction in neonates after hypoxic-ischemic brain damage (HIBD). Our previous study demonstrated that oxymatrine (OMT) exerts potential neuroprotective effects on neonatal rats subjected to hypoxic-ischemic insult. However, the underlying molecular mechanism remains unclear. In this study, we investigated the effects of OMT-mediated neuroprotection on neonatal HIBD by attempting to determine its effect on the Wnt/ß-catenin signaling pathway and explored the underlying mechanism. Both 7-day-old rat pups and primary hippocampus neurons were used to establish the HIBD and oxygen-glucose deprivation (OGD) injury models, respectively. Our results demonstrated that OMT treatment significantly increased cerebral blood flow and reduced S100B concentration, infarct volume, and neuronal apoptosis in neonatal rats. In vitro, OMT markedly increased cell viability and MMP level and decreased DNA damage. Moreover, OMT improved the mRNA and protein levels of Wnt1 and ß-catenin, inhibited the expression of DKK1 and GSK-3ß, enhanced the nuclear transfer of ß-catenin, and promoted the binding activity of ß-catenin with Tcf-4; however, it downregulated the expression of cleaved caspase-3 and cleaved caspase-9. Notably, the introduction of XAV-939 (a Wnt/ß-catenin signaling inhibitor) reversed the positive effects of OMT both in vivo and in vitro. Collectively, our findings demonstrated that OMT exerted a neuroprotective effect on neonatal HIBD by inhibiting neuronal apoptosis, which was partly via the activation of the Wnt/ß-catenin signaling pathway.

Cyclic hexadepsipeptides from the fermentation of Fusarium sp. DCJ-A and their cytotoxic activities.

Beauvercin H (1), a new cyclic hexadepsipeptide, and two known ones (2 and 3) were isolated from the EtOH extract of the solid culture of Fusarium sp. Their structures were elucidated by spectroscopic analysis, including extensive 1D and 2D NMR techniques, as well as comparison with literature values. Additionally, compounds 1-3 were tested for their cytotoxic activities. The results showed that all isolated compounds exhibited cytotoxic activities against five human cancer cell lines with IC50 values ranging from 1.379 to 13.12 µM.

Cidan Capsule in Combination with Adjuvant Transarterial Chemoembolization Reduces Recurrence Rate after Curative Resection of Hepatocellular Carcinoma: A Multicenter, Randomized Controlled Trial.

OBJECTIVE: To evaluate the efficacy and safety of Cidan Capsule combined with adjuvant transarterial chemoembolization (TACE) in patients with a high risk of early recurrence after curative resection of hepatocellular carcinoma (HCC). METHODS: A multicenter, randomized controlled trial was conducted in patients with high-risk recurrence factors after curative resection of HCC from 9 medical centers between July 2014 and July 2018. Totally 249 patients were randomly assigned to TACE with or without Cidan Capsule administration groups by stratified block in a 1:1 ratio. Postoperative adjuvant TACE was given 4-5 weeks after hepatic resection in both groups. Additionally, 125 patients in the TACE plus Cidan group were administrated Cidan Capsule (0.27 g/capsule, 5 capsules every time, 4 times a day) for 6 months with a 24-month follow-up. Primary endpoints included disease-free survival (DFS) and tumor recurrence rate (TRR). Secondary endpoint was overall survival (OS). Any drug-related adverse events (AEs) were observed and recorded. RESULTS: As the data cutoff in July 9th, 2018, the median DFS was not reached in the TACE plus Cidan group and 234.0 days in the TACE group (hazard ratio, 0.420, 95% confidence interval, 0.290-0.608; P<0.01). The 1- and 2-year TRR in the TACE plus Cidan and TACE groups were 31.5%, 37.1%, and 60.8%, 63.4%, respectively (P<0.01). Median OS was not reached in both groups. The 1- and 2-year OS rates in TACE plus Cidan and TACE groups were 98.4%, 98.4%, and 89.5%, 87.9%, respectively (P<0.05). The most common grade 3-4 AEs included fatigue, abdominal pain, lumbar pain, and nausea. One serious AE was reported in 1 patient in the TACE plus Cidan group, the death was due to retroperitoneal mass hemorrhage and hemorrhagic shock, and was not related to study drug. CONCLUSIONS: Cidan Capsule in combination with TACE can reduce the incidence of early recurrence in HCC patients at high-risk of recurrence after radical hepatectomy and may be an appropriate option in postoperative anti-recurrence treatment. (Registration No. NCT02253511).

Protective effects of leonurine hydrochloride on pyroptosis in premature ovarian insufficiency via regulating NLRP3/GSDMD pathway.

BACKGROUND: Premature ovarian insufficiency is common in clinically infertile patients. The NOD-like receptor family pyrin domain-containing 3 (NLRP3)/Gasdermin D (GSDMD) signaling pathway plays a key role in premature ovarian insufficiency. Leonurine (Leo) is one of the important active ingredients extracted from Leonurus japonicus Houttuyn, which can inhibit NLRP3 activation. However, whether leonurine hydrochloride plays a protective role in premature ovarian insufficiency through actions on NLRP3/GSDMD signaling is not yet known. METHODS: After cyclophosphamide-induced premature ovarian insufficiency was established in female mice, Leo was injected intraperitoneally over four weeks to evaluate the ovarian function and anti-pyroptosis effects using the metrics of fertility, serum hormone level, ovary weight, follicle number, expression of NLRP3/GSDMD pathway-related proteins, and serum IL-18 and IL-1ß levels. RESULTS: Intraperitoneal administration of leonurine hydrochloride was found to significantly protect fertility and maintain both serum hormone levels and follicle number in mice with premature ovarian insufficiency. Mice treated with leonurine hydrochloride consistently resisted cyclophosphamide-induced ovarian damage by inhibiting the activation of NLRP3 inflammasome, Caspase-1 and GSDMD in both ovarian tissue and granulosa cells, which led to lower levels of IL-18 and IL-1ß in the serum (p < 0.05, p < 0.01, p < 0.001). CONCLUSION: Intraperitoneal administration of leonurine hydrochloride prevents cyclophosphamide-induced premature ovarian insufficiency in mice by inhibiting NLRP3/GSDMD-mediated pyroptosis.

Expert Consensus on Pathological Diagnosis of Intrahepatic Cholangiocarcinoma (2022 version).

Intrahepatic cholangiocarcinoma (iCCA) can originate from the large bile duct group (segment bile ducts and area bile ducts), small bile duct group (septal bile ducts and interlobular bile ducts), and terminal bile duct group (bile ductules and canals of Hering) of the intrahepatic biliary tree, which can be histopathological corresponding to large duct type iCCA, small duct type iCCA and iCCA with ductal plate malformation pattern, and cholangiolocarcinoma, respectively. The challenge in pathological diagnosis of above subtypes of iCCA falls in the distinction of cellular morphologies, tissue structures, growth patterns, invasive behaviors, immunophenotypes, molecular mutations, and surgical prognoses. For these reasons, this expert consensus provides nine recommendations as a reference for standardizing and refining the diagnosis of pathological subtypes of iCCA, mainly based on the 5th edition of the World Health Organization Classification of Tumours of the Digestive System.

Development of protective agents against ovarian injury caused by chemotherapeutic drugs.

BACKGROUND: Chemotherapy is one of the causes of ovarian injury and infertility. Although assisted reproductive technology helps young female patients with cancer become pregnant, preventing chemotherapy-induced ovarian injury will often possess even more significant benefits. OBJECTIVE: We aimed at demonstrating the hazardous effects and mechanisms of ovarian injury by chemotherapeutic agents, as well as demonstrating agents that protect the ovary from chemotherapy-induced injury. RESULTS: Chemotherapeutic agents cause death or accelerate activation of follicles and damage to the blood vessels in the ovary, resulting in inflammation. These often require drug development to protect the ovaries from injury. CONCLUSIONS: Our findings provide a basis for the development of drugs to protect the ovaries from injury. Although there are many preclinical studies on potential protective drugs, there is still an urgent need for a large number of clinical experiments to verify their potential use.

Geniposide attenuates spermatogenic dysfunction via inhibiting endoplasmic reticulum stress in male mice.

BACKGROUND: Spermatogenesis dysfunction is common in clinically infertile patients. Geniposide (GP) is one of the important active ingredients extracted from Eucommia ulmoides. However, the protective effect and mechanism of GP in the treatment of spermatogenic dysfunction is not known yet. METHODS: After cyclophosphamide-induced spermatogenic dysfunction was established in male mice, we gavaged GP for 4 weeks to evaluate spermatogenic function and anti-apoptotic effects by fertility, testicular weight, sperm quality, endoplasmic reticulum stress (ER stress), comet assay and serum testosterone level. RESULTS: GP can improve the damage of fertility and reproductive organs induced by cyclophosphamide and increase the number and activity of sperm. In comet assay, it was found that GP administration could alleviate sperm DNA damage induced by cyclophosphamide. In addition, GP treatment can significantly reduce ThT fluorescence intensity and improve endoplasmic reticulum stress induced by cyclophosphamide. Besides, TUNEL staining and WB showed that GP could inhibit the excessive apoptosis of cells and protect testis. (p < 0.05, p < 0.01, p < 0.001). CONCLUSION: The protective effect of Geniposide on cyclophosphamide-induced spermatogenic dysfunction in mice is related to the inhibition of endoplasmic reticulum stress.

Hippocampal Proteomic Analysis in Male Mice Following Aggressive Behavior Induced by Long-Term Administration of Perampanel.

Antiepileptic drugs have been shown to be associated with inducing or exacerbating adverse psychotropic reaction, including aggressive behavior. Perampanel, the first pharmacological compound approved by the FDA in 2012, is an effective antiepileptic drug for intractable epilepsy but induces severe aggression. So far, the underlying molecular mechanisms of aggression induced by perampanel remain incompletely understood. In the present study, a model of aggressive behavior based on the clinical use of perampanel was established and resident-intruder test and open field test were performed. Changes in hippocampal protein profiles were detected by tandem mass tag (TMT) proteomics. The behavioral results indicated that long-term use of perampanel increased the aggressive behavior of C57BL/6J mice. Proteomic analysis revealed that 93 proteins were significantly altered in the hippocampus of the perampanel-treated group (corrected p < 0.05), which were divided into multiple functional groups, mainly related to synaptic function, synaptogenesis, postsynaptic density protein, neurite outgrowth, AMPA-type glutamate receptor immobilization, and others. Bioinformatic analysis showed that differentially expressed proteins were involved in synaptic plasticity and the Ras signaling pathway. Furthermore, validation results by western blot demonstrated that glutamate receptor 1 (GluA1) and phosphorylation of mitogen-activated protein kinase (ERK1/2) were notably up-regulated, and synaptophysin (Syn) and postsynaptic density 95 (PSD95) were down-regulated in perampanel-treated mice. Therefore, our results provide valuable insight into the molecular mechanisms of aggressive behavior induced by perampanel, as well as potential options for safety treatment of perampanel in the future.

Protective Effects of Sesamin on Cytoxan-Induced Spermatogenesis Dysfunction by Regulating RNF8-ubH2A/ubH2B Pathways in Male Mice.

Most of the clinically infertile patients show spermatogenesis dysfunction. Cyclophosphamide, as an anticancer drug, can induce spermatogenesis dysfunction. Sesamin is the main bioactive component of natural lignans in sesame. It is abundant in sesame oil and has strong biological activities such as antioxidant, antibacterial, and hypoglycemic properties. By establishing the model of spermatogenic dysfunction induced by cyclophosphamide in male mice and then feeding sesamin (50, 100, and 200 mg/kg) for 2 weeks, we proved that sesamin can improve the reproductive organ damage induced by cyclophosphamide and increase the number and activity of sperms. Sesamin can resist cyclophosphamide-induced sperm nuclear maturity and DNA damage by increasing the expression levels of histones H2A and H2B in the testis. In addition, sesamin can improve the ubiquitination of histones regulated by RNF8 to protect the testis. In conclusion, these results suggest that sesamin can improve spermatogenic dysfunction induced by cyclophosphamide, which may be mediated by ubiquitination of histones.

TRPM2 in ischemic stroke: Structure, molecular mechanisms, and drug intervention.

Ischemic stroke has a high lethality rate worldwide, and novel treatments are limited. Calcium overload is considered to be one of the mechanisms of cerebral ischemia. Transient receptor potential melastatin 2 (TRPM2) is a reactive oxygen species (ROS)-sensitive calcium channel. Cerebral ischemia-induced TRPM2 activation triggers abnormal intracellular Ca2+ accumulation and cell death, which in turn causes irreversible brain damage. Thus, TRPM2 has emerged as a new therapeutic target for ischemic stroke. This review provides data on the expression, structure, and function of TRPM2 and illustrates its cellular and molecular mechanisms in ischemic stroke. Natural and synthetic TRPM2 inhibitors (both specific and nonspecific) are also summarized. The three-dimensional protein structure of TRPM2 has been identified, and we speculate that molecular simulation techniques will be essential for developing new drugs that block TRPM2 channels. These insights about TRPM2 may be the key to find potent therapeutic approaches for the treatment of ischemic stroke.

Glycosides for Peripheral Neuropathic Pain: A Potential Medicinal Components.

Neuropathic pain is a refractory disease that occurs across the world and pharmacotherapy has limited efficacy and/or safety. This disease imposes a significant burden on both the somatic and mental health of patients; indeed, some patients have referred to neuropathic pain as being 'worse than death'. The pharmacological agents that are used to treat neuropathic pain at present can produce mild effects in certain patients, and induce many adverse reactions, such as sedation, dizziness, vomiting, and peripheral oedema. Therefore, there is an urgent need to discover novel drugs that are safer and more effective. Natural compounds from medical plants have become potential sources of analgesics, and evidence has shown that glycosides alleviated neuropathic pain via regulating oxidative stress, transcriptional regulation, ion channels, membrane receptors and so on. In this review, we summarize the epidemiology of neuropathic pain and the existing therapeutic drugs used for disease prevention and treatment. We also demonstrate how glycosides exhibit an antinociceptive effect on neuropathic pain in laboratory research and describe the antinociceptive mechanisms involved to facilitate the discovery of new drugs to improve the quality of life of patients experiencing neuropathic pain.

Anti-inflammatory and analgesic activities of indigo through regulating the IKKß/IκB/NF-κB pathway in mice.

This study investigated the anti-inflammatory and analgesic activities of indigo in mice and explored the possible related mechanisms. Xylene-induced ear edema, carrageenan-induced paw edema, and acetic acid-induced vascular permeability tests were used in investigating the anti-inflammatory activities. The anti-nociceptive effects of indigo were assessed through acetic acid-induced writhing, hot plate test, and formalin test, and spontaneous locomotor activity and motor performance were evaluated. The mechanisms of activities of indigo were explored by evaluating the expression levels of IκB kinase (IKK)ß, p-IKKß, inhibitor κB (IκB)α, p-IκBα, p65 nuclear factor (NF)-kB, p-p65 NF-κB, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) through western blotting and the expression levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and prostaglandin E2 (PGE2) through enzyme-linked immunosorbent assay. The results showed that indigo significantly reduced xylene-induced ear edema, carrageenan-induced paw edema, and acetic acid-induced vascular permeation. In addition, indigo significantly inhibited nociception induced by acetic acid and formalin. However, the level of nociception was not decreased by indigo in the hot plate test, and indigo did not affect spontaneous locomotor activity and motor performance. The expression levels of p-IKKß, p-IκBα, p65 NF-kB, p-p65 NF-κB, COX-2, iNOS, TNF-α, IL-1ß, IL-6, and PGE2 decreased, whereas the expression level of IκBα increased obviously after indigo treatment. In conclusion, indigo exerts significant anti-inflammatory and analgesic activities in mice by inhibiting IKKß phosphorylation and reducing the production of important pain mediators, such as PGE2 and COX-2, via the IKKß/IκB/NF-κB pathway.

Interplay between male reproductive system dysfunction and the therapeutic effect of flavonoids.

Male infertility has affected many families around the world. However, due to the mechanism underlying male reproductive system dysfunction are not completely elucidated, the use of drugs for male reproductive system dysfunction treatment only insignificant higher pregnancy outcomes, low-quality evidence suggests that clinical pregnancy rates may increase. Therefore, the focus in the future will be on developing more viable treatment options to prevent or treatment of male reproductive system dysfunction and achieve the purpose of improving fertility. Interestingly, natural products, as the potential inhibitors for the treatment of male reproductive system dysfunction, have shown a good therapeutic effect. Among many natural products, flavonoids have been extensively investigated for the treatment of male reproductive system dysfunction, such as testicular structural disruption, spermatogenesis disturbance and sperm quality decline. Flavonoids have been reported to have antioxidant, anti-inflammatory, immune stimulating, anti-apoptotic, anticarcinogenic, anti-allergic and antiviral activities, investigating for the treatment of male reproductive system dysfunction. In this review, we evaluate the therapeutic effects of flavonoids on male reproductive system dysfunction under different cellular scenarios and summarize the therapeutic strategies of flavonoids based on the aforementioned retrospective analysis. In the end, we describe some perspective research areas relevant to the application of flavonoids in the treatment of male reproductive system dysfunction.

Protective effects of Salidroside on spermatogenesis in streptozotocin induced type-1 diabetic male mice by inhibiting oxidative stress mediated blood-testis barrier damage.

Spermatogenic dysfunction is one of the major secondary complications of male diabetes. Salidroside (SAL) is the important active ingredients isolated from Herba Cistanche, which exhibits numerous pharmacological activities such as antioxidant, anti-diabetic, and anti-inflammatory effects. The present study was designed to determine whether SAL contributes to the recovery from spermatogenic dysfunction in streptozotocin (STZ) induced type-1 diabetic mice. SAL (25, 50, or 100 mg/kg) and Clomiphene citrate (CC, 5 mg/kg) were orally administered to male type-1 diabetic mice for 10 weeks. Testis tissues were collected for histopathological and biochemical analysis. Moreover, reproductive organ weight, sperm parameters, and testicular cell DNA damage were estimated. The results revealed that SAL significantly improved the weight of the reproductive organs, sperm parameters and testicular morphology to different degrees in type-1 diabetic mice. Furthermore, reactive oxygen species (ROS) and malondialdehyde (MDA) levels were significantly reduced, and the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), markedly increased in the testicular tissue after SAL treatment. In addition, our data also showed a marked downregulation the fluorescence expressions of p38 MAPK phosphorylation and upregulation the protein expressions of ZO-1, Occludin, Claudin-11 and N-cadherin after SAL administration (100 mg/kg) compared with the type-1 diabetic group. In conclusion, these results demonstrated that SAL exerts protective effects on type-1 diabetes-induced male spermatogenic dysfunction, which is likely mediated by inhibiting oxidative stress-mediated blood testis barrier damage.

[Spatial Temporal Characteristics and Cluster Analysis of Chemical Components for Ambient PM2.5 in Wuhan].

The characteristics of chemical components of particulate matter are good indicators for analyzing sources and causes of pollution. The spatial and temporal distribution characteristics of particulate matter can reflect regional pollution problems in urban development, providing a basic dataset to support effective control of particulate matter sources. We collected PM2.5 and analyzed its concentration and chemical components at eight sites during different seasons. The results indicated that the average concentration of PM2.5 in Wuhan reached 70.7 µg·m-3. The concentration of PM2.5 in winter (103.1 µg·m-3) was significantly higher than that of other seasons, and the lowest concentration was in autumn (52.4 µg·m-3). The concentrations of PM2.5 in Donghu Gaoxin, Zhuankou New Area, and Qingshan Ganghua Station were significantly higher than those at the other sites. The main chemical components in PM2.5 were OC and SO42-, accounting for 15.4% and 14.2%, respectively. The OC concentration was the highest in winter, whereas SO42-concentration was the highest in summer. The average annual OC/EC ratio was up to 2.80, lower in winter and spring, and higher in summer and autumn. Material reconstruction showed that secondary particles and organic matter (OM) were major substances, accounting for 32.34% and 20.44% of PM2.5 mass, respectively. Coal combustion and vehicle exhaust might be the main contributors to ambient PM2.5. The highest fractions for OM were at the Wujiashan and Donghu Gaoxin sites, whereas the fraction of secondary particles was higher at each site, suggesting that secondary pollution had obvious regional characteristics in Wuhan. Cluster analysis based on the characteristics of chemical components showed that the eight sites were divided into three clusters:1 Hanyang Yuehu, Haze, Donghu Liyuan, and Huangpi sites, where the main characteristics were that the concentrations of components at each point were low; ② Zhuankou New Area and Qingshan Ganghua, which were characterized by higher nitrogen components; and ③ Donghu Gaoxin and Wujiashan, where not only industrial sources were heavily polluted in Wuhan, but also motor vehicles and dust pollution greatly contributed.

Protective effects of betaine on diabetic induced disruption of the male mice blood-testis barrier by regulating oxidative stress-mediated p38 MAPK pathways.

BACKGROUND: Blood-testis barrier (BTB) impairments is one of the major secondary complications of diabetes. Betaine (BET) is the important active ingredients isolated from Lycium barbarum, which exhibits numerous pharmacological activities such as antioxidant, anti-diabetic, and anti-inflammatory effects. This study aimed to establish whether BET contributes to the recovery from BTB dysfunction in streptozotocin (STZ) induced diabetic mice. METHODS: BET (200, 400, 800 mg/kg) was orally administered to diabetic mice for 8 weeks. Testis tissues were collected for histopathological and biochemical analysis, the reproductive organ weight was estimated. Antioxidant enzyme activity and BTB associated protein expressions were determined with their corresponding assay kits and western blot analysis. The results revealed that BET significantly improved the weight of the reproductive organs and testicular morphology in diabetic mice. Furthermore, reactive oxygen species (ROS) and malondialdehyde (MDA) levels were significantly reduced, and the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), markedly increased in the testicular tissue after SAL treatment. In addition, our data also showed a marked down-regulated the expressions of p38 MAPK phosphorylation and up-regulation the protein expressions of ZO-1, Occludin, Claudin-11, N-cadherin, and Connexin-43 after BET administration compared with the diabetic group. In conclusion, these results demonstrated that BET exerts protective effects on diabetes-induced BTB dysfunction, which may be through regulating oxidative stress-mediated p38 MAPK pathways.

Neuroprotective effect of Vanillin on hypoxic-ischemic brain damage in neonatal rats.

Neonatal hypoxic-ischemic brain damage (HIBD) is a leading cause of death and perpetual neurological dysfunction in neonates. Vanillin (Van), a natural phenolic compound with neuroprotective properties, exerts neuroprotection on a gerbil model of global ischemia by inhibiting oxidative damage. This study aimed to explore the potential neuroprotective roles of Van in neonatal rats suffering from hypoxic-ischemic (HI). An HI model of 7-day-old SD rats was induced by left carotid artery ligation followed by exposure to 8% oxygen (balanced with nitrogen) for 2.5 h at 37 °C. At 48 h after intraperitoneal injection with Van (20, 40, and 80 mg/kg) or saline, neurobehavioral function, cerebral infract volume, brain water content, and histomorphological changes were performed to evaluate brain injury. Transmission electron microscopy and immunoglobulin G (IgG) staining were conducted to evaluate the integrity of the blood-brain barrier (BBB). The levels of oxidative stress and tight junction proteins, as well as the activities of matrix metalloproteinases (MMPs), were also determined in the ipsilateral hemisphere. Results showed that Van post-treatment significantly ameliorated early neurobehavioral deficits, decreased infarct volume and brain edema, as well as attenuated histopathologic injury and IgG extravasation. Furthermore, Van markedly increased the activities of endogenous antioxidant enzymes and decreased malondialdehyde content. Meanwhile, the activation of MMP-2 and MMP-9 induced by HI was partially blocked by Van. Finally, Van obviously increased the expression of ZO-1, Occludin, and Claudin-5 compared with the HI group. Collectively, Van can provide neuroprotective effects against neonatal HIBD possibly by attenuating oxidative damage and preserving BBB integrity.

Long-Term Survival Outcomes After Liver Resection for Binodular Hepatocellular Carcinoma: A Multicenter Cohort Study.

BACKGROUND: The long-term prognosis after liver resection for multinodular (≥3 nodules) hepatocellular carcinoma (HCC) is generally considered to be unfavorable. However, the role of liver resection for binodular HCC is less investigated. SUBJECTS, MATERIALS, AND METHODS: From a multicenter database, consecutive patients who underwent curative-intent liver resection for binodular HCC and without macrovascular invasion between 2003 and 2015 were retrospectively reviewed. Patients' clinical variables as well as perioperative and long-term survival outcomes were analyzed. Univariable and multivariable analyses were performed to identify the risk factors associated with overall survival (OS) and recurrence-free survival (RFS) after curative resection. RESULTS: Of 263 enrolled patients, the perioperative 30-day mortality and morbidity rates were 1.5% and 28.5%. The 1-, 3-, and 5-year OS and RFS rates were 81.5%, 52.4%, and 39.1% and 57.1%, 35.8%, and 26.6%, respectively. Multivariable Cox-regression analyses identified preoperative alpha-fetoprotein level >400 µg/L, tumor size with a sum of two nodules >8 cm, tumor size ratio of large/small nodule >1.5 (asymmetrical proportion), unilateral hemiliver distribution of two nodules, distance of ≤3 cm between two nodules, and microvascular invasion in any nodule as independent risk factors associated with decreased OS and RFS. CONCLUSION: Liver resection was safe and feasible in patients with binodular HCC, with acceptable perioperative and long-term outcomes. Sum of two tumor sizes, size ratio and distribution, and distance between two nodules were independent risk factors associated with long-term survival outcomes after surgery. These results may guide clinicians to make individualized surgical decisions and estimate long-term prognosis for these patients. IMPLICATIONS FOR PRACTICE: Liver resection was safe and feasible in patients with binodular hepatocellular carcinoma, with acceptable perioperative and long-term outcomes. The sum of two tumor sizes, the size ratio and distribution of the two nodules, and the distance between two nodules were independent risk factors associated with long-term overall survival and recurrence-free survival after liver resection. The results of this study may guide clinicians to make individualized surgical decisions, estimate long-term prognosis, and plan recurrence surveillance and adjuvant therapy for these patients.