The marine-derived compound TAG alleviates Parkinson's disease by restoring RUBCN-mediated lipid metabolism homeostasis.

Parkinson's disease (PD) is the second most common neurodegenerative disease, and its prevalence is increasing. Currently, no effective therapies for PD exist. Marine-derived natural compounds are considered important resources for the discovery of new drugs due to their distinctive structures and diverse activities. In this study, tetrahydroauroglaucin (TAG), a polyketide isolated from a marine sponge, was found to have notable neuroprotective effects on MPTP/MPP+-induced neurotoxicity. RNA sequencing analysis and metabolomics revealed that TAG significantly improved lipid metabolism disorder in PD models. Further investigation indicated that TAG markedly decreased the accumulation of lipid droplets (LDs), downregulated the expression of RUBCN, and promoted autophagic flux. Moreover, conditional knockdown of Rubcn notably attenuated PD-like symptoms and the accumulation of LDs, accompanied by blockade of the neuroprotective effect of TAG. Collectively, our results first indicated that TAG, a promising PD therapeutic candidate, could suppress the accumulation of LDs through the RUBCN-autophagy pathway, which highlighted a novel and effective strategy for PD treatment.

Assessing Severity of Low Anterior Resection Syndrome After Intersphincteric Resection for Ultralow Rectal Cancer: A Pilot Study Using an Exploratory Instrument.

BACKGROUND: The Delphi consensus identified 8 symptoms and 8 consequences as the highest priorities for defining low anterior resection syndrome. OBJECTIVE: To describe an exploratory scoring instrument correlating the Delphi consensus on low anterior resection syndrome with functional and quality-of-life scores following intersphincteric resection for ultralow rectal cancer. DESIGN: This was a prospective pilot study. In accordance with the Wexner incontinence score, 5 frequency responses ranging from never (score 0) to always (score 4) were used to measure the severity of symptom- and consequence-specific variables. SETTINGS: Colorectal surgery referral center. PATIENTS: Among 161 eligible patients, 137 participants (85%) completed an electronic self-assessment survey regarding function and quality of life at scheduled follow-up, including 3 to 6, 12, and ≥24 months after ileostomy reversal. MAIN OUTCOME MEASURES: Outcome measures included patient-reported severity of the identified priorities, and their correlation with condition-specific quality of life. RESULTS: The most frequent symptom and consequence were "emptying difficulties" and "dissatisfaction with the bowels," respectively. Aside from "emptying difficulties," the proportions of negative symptom domains increased after reversal. In particular, neither the frequency responses nor the severity scores of "emptying difficulties" differed between groups. The percentages of "always" selection for consequence domains improved at 12-month follow-up, whereas a higher rate was observed at 24 months, except for "toilet dependence" and "dissatisfaction with the bowels." We found significant improvements in the summary score of the Fecal Incontinence Quality-of-Life Scale ( p = 0.04) and our exploratory instrument ( p = 0.009) but not in functional scores measured by traditional questionnaires. Furthermore, the condition-specific quality of life strongly correlated with the Delphi consensus severity score ( rs = -0.73). LIMITATIONS: Single-institution data and limited sample size. CONCLUSIONS: The important priorities identified by the Delphi consensus might enable a comprehensive overview and a better assessment of low anterior resection syndrome after intersphincteric resection. See Video Abstract . EVALE LA GRAVEDAD DEL SNDROME DE RESECCIN ANTERIOR BAJA DESPUS DE LA RESECCIN INTERESFINTRICA PARA EL CNCER DE RECTO ULTRABAJO UN ESTUDIO PILOTO QUE UTILIZA UN INSTRUMENTO EXPLORATORIO: ANTECEDENTES:El consenso Delphi identificó ocho síntomas y ocho consecuencias como las máximas prioridades para definir el síndrome de resección anterior baja.OBJETIVO:Describir un instrumento de puntuación exploratorio que correlaciona el consenso Delphi sobre el síndrome de resección anterior baja con puntuaciones funcionales y de calidad de vida después de la resección interesfinteriana para el cáncer de recto ultrabajo.DISEÑO:Este fue un estudio piloto prospectivo. De acuerdo con la puntuación de incontinencia de Wexner, se utilizaron cinco respuestas de frecuencia que van desde nunca (puntuación 0) hasta siempre (puntuación 4) para medir la gravedad de las variables específicas de los síntomas y las consecuencias.AJUSTES:Centro de referencia de cirugía colorrectal.PACIENTES:Entre 161 pacientes elegibles, 137 (85%) participantes completaron una encuesta electrónica de autoevaluación sobre la función y la calidad de vida en el seguimiento programado, incluidos 3 a 6, 12 y ≥ 24 meses después de la reversión de la ileostomía.MEDIDAS PRINCIPALES DE RESULTADO:Las medidas de resultado incluyeron la gravedad de estas prioridades informada por los pacientes, así como su correlación con la calidad de vida específica de la afección.RESULTADOS:El síntoma y la consecuencia más frecuentes fueron "dificultades para vaciar" e "insatisfacción con las deposiciones", respectivamente. Aparte de las "dificultades de vaciado", las proporciones de dominios de síntomas negativos aumentaron después de la reversión. En particular, tanto las respuestas de frecuencia como las puntuaciones de gravedad de las "dificultades para vaciar" no difirieron entre los grupos. Los porcentajes de "opción siempre" para los dominios de consecuencias mejoraron a los 12 meses de seguimiento, mientras que se observó una tasa más alta a los 24 meses después, excepto para "dependencia del baño" e "insatisfacción con los intestinos". Encontramos mejoras significativas en la puntuación resumida de la Escala de calidad de vida de incontinencia fecal ( p = 0,04) y nuestro instrumento exploratorio ( p = 0,009), pero no en las puntuaciones funcionales medidas con los cuestionarios tradicionales. Además, la calidad de vida específica de la condición se correlacionó fuertemente con la puntuación de gravedad del consenso Delphi (rs = -0,73).LIMITACIONES:Datos de una sola institución y tamaño de muestra limitado.CONCLUSIONES:Las importantes prioridades identificadas por el consenso Delphi podrían permitir una visión global y una mejor evaluación del síndrome de resección anterior baja después de la resección interesfintérica. (Traducción-Dr. Yesenia Rojas-Khalil ).

Conformal sphincteric resection for ultra-low rectal cancer located below the dentate line: A pilot report.

AIM: Sphincter-sparing surgery can be achieved in most cases of low rectal cancer with the development of intersphincteric resection. However, abdominoperineal resection is still inevitable for patients with tumours located below the dentate line. To address this, we have developed a procedure called conformal sphincteric resection (CSR) in which the corresponding part of the subcutaneous portion of the external anal sphincter and the perianal skin on the tumour side is removed to achieve a safe distal resection margin and lateral resection margin while the dentate line and the internal anal sphincter on the tumour-free side are preserved as much as possible, to achieve sphincter preservation without compromising oncological safety and functional acceptability, and to render tumour location no longer a contraindication for sphincter-sparing surgery. This is the first study to describe the concept, indication and surgical procedure of CSR and to report its preliminary surgical, oncological and functional results. METHODS: This is a retrospective, single-centre, single-arm pilot study conducted at Huashan Hospital, Fudan University. Demographic, clinicopathological, oncological and functional follow-up data were collected from 20 consecutive patients with rectal tumours located below the dentate line who underwent laparoscopic CSR by the same surgical team from June 2018 to March 2022. RESULTS: The mean distance of the tumour's lower edge from the anal verge was 13.1 ± 6.0 mm. The mean distal resection margin was 10.6 ± 4.3 mm. All circumferential resection margins were negative. There were no instances of perioperative mortality. The complication rate was 25% but all were Clavien-Dindo Grade I. Among the 20 cases, 17 were diagnosed with adenocarcinoma, one with squamous cell carcinoma and two with adenoma featuring high-grade intraepithelial neoplasia. Pathological TNM staging revealed two, seven, five, five and one case(s) in Stages 0, I, II, III and IV, respectively. The median follow-up period was 20 months (interquartile range 22 months), with no withdrawals. The overall and disease-free survival rates were both 95%. The mean Wexner incontinence score and low anterior resection syndrome score recorded 18 months following diverting ileostomy closure were 6.3 ± 3.8 and 27.3 ± 3.6, respectively. CONCLUSIONS: This study has proposed the CSR procedure for the first time, which is a technically feasible, oncologically safe and functionally acceptable procedure for carefully selected patients with rectal tumours located below the dentate line.

Quality of Life and Functional Outcomes After Intersphincteric Resection for Ultralow Rectal Cancer: A Prospective Observational Study.

BACKGROUND: Intersphincteric resection is the ultimate sphincter-preserving surgical technique for ultralow rectal cancer, but quality-of-life changes after surgery remain unclear. It is also unknown which questionnaire has better associations with functional results for capturing clinical variation in quality of life. OBJECTIVE: This study aimed to assess change in the quality of life and its correlation with functional outcomes among patients undergoing intersphincteric resection for ultralow rectal cancer. DESIGN: This was a prospective, observational, single-center study. SETTINGS: Colorectal surgery referral center. PATIENTS: Patients with ultralow rectal cancer who underwent intersphincteric resection were included. MAIN OUTCOME MEASURES: The primary outcomes were quality-of-life and functional results at 3 to 6, 12, and 24 months after ileostomy closure using validated questionnaires. The secondary outcome was the relationship between quality of life and neorectal function. RESULTS: A total of 102 patients (62.7% men) completed follow-up surveys. Wexner incontinence score and Kirwan's incontinence score significantly improved at 12 months after ileostomy reversal, but such improvement in low anterior resection syndrome score was proved until 24 months later ( p = 0.01). Condition-specific quality-of-life domains improved over time, with significant changes in lifestyle ( p = 0.02) and coping/behavior ( p = 0.01), as well as the summary score of Fecal Incontinence Quality of Life ( p = 0.02) and visual analog scale score ( p < 0.001). Among health-related quality-of-life domains, the subscale scores did not differ significantly. The functional systems scores were significantly correlated with all the domains of condition-specific quality-of-life but only a few health-related quality-of-life domains. Only weak to moderate associations with the functional outcomes were observed for both quality-of-life questionnaires. LIMITATIONS: Single-center data and limited sample size. CONCLUSIONS: Although low anterior resection syndrome persists for years after intersphincteric resection, condition-specific quality of life and functional outcomes improve over time. Compared to health-related quality-of-life questionnaires, condition-specific quality-of-life instruments might be preferable to evaluate changes in quality-of-life after surgery. See Video Abstract at http://links.lww.com/DCR/C130 . CALIDAD DE VIDA Y RESULTADOS FUNCIONALES DESPUS DE UNA RESECCIN INTERESFINTRICA EN CASO DE CNCER RECTAL ULTRABAJO ESTUDIO PROSPECTIVO OBSERVACIONAL: ANTECEDENTES:La resección inter-esfintérica es la última técnica quirúrgica conservadora de esfínteres en casos de cáncer rectal ultrabajo, pero los cambios en la calidad de vida después de la cirugía siguen sin estar claros. Se desconoce también, qué tipo de cuestionario tiene mejor asociación con los resultados funcionales para así captar las variaciones clínicas en la calidad de vida.OBJETIVO:Evaluar el cambio en la calidad de vida y su correlación con los resultados funcionales durante el período postoperatorio en pacientes sometidos a resección interesfintérica por cáncer de recto ultrabajo.DISEÑO:Estudio prospectivo, observacional y de un solo centro.AJUSTES:Centro de referencia de cirugía colorrectal.PACIENTES:Se incluyeron pacientes con cáncer de recto ultra bajo que se sometieron a resección interesfintérica con el cierre de la ileostomía.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue la calidad de vida y los resultados funcionales a los 3-6, 12 y 24 meses después del cierre de la ileostomía utilizando cuestionarios validados. El resultado secundario fue la relación entre la calidad de vida y la función del néorecto.RESULTADOS:Un total de 102 pacientes (62,7% hombres) completaron las encuestas de seguimiento. La puntuación de incontinencia de Wexner y la puntuación de incontinencia de Kirwan mejoraron significativamente a los 12 meses después del cierre de la ileostomía, pero dicha mejoría en la puntuación del síndrome de resección anterior baja se demostró solo hasta 24 meses después ( p = 0,01). Las condiciones en el dominio de la calidad de vida específicos mejoraron con el tiempo, con cambios significativos en el estilo de vida ( p = 0,02) y el afrontamiento/comportamiento ( p = 0,01), así como la puntuación general de la calidad de vida y de la incontinencia fecal ( p = 0,02), puntuación de la escala analógica visual ( p < 0,001). Entre los dominios de la calidad de vida relacionada con la salud, las puntuaciones de las sub-escalas no difirieron significativamente. Las puntuaciones de los sistemas funcionales se correlacionaron significativamente con todos los dominios de la calidad de vida específica de la nueva condición, pero solo con pocos dominios de calidad de vida relacionados con la salud. Solo se observaron asociaciones débiles a moderadas con los resultados funcionales para ambos cuestionarios de calidad de vida.LIMITACIONES:Datos de un solo centro y tamaño de muestra limitado.CONCLUSIONES:Aunque el síndrome de resección anterior baja persiste durante años después de la resección interesfintérica, la calidad de vida específica de la nueva condición y los resultados funcionales mejoran con el tiempo. En comparación con los cuestionarios de calidad de vida relacionados con la salud, los instrumentos de calidad de vida específicos de la nueva condición pueden ser preferibles para evaluar los cambios en la calidad de vida después de la cirugía. Consulte Video Resumen en http://links.lww.com/DCR/C130 . (Traducción-Dr. Xavier Delgadillo ).

Neuroprotective effects of a lead compound from coral via modulation of the orphan nuclear receptor Nurr1.

AIMS: To screen coral-derived compounds with neuroprotective activity and clarify the potential mechanism of lead compounds. METHODS: The lead compounds with neuroprotective effects were screened by H2 O2 and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPP+ )-induced cell damage models in SH-SY5Y cells. CCK8 and LDH assays were used to detect cell viability. The anti-apoptosis of lead compounds was evaluated by flow cytometry. JC-1 and MitoSox assays were performed to examine the changes in mitochondrial membrane potential and mitochondrial ROS level. Survival of primary cortical and dopaminergic midbrain neurons was measured by MAP2 and TH immunoreactivities. The Caenorhabditis elegans (C. elegans) model was established to determine the effect of lead compounds on dopaminergic neurons and behavior changes. RESULTS: Three compounds (No. 63, 68, and 74), derived from marine corals, could markedly alleviate the cell damage and notably reverse the loss of worm dopaminergic neurons. Further investigation indicated that compound 63 could promote the expression of Nurr1 and inhibit neuronal apoptosis signaling pathways. CONCLUSION: Lead compounds from marine corals exerted significant neuroprotective effects， which indicated that coral might be a new and potential resource for screening and isolating novel natural compounds with neuroprotective effects. Furthermore, this study also provided a new strategy for the clinical treatment of neurodegenerative diseases such as Parkinson's disease.

Characterization of LTr1 derived from cruciferous vegetables as a novel anti-glioma agent via inhibiting TrkA/PI3K/AKT pathway.

Malignant glioma is the most fatal, invasive brain cancer with limited treatment options. Our previous studies show that 2-(indol-3-ylmethyl)-3,3'-diindolylmethane (LTr1), a major metabolite of indole-3-carbinol (I3C) derived from cruciferous vegetables, produces anti-tumour effect against various tumour cell lines. In this study we characterized LTr1 as a novel anti-glioma agent. Based on screening 134 natural compounds and comparing the candidates' efficacy and toxicity, LTr1 was selected as the lead compound. We showed that LTr1 potently inhibited the viability of human glioma cell lines (SHG-44, U87, and U251) with IC50 values of 1.97, 1.84, and 2.03 µM, respectively. Furthermore, administration of LTr1 (100,300 mg· kg-1 ·d-1, i.g. for 18 days) dose-dependently suppressed the tumour growth in a U87 xenograft nude mouse model. We demonstrated that LTr1 directly bound with TrkA to inhibit its kinase activity and the downstream PI3K/AKT pathway thus inducing significant S-phase cell cycle arrest and apoptosis in SHG-44 and U87 cells by activating the mitochondrial pathway and inducing the production of reactive oxygen species (ROS). Importantly, LTr1 could cross the blood-brain barrier to achieve the therapeutic concentration in the brain. Taken together, LTr1 is a safe and promising therapeutic agent against glioma through inhibiting TrkA/PI3K/AKT pathway.

Cumulative Incidence and Risk Factors of Permanent Stoma After Intersphincteric Resection for Ultralow Rectal Cancer.

BACKGROUND: A permanent stoma is an unintended consequence that cannot be avoided completely after intersphincteric resection for ultralow rectal cancer. Unfortunately, its incidence and risk factors have been poorly defined. OBJECTIVE: The objective was to determine the cumulative incidence and risk factors of permanent stoma after intersphincteric resection for ultralow rectal cancer. DESIGN: This study was a retrospective analysis of prospectively collected data. SETTINGS: This study was conducted at a colorectal surgery referral center. PATIENTS: A total of 185 consecutive patients who underwent intersphincteric resection with diverting ileostomy from 2011 to 2019 were included. MAIN OUTCOME MEASURES: The primary outcome was the incidence of and risk factors for the permanent stoma. The secondary outcome included differences in stoma formation between patients with partial, subtotal, and total intersphincteric resection. RESULTS: After a median follow-up of 40 months (range, 6-107 months), 26 of 185 patients eventually required a permanent stoma, accounting for a 5-year cumulative incidence of 17.4%. The causes of permanent stoma were anastomotic morbidity (46.2%, 12/26), local recurrence (19.2%, 5/26), distant metastasis (19.2%, 5/26), fecal incontinence (3.8%, 1/26), perioperative mortality (3.8%, 1/26), patients' refusal (3.8%, 1/26), and poor general condition (3.8%, 1/26). Although the incidence of permanent stoma was significantly different between the intersphincteric resection groups (partial vs subtotal vs total: 8.3% vs 20% vs 25.8%, p = 0.02), it was not an independent predictor of stoma formation. Multivariate analysis demonstrated that anastomotic leakage (OR = 5.29; p = 0.001) and anastomotic stricture (OR = 5.13; p = 0.002) were independently predictive of permanent stoma. LIMITATIONS: This study was limited by its retrospective nature and single-center data. CONCLUSIONS: The 5-year cumulative incidence of permanent stoma was 17.4%. Anastomotic complications were identified as risk factors. Patients should be informed of the risks and benefits when contemplating the ultimate sphincter-sparing surgery. It might be preferable to decrease the probability of permanent stoma by further minimizing anastomotic complications. See Video Abstract at http://links.lww.com/DCR/B704. INCIDENCIA ACUMULADA Y FACTORES DE RIESGO DE ESTOMA PERMANENTE DESPUS DE UNA RESECCIN INTERESFNTRICA EN CNCER RECTAL ULTRA BAJO: ANTECEDENTES:La necesidad de efectuar un estoma permanente es la consecuencia no intencional e inevitable por completo después de una resección interesfintérica en presencia de un cáncer rectal ultra bajo. Desafortunadamente, la incidencia y los factores de riesgo se han definido en una forma limitada.OBJETIVO:El objetivo fue determinar la incidencia acumulada y los factores de riesgo para la necesidad de efectuar un estoma permanente después de la resección intersfintérica de un cáncer rectal ultra bajo.DISEÑO:El presente estudio es un análisis retrospectivo de la información obtenida.ESCENARIO:Centro de referencia de cirugía colo-rectal.PACIENTES:Se incluyeron un total de 185 pacientes consecutivos que se sometieron a resección intersfintérica de un cáncer rectal ultra bajo con ileostomía de derivación de 2011 a 2019.MEDICION DE RESULTADOS:El resultado principal fue la identificación de la incidencia y los factores de riesgo para la presencia de un estoma permanente. En forma secundaria se describieron los resultados de las diferentes técnicas de la formación de un estoma entre los pacientes con resección interesfintérica parcial, subtotal o total.RESULTADOS:Posterior a una media de seguimiento de cuarenta meses (rango de 6 a 107), 26 de 185 pacientes requirieron en forma eventual un estoma permanente, lo que equivale a una incidencia acumulada a cinco años de 17.4 %. Las causas para dejar un estoma permanente fueron morbilidad de la anastomosis (46.2%, 12/26), recurrencia local (19.2%, 5/26), metástasis a distancia (19.2%, 5/26), incontinencia fecal (3.8%, 1/26), mortalidad perioperatoria (3.8%, 1/26), rechazo del paciente (3.8%, 1/26), y malas condiciones generales (3.8%, 1/26). Aunque la incidencia de un estoma permanente fue significativamente diferente entre los grupos de resección interesfintérica (parcial vs subtotal vs total: 8.3% vs 20% vs 25.8%, p = 0.02), no se consideró un factor predictor independiente para la formación de estoma. En el análisis multivariado se demostró que la fuga anatomótica (OR = 5.29; p = 0.001) y la estenosis anastomótica (OR = 5.13; p = 0.002) fueron factores independientes para predecir la necesidad de un estoma permanente.LIMITACIONES:La naturaleza retrospectiva del estudio y la información proveniente de un solo centro.CONCLUSIONES:La incidencia acumulada a cinco años de estoma permantente fue de 17.4%. Se consideran a las complicaciones anastomóticas como factores de riesgo. Los pacientes deberán ser informados de los riesgos y beneficios cuando se considere la posibilidad de efectuar una cirugía preservadora de esfínteres finalmente. Puede ser preferible disminuir la probabilidad de dejar un estoma permanente tratando de minimizar la posibilidad de complicaciones de la anastomosis. Consulte Video Resumen en http://links.lww.com/DCR/B704.

Critical Review of Synthesis, Toxicology and Detection of Acyclovir.

Acyclovir (ACV) is an effective and selective antiviral drug, and the study of its toxicology and the use of appropriate detection techniques to control its toxicity at safe levels are extremely important for medicine efforts and human health. This review discusses the mechanism driving ACV's ability to inhibit viral coding, starting from its development and pharmacology. A comprehensive summary of the existing preparation methods and synthetic materials, such as 5-aminoimidazole-4-carboxamide, guanine and its derivatives, and other purine derivatives, is presented to elucidate the preparation of ACV in detail. In addition, it presents valuable analytical procedures for the toxicological studies of ACV, which are essential for human use and dosing. Analytical methods, including spectrophotometry, high performance liquid chromatography (HPLC), liquid chromatography/tandem mass spectrometry (LC-MS/MS), electrochemical sensors, molecularly imprinted polymers (MIPs), and flow injection-chemiluminescence (FI-CL) are also highlighted. A brief description of the characteristics of each of these methods is also presented. Finally, insight is provided for the development of ACV to drive further innovation of ACV in pharmaceutical applications. This review provides a comprehensive summary of the past life and future challenges of ACV.

Taxonomic revision of Phaesticus Uvarov and synonymy with Flatocerus Liang amp; Zheng syn. nov. (Orthoptera: Tetrigidae).

The genus Phaesticus Uvarov, 1940 is revised here with updated generic characteristics and a key to the species. New synonyms and a new combination are proposed: 1) Phaesticus Uvarov, 1940 = Flatocerus Liang Zheng, 1984 syn. nov.; 2) P. mellerborgi (Stål, 1855) = P. insularis (Hancock, 1907) syn. nov., = P. carinatus Zheng, 1998 syn. nov., = P. azemii Mahmood, Idris Salmah, 2007 syn. nov., = F. brachynotus Liang, Chen Chen, 2008 syn. nov., = P. uvarovi Storozhenko Dawwrueng, 2015 syn. nov.; 3) P. moniliantennatus (Günther, 1940) = F. nankunshanensis Liang Zheng, 1984 syn. nov., = F. wuyishanensis Zheng, 1991 syn. nov., = F. guizhouensis Wang, 1992 syn. nov., = F. daqingshanensis Zheng Jiang, 1998 syn. nov., = F. dentifemura Zheng, 2003 syn. nov.; 4) P. hainanensis (Liang, 1988) comb. nov. = F. hainanensis Liang, 1988. Intraspecific variation in the lengths of the hind pronotal processes and hind wings in the family Tetrigidae are discussed in detail.

Novel taxa and species diversity of Cordyceps sensu lato (Hypocreales, Ascomycota) developing on wireworms (Elateroidea and Tenebrionoidea, Coleoptera).

Species of Cordyceps sensu lato (Hypocreales, Sordariomycetes) have always attracted much scientific attention for their abundant species diversity, important medicinal values and biological control applications. The insect superfamilies Elateroidea and Tenebrionoidea are two large groups of Coleoptera and their larvae are generally called wireworms. Most wireworms inhabit humid soil or fallen wood and are often infected with Cordyceps s.l. However, the species diversity of Cordyceps s.l. on Elateroidea and Tenebrionoidea is poorly known. In the present work, we summarise taxonomic information of 63 Cordyceps s.l. species that have been reported as pathogens of wireworms. We review their hosts and geographic distributions and provide taxonomic notes for species. Of those, 60 fungal species are accepted as natural pathogens of wireworms and three species (Cordyceps militaris, Ophiocordyceps ferruginosa and O. variabilis) are excluded. Two new species, O. borealis from Russia (Primorsky Krai) and O. spicatus from China (Guizhou), are described and compared with their closest allies. Polycephalomyces formosus is also described because it is reported as a pathogen of wireworms for the first time. Phylogeny was reconstructed from a combined dataset, comprising SSU, LSU and TEF1-α gene sequences. The results, presented in this study, support the establishment of the new species and confirm the identification of P. formosus.

Astrocytic Kir6.1 deletion aggravates neurodegeneration in the lipopolysaccharide-induced mouse model of Parkinson's disease via astrocyte-neuron cross talk through complement C3-C3R signaling.

Complement pathway over-activation has been implicated in a variety of neurological diseases. However, the signaling pathways governing astrocytic complement activation in Parkinson's disease (PD) are poorly understood. Kir6.1, a pore-forming subunit of ATP-sensitive potassium (K-ATP) channel, is prominently expressed in astrocytes and exhibits anti-inflammatory effects. Therefore, we hypothesize that Kir6.1/K-ATP channel may regulate astrocytic complement activation in the pathogenesis of PD. In this study, astrocytic Kir6.1 knockout (KO) mice were used to examine the effect of astrocytic Kir6.1/K-ATP channel on astrocytic complement activation triggered by the lipopolysaccharide (LPS). Here, we found that astrocytic Kir6.1 KO mice showed more dopaminergic neuron loss and more astrocyte reactivity in substantia nigra compacta than controls. We also found that astrocytic Kir6.1 KO increased the expression of complement C3 in astrocytes in LPS-induced mouse model of PD. Mechanistically, astrocytic Kir6.1 KO promoted astroglial NF-κB activation to elicit extracellular release of C3, which in turn interacted with neuronal C3aR to induce neuron death. Blocking complement function by NF-κB inhibitor or C3aR antagonist rescued the aggravated neuron death induced by Kir6.1 KO. Collectively, our findings reveal that astrocytic Kir6.1/K-ATP channel prevents neurodegeneration in PD via astrocyte-neuron cross talk through NF-κB/C3/C3aR signaling and suggest that targeting astroglial Kir6.1/K-ATP channel-NF-κB-C3-neuronal C3aR signaling represents a novel therapeutic strategy for PD.

ß-arrestin 2 is essential for fluoxetine-mediated promotion of hippocampal neurogenesis in a mouse model of depression.

Over the last decade, the roles of ß-arrestins in the treatment of neuropsychological diseases have become increasingly appreciated. Fluoxetine is the first selective serotonin reuptake inhibitor developed and is approved for the clinical treatment of depression. Emerging evidence suggests that fluoxetine can directly combine with the 5-HT receptor, which is a member of the G protein-coupled receptor (GPCR) family, in addition to suppressing the serotonin transporter. In this study, we prepared a chronic mild stress (CMS)-induced depression model with ß-arrestin2-/- mice and cultured adult neural stem cells (ANSCs) to investigate the involvement of the 5-HT receptor-ß-arrestin axis in the pathogenesis of depression and in the therapeutic effect of fluoxetine. We found that ß-arrestin2 deletion abolished the fluoxetine-mediated improvement in depression-like behaviors and monoamine neurotransmitter levels, although ß-arrestin2 knockout did not aggravate CMS-induced changes in mouse behaviors and neurotransmitters. Notably, the ß-arrestin2-/- mice had a shortened dendritic length and reduced dendritic spine density, as well as decreased neural precursor cells, compared to the WT mice under both basal and CMS conditions. We further found that ß-arrestin2 knockout decreased the number of proliferating cells in the hippocampal dentate gyrus and suppressed the proliferative capability of ANSCs in vitro. Moreover, ß-arrestin2 knockout aggravated the impairment of cell proliferation induced by corticosterone and further blocked the fluoxetine-mediated promotion of mouse hippocampal neurogenesis. Mechanistically, we found that the 5-HT2BR-ß-arrestin2-PI3K/Akt axis is essential to maintain the modulation of hippocampal neurogenesis in depressed mice. Our study may provide a promising target for the development of new antidepressant drugs.

Taxonomical clarification of Tetrix gibberosa (Wang amp; Zheng), a high-backed pygmy grasshopper species from eastern PR China (Orthoptera: Tetrigidae).

Tetrix gibberosa (Wang Zheng) is a high-backed pygmy grasshopper species from eastern PR China. Due to its reduced hind wings and pleomorphism (length changes of hind wings and the hind pronotal process, which is generally called macropterous and brachypterous morphs), the species have been described into different species which involve several taxonomically confused genera. This study clarifies its taxonomy and distribution and provides ecological information for the species. At the same time, we comment the relationships of related genera in the subfamily Tetriginae, including Tetrix Latreille, Exothotettix Zheng Jiang, Alulatettix Liang, Aalatettix Zheng Mao, Formosatettix Tinkham, and Formosatettixoides Zheng. Additionally, we report for the first time that nematodes can parasitize pygmy grasshoppers. New synonyms are proposed: Tetrix gibberosa (Wang Zheng, 1993) = Alulatettix bulbosus Zheng Zhong, 2001, syn. nov., = Exothotettix jiangxiensis Liang Jia, 2008, syn. nov., = Tetrix glochinota Zhao, Niu Zheng, 2010, syn. nov., = Alulatettix nigromarginalis Zhang, Deng Zha, 2014, syn. nov., = Alulatettix flavotibialis Zhang, Deng Zha, 2014, syn. nov..

Variation in rectoanal inhibitory reflex after laparoscopic intersphincteric resection for ultralow rectal cancer.

AIM: The aim was to evaluate the physiological variation in rectoanal inhibitory reflex (RAIR) after laparoscopic intersphincteric resection (Lap-ISR) for ultralow rectal cancer. METHOD: This was a retrospective study that included 56 patients who underwent Lap-ISR from a prospectively collected database. The RAIR was examined preoperatively and up to 12 months after ileostomy closure. The primary outcome included physiological variation in RAIR and its difference between partial, subtotal and total ISR. The secondary outcome was its correlation with functional outcome. RESULTS: The reflex was present in 95% (53/56) of patients preoperatively, in 36% (20/56) before ileostomy closure, in 48% (27/56) at 3-6 months and in 61% (34/56) at 12 months after ileostomy closure. The elicited volume of RAIR was significantly increased at 12 months after ileostomy closure than at baseline (P = 0.005), but its duration and amplitude did not differ significantly. There was no significant difference in the reflex recovery between the ISR groups (partial vs. subtotal vs. total: 65% vs. 63% vs. 44%, P = 0.61). At 12 months after ileostomy closure, the RAIR-present group had favourable functional results and patient satisfaction (P < 0.05). Major faecal incontinence was found in 82% of patients in the RAIR-absent group. CONCLUSION: The RAIR is abolished in the majority of patients after Lap-ISR, but a time-dependent recovery could be observed in more than half of the patients. The reflex recovery is not influenced by the resection grade of the internal sphincter. However, persistent loss of the RAIR correlates with worse continence.

Two new species of the genus Formosatettix Tinkham, 1937 (Orthoptera, Tetrigidae) from Guizhou and Chongqing, PR China.

Two new pygmy grasshopper species are described from PR China and are assigned to Formosatettix Tinkham, 1937, a large Asian tetrigin genus composed of species with reduced tegmina and hind wings: F. leigongshanensis Zha & Ding, sp. nov. from Guizhou and F. wulongensis Zha & Ding, sp. nov. from Chongqing. We provide descriptions of morphology and habit, supplemented with photographs. Flying organs of the genus Formosatettix are discussed and the genus is compared with other Asian genera with reduced flying organs, such as Formosatettixoides Zheng, 1994 and Alulatettix Liang, 1993 in Tetriginae, Deltonotus Hancock, 1904, Epitettix Hancock, 1907 and Pseudepitettix Zheng, 1995 in Cladonotinae, and Macromotettixoides Zheng, Wei & Jiang, 2005 and Pseudomacromotettix Zheng, Li & Lin, 2012 in Metrodorinae.

Astragaloside IV inhibits astrocyte senescence: implication in Parkinson's disease.

BACKGROUND: Senescent astrocytes have been implicated in the aging brain and neurodegenerative disorders, including Parkinson's disease (PD). Astragaloside IV (AS-IV) is an antioxidant derivative from a traditional Chinese herbal medicine Astragalus membraneaceus Bunge and exerts anti-inflammatory and longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined. METHODS: Long culture-induced replicative senescence model and lipopolysaccharide/1-methyl-4-phenylpyridinium (LPS/MPP+)-induced premature senescence model and a mouse model of PD were used to investigate the effect of AS-IV on astrocyte senescence in vivo and in vitro. Immunocytochemistry, qPCR, subcellular fractionation, flow cytometric analyses, and immunohistochemistry were subsequently conducted to determine the effects of AS-IV on senescence markers. RESULTS: We found that AS-IV inhibited the astrocyte replicative senescence and LPS/MPP+-induced premature senescence, evidenced by decreased senescence-associated ß-galactosidase activity and expression of senescence marker p16, and increased nuclear level of lamin B1, and reduced pro-inflammatory senescence-associated secretory phenotype. More importantly, we showed that AS-IV protected against the loss of dopamine neurons and behavioral deficits in the mouse model of PD, which companied by reduced accumulation of senescent astrocytes in substantia nigra compacta. Mechanistically, AS-IV promoted mitophagy, which reduced damaged mitochondria accumulation and mitochondrial reactive oxygen species generation and then contributed to the suppression of astrocyte senescence. The inhibition of autophagy abolished the suppressive effects of AS-IV on astrocyte senescence. CONCLUSIONS: Our findings reveal that AS-IV prevents dopaminergic neurodegeneration in PD via inhibition of astrocyte senescence through promoting mitophagy and suggest that AS-IV is a promising therapeutic strategy for the treatment of age-associated neurodegenerative diseases such as PD.

Complete mitochondrial genome of Cerace xanthocosma and its phylogenetic position in the family Tortricidae.

Cerace xanthocosma Diakonoff, 1950 belongs to the Tortricidae of Lepidoptera, distributed in China and Japan. Its mitochondrial genome is 15,344 bp in size, containing 37 genes (13 protein-coding genes, 2 ribosomal RNA genes, and 22 transfer RNA genes) and a non-coding A + T-rich region. In the 37 genes, 14 genes are located on the minority-strand (N-strand) with the remaining genes on the majority-strand (J-strand). The A + T-rich region has a poly-T stretch and a motif ATAGA. Phylogenetic analysis using Bayesian Inference method shows the sister relationship between Tortricinae and Olethreutinae with the placement of C. xanthocosma as the basal lineage of Tortricinae.

The pore-forming subunit Kir6.1 of the K-ATP channel negatively regulates the NLRP3 inflammasome to control insulin resistance by interacting with NLRP3.

Excessive activation of the NLRP3 inflammasome is a key component contributing to the pathogenesis of various inflammatory diseases. However, the molecular mechanisms underlying its activation and regulation remain poorly defined. The objective of this study was to explore the possible function of the K+ channel pore-forming subunit Kir6.1 in regulating NLRP3 inflammasome activation and insulin resistance. Here, we demonstrate that Kir6.1 depletion markedly activates the NLRP3 inflammasome, whereas enhanced Kir6.1 expression produces opposing effects both in mice in vivo and in primary cells in vitro. We also demonstrate that Kir6.1 controls insulin resistance by inhibiting NLRP3 inflammasome activation in mice. We further show that Kir6.1 physically associates with NLRP3 and thus inhibits the interactions between the NLRP3 inflammasome subunits. Our results reveal a previously unrecognized function of Kir6.1 as a negative regulator of the NLRP3 inflammasome and insulin resistance, which is mediated by virtue of its ability to inhibit NLRP3 inflammasome assembly. These data provide novel insights into the regulatory mechanism of NLRP3 inflammasome activation and suggest that Kir6.1 is a promising therapeutic target for inflammasome-mediated inflammatory diseases.

Kir6.1/K-ATP channel on astrocytes protects against dopaminergic neurodegeneration in the MPTP mouse model of Parkinson's disease via promoting mitophagy.

ATP-sensitive potassium (K-ATP) channels, coupling cell metabolism to cell membrane potential, are involved in brain diseases, including Parkinson's disease (PD). Kir6.1, a pore-forming subunit of K-ATP channel, is prominently expressed in astrocytes and participates in regulating its function. However, the precise role of astrocytic Kir6.1-contaning K-ATP channel (Kir6.1/K-ATP) in PD is not well characterized. In this study, astrocytic Kir6.1 knockout (KO) mice were used to examine the effect of astrocytic Kir6.1/K-ATP channel on dopaminergic (DA) neurodegeneration triggered by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Here, we found that astrocytic Kir6.1 KO mice showed more DA neuron loss in substantia nigra compacta (SNc), lower level of dopamine in the striatum, and more severe motor dysfunction than controls. Interestingly, this companied by increased neuroinflammation and decreased autophagy level in SNc in vivo and astrocytes in vitro. Mechanistically, astrocytic Kir6.1 KO inhibited mitophagy which resulted in an increase in the accumulation of damaged mitochondria, production of reactive oxygen species and neuroinflammation in astrocytes. Restoration of astrocytic mitophagy rescued the deleterious effects of astrocytic Kir6.1 ablation on mitochondrial dysfunction, inflammation and DA neuron death. Collectively, our findings reveal that astrocytic Kir6.1/K-ATP channel protects against DA neurodegeneration in PD via promoting mitophagy and suggest that astrocytic Kir6.1/K-ATP channel may be a promising therapeutic target for PD.

Establishment and evaluation of a novel mouse model of peri/postmenopausal depression.

Women are believed to be more vulnerable to develop depressive symptoms during the perimenopause compared to postmenopause. The traditional bilateral ovariectomy and chronic mild stress (CMS) stimulation animal model produces a postmenopausal depressive-like state but the transition from perimenopausal period to postmenopausal period was ignored. Thus we establish a novel animal model in which the mice were stimulated by CMS for three months and removed the ovaries by two-step operation, and then evaluate whether this novel model could be much better for preclinical study used as a peri/postmenopause depressive model. The present study systemically evaluated the changes induced by two-step ovariectomy plus CMS in the mice. The depression-like behaviors, the levels of corticosterone, estrogen, pro-inflammatory factors, neurotransmitters, as well as brain-derived neurotrophic factor were determined; the changes of estrogen receptors, serotonin receptors, uterine weight and bone microarchitecture were also observed. The results show that the behaviors and biochemical indexes of mice changed gradually over time. Our study suggests that this two-step ovariectomy operation plus CMS successfully establishes a more reasonable peri/postmenopausal depression animal model which effectively simulates the clinical symptoms of peri/postmenopausal depressive women.