iridoids and Infarction--Middle-Cerebral-Artery

Unprecedented community containment measures were taken following the recent outbreak of COVID-19 in Italy. The aim of the study was to explore the self-reported future compliance of citizens with such measures and its relationship with potentially impactful psychological variables.. An online survey was completed by 931 people (18-76 years) distributed across the Italian territory. In addition to demographics, five dimensions were measured: self-reported compliance with containment measures over time (today, at 7, 14, 30, 60, 90, and 180 days from now) at three hypothetical risk levels (10, 50, 90% of likelihood of contracting the COVID-19), perceived risk, generalized anxiety, intolerance of uncertainty, and relevance of several psychological needs whose satisfaction is currently precluded.. The duration of containment measures plays a crucial role in tackling the spread of the disease as people will be less compliant over time. Psychological needs of citizens impacting on the compliance should be taken into account when planning an easing of the lockdown, along with interventions for protecting vulnerable groups from mental distress.. La apendicitis aguda (AA) es la urgencia quirúrgica abdominal más frecuente. No encontramos estudios específicos que evalúen el impacto de la pandemia causada por el coronavirus 2 (SARS-Cov-2) sobre la AA y su tratamiento quirúrgico. Analizamos la influencia de esta nueva patología sobre la AA.. Estudio observacional retrospectivo en pacientes intervenidos por AA desde enero hasta abril de 2020. Fueron clasificados según el momento de la apendicectomía, antes de la declaración del estado de alarma (Pre-COVID19) y después de la declaración del estado de alarma (Post-COVID19) en España. Se evaluaron variables demográficas, duración de la sintomatología, tipo de apendicitis, tiempo quirúrgico, estancia hospitalaria y complicaciones postoperatorias.. La pandemia por SARS-Cov-2 influye en el momento de diagnóstico de la apendicitis, así como en su grado de evolución y estancia hospitalaria. La peritonitis fue lo más frecuentemente observado. Una sospecha y orientación clínica más temprana, es necesaria para evitar un manejo inadecuado de este trastorno quirúrgico común.. The primary outcome is improvement in PaO. Findings will provide timely information on the safety, efficacy, and optimal dosing of t-PA to treat moderate/severe COVID-19-induced ARDS, which can be rapidly adapted to a phase III trial (NCT04357730; FDA IND 149634).. None.. The gut barrier is crucial in cirrhosis in preventing infection-causing bacteria that normally live in the gut from accessing the liver and other organs via the bloodstream. Herein, we characterised gut inflammation by measuring different markers in stool samples from patients at different stages of cirrhosis and comparing this to healthy people. These markers, when compared with equivalent markers usually measured in blood, were found to be very different in pattern and absolute levels, suggesting that there is significant gut inflammation in cirrhosis related to different immune system pathways to that seen outside of the gut. This provides new insights into gut-specific immune disturbances that predispose to complications of cirrhosis, and emphasises that a better understanding of the gut-liver axis is necessary to develop better targeted therapies.. La surveillance de l’intervalle QT a suscité beaucoup d’intérêt durant la pandémie de la COVID-19 en raison de l’utilisation de médicaments prolongeant l’intervalle QT et les préoccupations quant à la transmission virale par les électrocardiogrammes (ECG) en série. Nous avons posé l’hypothèse que la surveillance en continu de l’intervalle QT par télémétrie était associée à une meilleure détection des épisodes de prolongation de l’intervalle QT.. Nous avons introduit la télémétrie cardiaque en continu (TCC) à l’aide d’un algorithme de surveillance automatisée de l’intervalle QT dans nos unités de COVID-19. Les mesures automatisées quotidiennes de l’intervalle QT corrigé (auto-QTc) en fonction de la fréquence cardiaque maximale ont été enregistrées. Nous avons comparé la proportion des épisodes de prolongation marquée de l’intervalle QTc (QTc long), définie par un intervalle QTc ≥ 500 ms, chez les patients montrant une suspicion de COVID-19 ou ayant la COVID-19 qui avaient été admis avant et après la mise en place de la TCC (groupe témoin. La surveillance en continu de l’intervalle QT est supérieure à la norme de soins dans la détection des épisodes de QTc long et exige peu d’ECG. La réponse clinique aux épisodes de QTc long est sous-optimale.. Exposure to a model wildfire air pollution source modifies cardiovascular responses to HC challenge, suggesting air pollution sensitizes the body to systemic triggers.. Though the majority of HIV-infected adults who were on HAART had shown viral suppression, the rate of suppression was sub-optimal according to the UNAIDS 90-90-90 target to help end the AIDS pandemic by 2020. Nonetheless, the rate of immunological recovery in the study cohort was low. Hence, early initiation of HAART should be strengthened to achieve good virological suppression and immunological recovery.. Dust in Egyptian laying hen houses contains high concentrations of microorganisms and endotoxins, which might impair the health of birds and farmers when inhaled. Furthermore, laying hens in Egypt seem to be a reservoir for ESBL-producing Enterobacteriaceae. Thus, farmers are at risk of exposure to ESBL-producing bacteria, and colonized hens might transmit these bacteria into the food chain.. The lack of significant differences in the absolute changes and relative ratios of injury and repair biomarkers by contrast-associated AKI status suggests that the majority of mild contrast-associated AKI cases may be driven by hemodynamic changes at the kidney.. Most comparisons for different outcomes are based on very few studies, mostly low-powered, with an overall low CoE. Thus, the available evidence is considered insufficient to either support or refute CH effectiveness or to recommend one ICM over another. Therefore, further well-designed, larger RCTs are required.. PROSPERO database Identifier: CRD42016041953.. Untouched root canal at cross-section perimeter, the Hero 642 system showed 41.44% ± 5.62% and Reciproc R40 58.67% ± 12.39% without contact with instruments. Regarding the untouched area, Hero 642 system showed 22.78% ± 6.42% and Reciproc R40 34.35% ± 8.52%. Neither instrument achieved complete cross-sectional root canal debridement. Hero 642 system rotary taper 0.02 instruments achieved significant greater wall contact perimeter and area compared to reciprocate the Reciproc R40 taper 0.06 instrument.. Hero 642 achieved higher wall contact perimeter and area but, regardless of instrument size and taper, vital pulp during. The functional properties of the main mechanisms involved in the control of muscle Ca. This study showed that the anti-inflammatory effect of the iron-responsive product DHA in arthritis can be monitored by an iron-like radioactive tracer (. Attenuated vascular reactivity during pregnancy suggests that the systemic vasodilatory state partially depletes nitric oxide bioavailability. Preliminary data support the potential for MRI to identify vascular dysfunction in vivo that underlies PE. Level of Evidence 2 Technical Efficacy Stage 1 J. MAGN. RESON. IMAGING 2021;53:447-455.. La evaluación de riesgo es importante para predecir los resultados postoperatorios en pacientes con cáncer gastroesofágico. Este estudio de cohortes tuvo como objetivo evaluar los cambios en la composición corporal durante la quimioterapia neoadyuvante e investigar su asociación con complicaciones postoperatorias. MÉTODOS: Los pacientes consecutivos con cáncer gastroesofágico sometidos a quimioterapia neoadyuvante y cirugía con intención curativa entre 2016 y 2019, identificados a partir de una base de datos específica, se incluyeron en el estudio. Se utilizaron las imágenes de tomografía computarizada, antes y después de la quimioterapia neoadyuvante, para evaluar el índice de masa muscular esquelética, la sarcopenia y el índice de grasa visceral y subcutánea.. In this in vitro premature infant lung model, HF oscillation of BCPAP was associated with improved CO. Our results showed that HPC significantly promotes neurogenesis after MCAO and ameliorates neuronal injury.. Inflammatory markers are highly related to signs of systemic hypoperfusion in CS. Moreover, high PCT and IL-6 levels are associated with poor prognosis.. These findings indicate that Tetrapleura tetraptera fruit has a protective potential against stroke through modulation of redox and electrolyte imbalances, and attenuation of neurotransmitter dysregulation and other neurochemical dysfunctions. Tetrapleura tetraptera fruit could be a promising source for the discovery of bioactives for stroke therapy.

Topics: 3T3-L1 Cells; A Kinase Anchor Proteins; Acetates; Achilles Tendon; Acute Kidney Injury; Acute Pain; Acyclic Monoterpenes; Adenine Nucleotides; Adhesins, Escherichia coli; Adipocytes; Adipocytes, Brown; Adipogenesis; Administration, Inhalation; Administration, Oral; Adrenal Cortex Hormones; Adsorption; Adult; Aeromonas hydrophila; Africa; Aged; Aged, 80 and over; Agrobacterium tumefaciens; Air; Air Pollutants; Air Pollution; Air Pollution, Indoor; Algorithms; Alkaloids; Alkynes; Allosteric Regulation; Amines; Amino Acid Sequence; Amino Acids; Amino Acids, Branched-Chain; Aminoisobutyric Acids; Aminopyridines; Amyotrophic Lateral Sclerosis; Anaerobic Threshold; Angiography; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animal Distribution; Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Ankle Joint; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Inflammatory Agents; Antibodies, Bacterial; Antifungal Agents; 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Unprecedented community containment measures were taken following the recent outbreak of COVID-19 in Italy. The aim of the study was to explore the self-reported future compliance of citizens with such measures and its relationship with potentially impactful psychological variables.. An online survey was completed by 931 people (18-76 years) distributed across the Italian territory. In addition to demographics, five dimensions were measured: self-reported compliance with containment measures over time (today, at 7, 14, 30, 60, 90, and 180 days from now) at three hypothetical risk levels (10, 50, 90% of likelihood of contracting the COVID-19), perceived risk, generalized anxiety, intolerance of uncertainty, and relevance of several psychological needs whose satisfaction is currently precluded.. The duration of containment measures plays a crucial role in tackling the spread of the disease as people will be less compliant over time. Psychological needs of citizens impacting on the compliance should be taken into account when planning an easing of the lockdown, along with interventions for protecting vulnerable groups from mental distress.. La apendicitis aguda (AA) es la urgencia quirúrgica abdominal más frecuente. No encontramos estudios específicos que evalúen el impacto de la pandemia causada por el coronavirus 2 (SARS-Cov-2) sobre la AA y su tratamiento quirúrgico. Analizamos la influencia de esta nueva patología sobre la AA.. Estudio observacional retrospectivo en pacientes intervenidos por AA desde enero hasta abril de 2020. Fueron clasificados según el momento de la apendicectomía, antes de la declaración del estado de alarma (Pre-COVID19) y después de la declaración del estado de alarma (Post-COVID19) en España. Se evaluaron variables demográficas, duración de la sintomatología, tipo de apendicitis, tiempo quirúrgico, estancia hospitalaria y complicaciones postoperatorias.. La pandemia por SARS-Cov-2 influye en el momento de diagnóstico de la apendicitis, así como en su grado de evolución y estancia hospitalaria. La peritonitis fue lo más frecuentemente observado. Una sospecha y orientación clínica más temprana, es necesaria para evitar un manejo inadecuado de este trastorno quirúrgico común.. The primary outcome is improvement in PaO. Findings will provide timely information on the safety, efficacy, and optimal dosing of t-PA to treat moderate/severe COVID-19-induced ARDS, which can be rapidly adapted to a phase III trial (NCT04357730; FDA IND 149634).. None.. The gut barrier is crucial in cirrhosis in preventing infection-causing bacteria that normally live in the gut from accessing the liver and other organs via the bloodstream. Herein, we characterised gut inflammation by measuring different markers in stool samples from patients at different stages of cirrhosis and comparing this to healthy people. These markers, when compared with equivalent markers usually measured in blood, were found to be very different in pattern and absolute levels, suggesting that there is significant gut inflammation in cirrhosis related to different immune system pathways to that seen outside of the gut. This provides new insights into gut-specific immune disturbances that predispose to complications of cirrhosis, and emphasises that a better understanding of the gut-liver axis is necessary to develop better targeted therapies.. La surveillance de l’intervalle QT a suscité beaucoup d’intérêt durant la pandémie de la COVID-19 en raison de l’utilisation de médicaments prolongeant l’intervalle QT et les préoccupations quant à la transmission virale par les électrocardiogrammes (ECG) en série. Nous avons posé l’hypothèse que la surveillance en continu de l’intervalle QT par télémétrie était associée à une meilleure détection des épisodes de prolongation de l’intervalle QT.. Nous avons introduit la télémétrie cardiaque en continu (TCC) à l’aide d’un algorithme de surveillance automatisée de l’intervalle QT dans nos unités de COVID-19. Les mesures automatisées quotidiennes de l’intervalle QT corrigé (auto-QTc) en fonction de la fréquence cardiaque maximale ont été enregistrées. Nous avons comparé la proportion des épisodes de prolongation marquée de l’intervalle QTc (QTc long), définie par un intervalle QTc ≥ 500 ms, chez les patients montrant une suspicion de COVID-19 ou ayant la COVID-19 qui avaient été admis avant et après la mise en place de la TCC (groupe témoin. La surveillance en continu de l’intervalle QT est supérieure à la norme de soins dans la détection des épisodes de QTc long et exige peu d’ECG. La réponse clinique aux épisodes de QTc long est sous-optimale.. Exposure to a model wildfire air pollution source modifies cardiovascular responses to HC challenge, suggesting air pollution sensitizes the body to systemic triggers.. Though the majority of HIV-infected adults who were on HAART had shown viral suppression, the rate of suppression was sub-optimal according to the UNAIDS 90-90-90 target to help end the AIDS pandemic by 2020. Nonetheless, the rate of immunological recovery in the study cohort was low. Hence, early initiation of HAART should be strengthened to achieve good virological suppression and immunological recovery.. Dust in Egyptian laying hen houses contains high concentrations of microorganisms and endotoxins, which might impair the health of birds and farmers when inhaled. Furthermore, laying hens in Egypt seem to be a reservoir for ESBL-producing Enterobacteriaceae. Thus, farmers are at risk of exposure to ESBL-producing bacteria, and colonized hens might transmit these bacteria into the food chain.. The lack of significant differences in the absolute changes and relative ratios of injury and repair biomarkers by contrast-associated AKI status suggests that the majority of mild contrast-associated AKI cases may be driven by hemodynamic changes at the kidney.. Most comparisons for different outcomes are based on very few studies, mostly low-powered, with an overall low CoE. Thus, the available evidence is considered insufficient to either support or refute CH effectiveness or to recommend one ICM over another. Therefore, further well-designed, larger RCTs are required.. PROSPERO database Identifier: CRD42016041953.. Untouched root canal at cross-section perimeter, the Hero 642 system showed 41.44% ± 5.62% and Reciproc R40 58.67% ± 12.39% without contact with instruments. Regarding the untouched area, Hero 642 system showed 22.78% ± 6.42% and Reciproc R40 34.35% ± 8.52%. Neither instrument achieved complete cross-sectional root canal debridement. Hero 642 system rotary taper 0.02 instruments achieved significant greater wall contact perimeter and area compared to reciprocate the Reciproc R40 taper 0.06 instrument.. Hero 642 achieved higher wall contact perimeter and area but, regardless of instrument size and taper, vital pulp during. The functional properties of the main mechanisms involved in the control of muscle Ca. This study showed that the anti-inflammatory effect of the iron-responsive product DHA in arthritis can be monitored by an iron-like radioactive tracer (. Attenuated vascular reactivity during pregnancy suggests that the systemic vasodilatory state partially depletes nitric oxide bioavailability. Preliminary data support the potential for MRI to identify vascular dysfunction in vivo that underlies PE. Level of Evidence 2 Technical Efficacy Stage 1 J. MAGN. RESON. IMAGING 2021;53:447-455.. La evaluación de riesgo es importante para predecir los resultados postoperatorios en pacientes con cáncer gastroesofágico. Este estudio de cohortes tuvo como objetivo evaluar los cambios en la composición corporal durante la quimioterapia neoadyuvante e investigar su asociación con complicaciones postoperatorias. MÉTODOS: Los pacientes consecutivos con cáncer gastroesofágico sometidos a quimioterapia neoadyuvante y cirugía con intención curativa entre 2016 y 2019, identificados a partir de una base de datos específica, se incluyeron en el estudio. Se utilizaron las imágenes de tomografía computarizada, antes y después de la quimioterapia neoadyuvante, para evaluar el índice de masa muscular esquelética, la sarcopenia y el índice de grasa visceral y subcutánea.. In this in vitro premature infant lung model, HF oscillation of BCPAP was associated with improved CO. Our results showed that HPC significantly promotes neurogenesis after MCAO and ameliorates neuronal injury.. Inflammatory markers are highly related to signs of systemic hypoperfusion in CS. Moreover, high PCT and IL-6 levels are associated with poor prognosis.. These findings indicate that Tetrapleura tetraptera fruit has a protective potential against stroke through modulation of redox and electrolyte imbalances, and attenuation of neurotransmitter dysregulation and other neurochemical dysfunctions. Tetrapleura tetraptera fruit could be a promising source for the discovery of bioactives for stroke therapy.

Topics: 3T3-L1 Cells; A Kinase Anchor Proteins; Acetates; Achilles Tendon; Acute Kidney Injury; Acute Pain; Acyclic Monoterpenes; Adenine Nucleotides; Adhesins, Escherichia coli; Adipocytes; Adipocytes, Brown; Adipogenesis; Administration, Inhalation; Administration, Oral; Adrenal Cortex Hormones; Adsorption; Adult; Aeromonas hydrophila; Africa; Aged; Aged, 80 and over; Agrobacterium tumefaciens; Air; Air Pollutants; Air Pollution; Air Pollution, Indoor; Algorithms; Alkaloids; Alkynes; Allosteric Regulation; Amines; Amino Acid Sequence; Amino Acids; Amino Acids, Branched-Chain; Aminoisobutyric Acids; Aminopyridines; Amyotrophic Lateral Sclerosis; Anaerobic Threshold; Angiography; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animal Distribution; Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Ankle Joint; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Inflammatory Agents; Antibodies, Bacterial; Antifungal Agents; 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N-Methyl-D-aspartate receptor (NMDAR)-induced antioxidation is a significant cause of neuronal injury after ischemic stroke. In a previous work, we verified the neuroprotective roles of geniposide during tMCAO in vivo. However, it remains unknown whether geniposide ameliorates injury to hippocampal neurons during Ischemic Long Term Potentiation (iLTP) induction in vitro. After induction of cells oxygen-glucose deprivation or hydrogen peroxide, the protection of geniposide evaluated by MTT assay and electrophysiological tests. In this study, we suggested neuronal cell apoptosis was attenuated by geniposide. Furthermore, field excitatory postsynaptic potentials (fEPSCs) following postischemic LTP were assessed by electrophysiological tests. Finally, we determined that medium and high doses of geniposide attenuated oxidative stress insult and improved iLTP. Importantly, these effects were abolished by cotreatment with geniposide and the GluN2A antagonist NVP. In contrast, the GluN2B inhibitor ifenprodil failed to have an effect. In conclusion, we suggest for the first time that treatment with geniposide can attenuate postischemic LTP induction in a concentration-dependent manner. We infer that GluN2A-containing NMDARs are involved in the neuroprotection induced by geniposide treatment in ischemia.

Topics: Animals; Apoptosis; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Hippocampus; Hydrogen Peroxide; Hypoxia-Ischemia, Brain; In Vitro Techniques; Infarction, Middle Cerebral Artery; Iridoids; Long-Term Potentiation; Neurons; Oxidants; PC12 Cells; Piperidines; Quinoxalines; Rats; Receptors, N-Methyl-D-Aspartate

Geniposide, an active component of Gardenia, has been reported to protect against cerebral ischemia in animals. Ginsenoside Rg1, a component of Panax notoginseng, is usually administered in combination with Gardenia for the treatment of acute ischemic stroke; however, there are unknown effects of ginsenoside Rg1 that require further investigation. In the present study, the effects of geniposide and ginsensoide Rg1 combination treatment on focal cerebral ischemic stroke were investigated. For in vivo analysis, male rats were separated into three groups, including the (control), model and geniposide + ginsenoside Rg1 groups (n=8 per group). A middle cerebral artery occlusion model was established as the model group. The treatment group was treated with geniposide (30 mg/kg, tail vein injection) + ginsenoside Rg1 (6 mg/kg, tail vein injection), and the model group received saline instead. Neurobehavioral deficits, infarct volume, brain edema, and the expression of microRNA (miR)‑155‑5p and CD11b by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and immunohistochemistry, were assessed following 24 h of ischemia. For in vitro analysis, BV2 mouse microglial cells were cultured and exposed to geniposide (40 µg/ml) + ginsenoside Rg1 (8 µg/ml) during various durations of oxygen‑glucose deprivation (OGD). The expression levels of miR‑155‑5p, pri‑miR‑155 and pre‑miR‑155 were detected by RT‑qPCR. The results demonstrated that increases in brain infarct volume, edema volume, CD11b‑positive cells and miR‑155‑5p levels were alleviated following geniposide + ginsenoside administration in rats exposed to ischemia. Furthermore, geniposide + ginsenoside Rg1 treatment suppressed the miR‑155‑5p, pri‑miR‑155 and pre‑miR‑155 expression levels in OGD‑injured BV2 microglial cells. The results of the present study demonstrated that tail vein administration of geniposide in combination with ginsenoside Rg1 protected against focal cerebral ischemia in rats through inhibition of microglial miR‑155‑5p following ischemic injury, which may serve as a novel therapeutic agent for the treatment of strokes.

Topics: Animals; Brain; Brain Ischemia; CD11b Antigen; Cell Hypoxia; Cells, Cultured; Disease Models, Animal; Ginsenosides; Glucose; Infarction, Middle Cerebral Artery; Iridoids; Male; Microglia; MicroRNAs; Neuroprotective Agents; Panax notoginseng; Rats; Rats, Sprague-Dawley

Both baicalin (BA) and jasminoidin (JA) are active ingredients in Chinese herb medicine Scutellaria baicalensis and Fructus gardeniae, respectively. They have been shown to exert additive neuroprotective action in ischemic stroke models. In this study we used transcriptome analysis to explore the pure therapeutic mechanisms of BA, JA and their combination (BJ) contributing to phenotype variation and reversal of pathological processes. Mice with middle cerebral artery obstruction were treated with BA, JA, their combination (BJ), or concha margaritifera (CM). Cerebral infarct volume was examined to determine the effect of these compounds on phenotype. Using the hippocampus microarray and ingenuity pathway analysis (IPA) software, we exacted the differentially expressed genes, networks, pathways, and functions in positive-phenotype groups (BA, JA and BJ) by comparing with the negative-phenotype group (CM). In the BA, JA, and BJ groups, a total of 7, 4, and 11 specific target molecules, 1, 1, and 4 networks, 51, 59, and 18 canonical pathways and 70, 53, and 64 biological functions, respectively, were identified. Pure therapeutic mechanisms of BA and JA were mainly overlapped in specific target molecules, functions and pathways, which were related to the nervous system, inflammation and immune response. The specific mechanisms of BA and JA were associated with apoptosis and cancer-related signaling and endocrine and hormone regulation, respectively. In the BJ group, novel target profiles distinct from mono-therapies were revealed, including 11 specific target molecules, 10 functions, and 10 pathways, the majority of which were related to a virus-mediated immune response. The pure additive effects between BA and JA were based on enhanced action in virus-mediated immune response. This pure mechanistic analysis may provide a clearer outline of the target profiles of multi-target compounds and combination therapies.

Topics: Animals; Apoptosis; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Flavonoids; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Hippocampus; Immunity, Innate; Infarction, Middle Cerebral Artery; Iridoids; Male; Mice; Neuroprotective Agents; Oligonucleotide Array Sequence Analysis; Phenotype; RNA, Messenger; Signal Transduction; Systems Biology; Transcriptome

Identifying the variation of core modules and hubs seems to be critical for characterizing variable pharmacological mechanisms based on topological alteration of disease networks. We first identified a total of eight core modules by using an approach of multiple modular characteristic fusing (MMCF) from different targeted networks in ischemic mice. Interestingly, the value of module disturbance intensity (MDI) increased in drug combination group. Second, we redefined a weak allosteric module and a strong allosteric module. Then, we identified 15 pharmacological module drivers (PMDs) by leave-one-out screening with a cutoff of two folds, which were at least, in part, validated by expression and variation of topological contribution. Finally, we revealed the fusional and emergent variation of PMD in core modules contributing to multidimensional synergistic mechanism in ischemic mice and rats. Our findings provide a new set of drivers that might promote the pharmacological modular flexibility and offer a potential avenue for disease treatment.

Topics: Animals; Cholic Acid; Cyclins; Drug Synergism; Gene Expression Regulation; Gene Regulatory Networks; Hippocampus; Infarction, Middle Cerebral Artery; Interleukin 1 Receptor Antagonist Protein; Iridoids; Mice; Models, Biological; Oligonucleotide Array Sequence Analysis; Rats

BACKGROUND In this study, we investigated the potential neuroprotective effect of oleuropein (OLE) on apoptotic changes via modulating Akt/glycogen synthase kinase 3 beta (Akt/GSK-3b) signaling in a rat model of cerebral ischemia/reperfusion injury (IRI). MATERIAL AND METHODS Sprague-Dawley male rats (12 weeks, n=200) were randomly assigned to 5 groups: sham group, vehicle (IRI+ vehicle) group, OLE (IRI+OLE) group, OLE+LY294002 (IRI+OLE+LY294002) group, and LY294002(IRI+LY294002) group. The rats were subjected to cerebral ischemia/reperfusion injury (IRI) model and treated once daily for 5 days with vehicle and OLE (100 mg/kg via intraperitoneal injection) after IRI injury. LY294002 (0.3 mg/kg) was intraperitoneally injected once at 30 min after IRI injury. Brain edema, neurological deficit, rotarod latencies, and Morris water maze (MWM) performance were evaluated after IRI. The number of dead cells were assayed by TUNEL staining. Western blot was used to detect the expression of Bcl-2, Bax, cleaved caspase-3 (CC3), neurotrophic factors, and the phosphorylation levels of Akt and GSK-3β. RESULTS Compared with the vehicle group, brain water content, neurological deficits, rotarod latencies, and escape latency following IRI were reduced in the OLE group. Cell apoptosis and reduced neurotrophic factor caused by IRI was also attenuated by OLE. Furthermore, increased p-Akt and decreased p-GSK-3β were caused by OLE, which were associated with decrease of Bax/Bcl-2 ratio and the suppression of Caspase-3 activity after IRI. Importantly, all the beneficial effects of OLE in the vehicle group were abrogated by PI3K inhibitor LY294002. CONCLUSIONS Cerebral ischemia was protected by OLE via suppressing apoptosis through the Akt/GSK-3β pathway and upregulating neurotrophic factor after IRI.

Topics: Animals; Apoptosis; Brain; Brain Ischemia; Disease Models, Animal; Glycogen Synthase Kinase 3 beta; Infarction, Middle Cerebral Artery; Iridoid Glucosides; Iridoids; Male; Neurons; Neuroprotective Agents; Oncogene Protein v-akt; Phosphatidylinositol 3-Kinases; Phosphorylation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction

Calcium-permeable ionotropic NMDAR-mediated hyperactivity is regarded as the critical factor in modulating the development of ischaemic stroke. Recently, there has been increasing interest in preventing post-stroke neuronal death by focusing on intervening in the function of subpopulations of NMDARs and their downstream signalling. Geniposide, an iridoid glycoside, has been found to have cytoprotective functions in various conditions. However, it is still unclear whether and how geniposide affects neuronal insult under experimental stroke.. We demonstrate that dose-dependent geniposide significantly decreased the infarct volume in tMCAO models.. A medium level of geniposide improved anti-apoptotic functions and inhibited BBB leakage/haemorrhage via elevating GluN2A-containing NMDAR expression in tMCAO rats. Importantly, these effects could be eliminated by co-treatment of geniposide with the GluN2A antagonist NVP but not the GluN2B inhibitor ifenprodil. Moreover, geniposide's protection was due to the enhancement of GluN2A-dependent survival signals, including pAKT, pERK and PSD-95.. The results suggest that geniposide protects neurons against post-ischaemic neurovascular injury through the activation of GluN2A/AKT/ERK pathways. As a very promising natural agent, geniposide may be a future therapeutic for stroke patients.

Topics: Animals; Cell Death; Extracellular Signal-Regulated MAP Kinases; Infarction, Middle Cerebral Artery; Iridoids; Male; MAP Kinase Signaling System; Middle Cerebral Artery; Neurons; Neuroprotective Agents; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Huang-Lian-Jie-Du-Decoction (HLJDD) is a Traditional Chinese Medicine (TCM) clinical prescription noted for its neuroprotective effects. The total alkaloids, flavonoids, and iridoids are the main active components of HLJDD. In the present study we explored the possible effects of the total alkaloids, flavonoids, and iridoids from HLJDD on behavioral recovery and cortical neurogenesis after stroke.. The stroke model was induced by permanent middle cerebral artery occlusion (pMACO). The total alkaloids (44 mg/kg), flavonoids (50 mg/kg), and iridoids (80 mg/kg) from HLJDD were orally administered for 2h after stroke and daily thereafter. Neurological function was assessed and then rats were sacrificed 7 days after pMACO. Following repeated intraperitoneal injections of the cell proliferation - specific marker 5-bromodeoxyuridine (BrdU) after stroke induction, precursor cell proliferation and differentiation was monitored by immunofluorescent staining. The levels of relevant proteins were determined by western blotting and the mRNA expressions were assessed by quantitative real time-polymerase chain reaction (qRT-PCR).. Total alkaloids, flavonoids and iridoids from HLJDD showed improved functional outcome after brain ischemia. The total alkaloids and iridoids increased number of BrdU-positive cells and enhanced neuronal differentiation in the cortex. Alkaloids-enhanced neurogenesis might be associated with increased VEGF, Ang-1, and Ang-2 protein expression. And the neuroproliferative effect of alkaloids was partially correlated with increased phosphorylation of AKT, and GSK-3β. Flavonoids treatment was found to promote differentiation of cortical precursor cells into neuronal but not glial cells, which may be at least attributable to the regulation of AKT, GSK-3β mRNA and Ang-1 protein levels.. Total alkaloids, iridoids and flavonoids from HLJDD promoted functional recovery likely via enhancing cortical neurogenesis and thus have potential as a treatment for ischemic brain injury.

Topics: Alkaloids; Animals; Brain Ischemia; Bromodeoxyuridine; Cell Differentiation; Cell Proliferation; Drugs, Chinese Herbal; Flavonoids; Infarction, Middle Cerebral Artery; Iridoids; Male; Medicine, Chinese Traditional; Neurogenesis; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Stroke

Oleuropein (OLE) was found to have anti-inflammatory and anti-oxidant effects. The latest study has shown that it can resist myocardial injury that follows an acute myocardial infarction and can rescue impaired spinal nerve cells. In this study, we investigated the neuroprotective effects of OLE on cerebral ischemia and reperfusion injury in a middle cerebral artery occlusion model in mice.OLE (100 mg/kg) was injected intraperitoneally 1h before ischemia. We found that the volume of cerebral infarction was significantly reduced after 75 min of ischemia and 24 h of reperfusion compared with the I/R (ischemia/reperfusion) group. This protective function occurred in a dose-dependent manner. We also found that treatment with OLE could reduce the cerebral infarct volume. The neuroprotective effect was prolonged from 2 h to 4 h when we injected OLE intracerebroventricularly after reperfusion. We then found that OLE can decrease the level of cleavedcaspase-3, an important marker of apoptosis, in the ischemic mouse brain. Finally, we explored the role of OLE in providing anti-apoptotic effects through the increased expression of Bcl-2 and the decreased expression of Bax, which are important markers in apoptosis. As shown above, the function and safety of OLE in cardiovascular disease may indicate that it is a potential therapeutic for stroke.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Brain; Caspase 3; Infarction, Middle Cerebral Artery; Iridoid Glucosides; Iridoids; Male; Mice, Inbred ICR; Neurons; Neuroprotection; Neuroprotective Agents; Olea; Plant Extracts; Plant Leaves; Proto-Oncogene Proteins c-bcl-2; Reperfusion Injury

Huang-Lian-Jie-Du-Decoction (HLJDD, Oren-gedoku-to in Japanese) is commonly used in traditional Chinese medicine (TCM) to treat ischemic stroke. This study investigated the efficacy of various combinations of the major components of HLJDD, berberine (A), baicalin (B), and jasminoidin (C), on the treatment of ischemic stroke modeled by middle cerebral artery occlusion (MCAO) in rats. The effects of A, B and C individually and their combinations were investigated using proton nuclear magnetic resonance (1H NMR)-based metabolomics complemented with neurologic deficit scoring, infarct volume measurement, biochemistry, histopathology and immunohistochemistry, as well as quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Ischemic stroke produces severe oxidative stress, which induces further damage. Our results show that the ABC combination treatment increased levels of cellular antioxidants that scavenged reactive oxygen species during ischemia-reperfusion via the nuclear erythroid 2-related factor 2 (Nrf2) signaling cascade. These protective effects were not observed with the other treatments. These results suggest that a combination of component herbs in HLJDD exhibit stronger effects than the individual herbs alone. Our integrated metabolomics approach also provides a tractable, powerful tool for understanding the science behind TCM formulations.

Topics: Animals; Berberine; Brain; Disease Models, Animal; Drug Synergism; Drugs, Chinese Herbal; Flavonoids; Free Radical Scavengers; Infarction, Middle Cerebral Artery; Iridoids; Male; Metabolomics; Neuroprotective Agents; NF-E2-Related Factor 2; Oxidative Stress; Phytotherapy; Plants, Medicinal; Proton Magnetic Resonance Spectroscopy; Rats, Sprague-Dawley; Reperfusion Injury

Cerebral ischemia is considered to be a highly complex disease resulting from the complicated interplay of multiple pathways. Disappointedly, most of the previous studies were limited to a single gene or a single pathway. The extent to which all involved pathways are translated into fusing mechanisms of a combination therapy is of fundamental importance.. We report an integrative strategy to reveal the additive mechanism that a combination (BJ) of compound baicalin (BA) and jasminoidin (JA) fights against cerebral ischemia based on variation of pathways and functional communities.. We identified six pathways of BJ group that shared diverse additive index from 0.09 to 1, which assembled broad cross talks from seven pathways of BA and 16 pathways of JA both at horizontal and vertical levels. Besides a total of 60 overlapping functions as a robust integration background among the three groups based on significantly differential subnetworks, additive mechanism with strong confidence by networks altered functions.. These results provide strong evidence that the additive mechanism is more complex than previously appreciated, and an integrative analysis of pathways may suggest an important paradigm for revealing pharmacological mechanisms underlying drug combinations.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Drug Therapy, Combination; Drugs, Chinese Herbal; Flavonoids; Infarction, Middle Cerebral Artery; Iridoids; Male; Mice; Mice, Inbred Strains; Microarray Analysis; Molecular Sequence Data; Principal Component Analysis; Reperfusion Injury; Signal Transduction

Huanglian-Zhizi couplet medicine comes from classical prescription Huang-Lian-Jie-Du-Tang (HLJDT), which has been proven by previous researches to be an effective compound for cerebral ischemia. This paper explores the integrated pharmacokinetics of gardenia acid and geniposide-time-antioxidant efficacy after the oral administration of Huanglian-Zhizi couplet medicine from HLJDT in rats with middle cerebral artery occlusion (MCAO). To investigate the differences in pharmacokinetics and antioxidant effect of Huanglian-Zhizi and HLJDT in MCAO rats, which have been scarcely reported, an oral dose, 24 crud drug g/kg, of Huanglian-Zhizi and 40 crud drug/kg of HLJDT were administered in two groups of normal rats and two groups of Sprague-Dawley (SD) MCAO rats, respectively. At different time points, concentrations of gardenia acid and geniposide were determined by high performance liquid chromatography (HPLC), and levels of superoxide dismutase (SOD) were calculated by ELIASA. Pharmacokinetic parameters including AUC, MRT, t1/2, T max , C max were estimated by statistical moment analysis using a data analysis system (DAS) 2.0. An AUC based on weighting approach was used for integrating gardenia acid and geniposide. Finally, the concentration-time efficacy profiles were obtained. The integrated pharmacokinetics profiles of index components could reveal the pharmacokinetics behavior of Huanglian-Zhizi and HLJDT, corresponding to the antioxidant efficacy.

Topics: Administration, Oral; Animals; Antioxidants; Chromatography, High Pressure Liquid; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Enzyme-Linked Immunosorbent Assay; Infarction, Middle Cerebral Artery; Iridoids; Phytotherapy; Rats, Sprague-Dawley; Superoxide Dismutase; Time Factors

Our previous studies showed that after oral administration of an Huang-Lian-Jie-Du-Tang (HLJDT) decoction, there is a higher concentration of the pure components, berberine, baicalin and gardenoside in the plasma of Middle cerebral artery occlusion (MCAO) rats than in sham-operated rats, The aim of the present study was to determine whether these components could be reliably measured in MCAO rat tissues. First, the plasma concentration-time profiles of berberine, palmatine, baicalin, baicalein and gardenoside were characterised in MCAO rats after oral administration of the aqueous extract of HLJDT. Subsequently, liver, lung and kidney tissues were obtained from sudden death MCAO rats in the absorption phase (0.25 h), the distribution phase (1.0 h) and the elimination phase (8.0 h) after administration of the HLJDT aqueous extract. An HPLC method was developed and validated for the determination of the distribution characteristics of berberine, palmatine, baicalin, baicalein and gardenoside simultaneously from the above-mentioned rat tissues. The results indicated that berberine, palmatine, baicalin and baicalein distributed rapidly and accumulated at high levels in the lung, while gardenoside distributed widely in the lung and the kidney. To the best of our knowledge, this is the first report to describe the distribution of the active ingredients derived from HLJDT in MCAO rat tissues. The tissue distribution results provide a biopharmaceutical basis for the design of the clinic application of HLJDT in cerebrovascular disease.

Topics: Animals; Berberine; Berberine Alkaloids; Drugs, Chinese Herbal; Flavanones; Flavonoids; Infarction, Middle Cerebral Artery; Iridoids; Male; Rats; Rats, Sprague-Dawley; Tissue Distribution

Recently, the pharmaceutical industry has shifted to pursuing combination therapies that comprise more than one active ingredient. Interestingly, combination therapies have been used for more than 2500 years in traditional Chinese medicine (TCM). Understanding optimal proportions and synergistic mechanisms of multi-component drugs are critical for developing novel strategies to combat complex diseases. A new multi-objective optimization algorithm based on least angle regression-partial least squares was proposed to construct the predictive model to evaluate the synergistic effect of the three components of a novel combination drug Yi-qi-jie-du formula (YJ), which came from clinical TCM prescription for the treatment of encephalopathy. Optimal proportion of the three components, ginsenosides (G), berberine (B) and jasminoidin (J) was determined via particle swarm optimum. Furthermore, the combination mechanisms were interpreted using PLS VIP and principal components analysis. The results showed that YJ had optimal proportion 3(G): 2(B): 0.5(J), and it yielded synergy in the treatment of rats impaired by middle cerebral artery occlusion induced focal cerebral ischemia. YJ with optimal proportion had good pharmacological effects on acute ischemic stroke. The mechanisms study demonstrated that the combination of G, B and J could exhibit the strongest synergistic effect. J might play an indispensable role in the formula, especially when combined with B for the acute stage of stroke. All these data in this study suggested that in the treatment of acute ischemic stroke, besides restoring blood supply and protecting easily damaged cells in the area of the ischemic penumbra as early as possible, we should pay more attention to the removal of the toxic metabolites at the same time. Mathematical system modeling may be an essential tool for the analysis of the complex pharmacological effects of multi-component drug. The powerful mathematical analysis method could greatly improve the efficiency in finding new combination drug from TCM.

Topics: Algorithms; Animals; Berberine; Brain Ischemia; Cerebrum; Drug Combinations; Drug Compounding; Drug Evaluation, Preclinical; Drug Synergism; Drugs, Chinese Herbal; Ginsenosides; Infarction, Middle Cerebral Artery; Iridoids; Least-Squares Analysis; Male; Medicine, Chinese Traditional; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Swelling; Neuroprotective Agents; Principal Component Analysis; Rats; Rats, Sprague-Dawley; Regional Blood Flow

This study was conducted to investigate the efficacy of cornin, an iridoid glycoside, in an experimental cerebral ischemia induced by middle cerebral artery occlusion (MCAO) and reperfusion (I/R), and to elucidate the potential mechanism. Adult male Sprague-Dawley rats were subjected to MCAO for 1 h, then reperfusion for 23 h. Behavioral tests were used to evaluate the damage to central nervous system. The cerebral infarct volume and histopathological damage were assessed to evaluate the brain pathophysiological changes. Spectrophotometric assay methods were used to determine the activities of superoxide dismutase (SOD) and glutathione-peroxidase (GPx). Contents of malondialdehyde (MDA), the generation of reactive oxygen species (ROS) as well as respiratory control ratio and respiratory enzymes of the brain mitochondria were also determined. The results showed that cornin significantly decreased neurological deficit scores, and reduced cerebral infarct volume and degenerative neurons. Meanwhile, cornin significantly increased the brain ATP content, improved mitochondrial energy metabolism, inhibited the elevation of MDA content and ROS generation, and attenuated the decrease of SOD and GPx activities in brain mitochondria. These findings indicate that cornin has protective potential against cerebral ischemia injury and its protective effects may be due to amelioration of cerebral mitochondrial function and its antioxidant property.

Topics: Animals; Brain; Calcium; Cell Respiration; Electron Transport; Glutathione Peroxidase; Infarction, Middle Cerebral Artery; Iridoid Glycosides; Iridoids; Male; Malondialdehyde; Membrane Fluidity; Mitochondria; Mitochondrial Membranes; Neuroprotective Agents; Phospholipids; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reperfusion Injury; Superoxide Dismutase; Verbena; Water

The capacity of cornel iridoid glycoside (CIG) to suppress the manifestations of ischemic stroke was investigated. CIG was administered to rats by the intragastric route once daily for 7 days. Focal cerebral ischemia was induced by 2 h of middle cerebral artery occlusion followed by 24 h of reperfusion. In non-treated rats large infarct areas were observed within 24 h of reperfusion. Examination of the ischemic cerebral cortex revealed microglia and astrocyte activation, increased interleukin-1beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) concentrations, increased DNA fragmentation in the ischemia penumbra, elevated Bax expression, increased caspase-3 cleavage, and decreased Bcl-2 expression. Pretreatment with CIG decreased the infarct area, DNA fragmentation, IL-1beta and TNF-alpha concentrations, microglia and astrocyte activation, Bax expression, and caspase-3 cleavage while increasing Bcl-2 expression. CIG exerts anti-neuroinflammatory and anti-apoptotic effects which should prove beneficial for prevention or treatment of stroke.

Topics: Animals; Apoptosis; Brain Ischemia; Cerebral Infarction; Cornus; Glycosides; Infarction, Middle Cerebral Artery; Inflammation; Interleukin-1beta; Iridoids; Male; Neuroglia; Plant Extracts; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tumor Necrosis Factor-alpha

The aim of this study was to investigate the effects of cornel iridoid glycoside (CIG), an ingredient extracted from a traditional Chinese herb Cornus officinalis, on neurological function and neurogenesis after ischemic stroke. CIG was intragastrically administered to rats in doses of 20, 60 and 180 mg/kg/day, starting 3 h after the onset of middle cerebral artery occlusion (MCAO). The behavioral test was performed by using the modified neurological severity score (mNSS). Rats were sacrificed 7, 14, or 28 days after ischemia occurred. Neurogenesis and angiogenesis were detected by using immunofluorescence staining. The messenger ribonucleic acid (mRNA) expression of vascular endothelial growth factor (VEGF) and its receptor Flk-1 was measured by RT-PCR, and the protein expression of VEGF was determined by Western blotting analysis. The treatment with CIG at the doses of 60 and 180 mg/kg/day significantly improved neurological function, and increased the number of bromodeoxyuridine (BrdU)-positive cells and nestin-positive cells in the subventricular zone of rats 7, 14 and 28 days after ischemia. The number of newly mature neurons and blood vessels in striatum, as indicated by BrdU/NeuN and vWF immunoreactivity, respectively, was also increased in CIG-treated rats 28 days after stroke. CIG treatment obviously enhanced the mRNA expression of VEGF and its receptor Flk-1 and the protein expression of VEGF 7 and 28 days after ischemia. The results indicated that CIG promoted neurogenesis and angiogenesis and improved neurological function after ischemia in rats, and the mechanism might be related to CIG's increasing VEGF and Flk-1 in the brain.

Topics: Angiogenesis Inducing Agents; Animals; Brain; Cognition; Cornus; Drugs, Chinese Herbal; Glycosides; Infarction, Middle Cerebral Artery; Iridoids; Male; Neurogenesis; Neurons; Neuroprotective Agents; Neuropsychological Tests; Phytotherapy; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2