A 42-Markers Pharmacokinetic Study Reveals Interactions of Berberine and Glycyrrhizic Acid in the Anti-diabetic Chinese Medicine Formula Gegen-Qinlian Decoction

Herbal medicines are commonly used as compound formulas in clinical practice to achieve optimal therapeutic effects. However, the combination mechanisms usually lack solid evidence. In this study, we report synergistic interactions through altering pharmacokinetics in Gegen-Qinlian Decoction (GQD), an anti-diabetic Chinese medicine formula. A multi-component pharmacokinetic study of GQD and the single herbs was conducted by simultaneously monitoring 42 major bioactive compounds (markers) in rats plasma using LC/MS/MS within 30 min. GQD could remarkably improve the plasma concentrations of berberine (BER) and other alkaloids in Huang-Lian by at least 30%, and glycyrrhizic acid (GLY) from Gan-Cao played a major role. A Caco-2 cell monolayer test indicated that GLY improved the permeability of BER by inhibiting P-glycoprotein. Although GLY alone did not show observable effects, the co-administration of GLY (ig, 50 or 80 mg/kg) could improve the anti-diabetic effects of berberine (ig, 50 mg/kg) in db/db mice in a dose-dependent manner. The blood glucose decreased by 46.9%, whereas the insulin level increased by 40.8% compared to the control group. This is one of the most systematic studies on the pharmacokinetics of Chinese medicine formulas, and the results demonstrate the significance of pharmacokinetic study in elucidating the combination mechanisms of compound formulas

Smoking Exposure and Survival of Patients with Esophagus Cancer: A Systematic Review and Meta-Analysis

Smoking is a well-known major risk factor in development of esophageal cancer, but few studies have reported the association between smoking status and prognosis of these patients. We conduct the present study to summarize current evidence. A computerized search of the PubMed and EMBASE was performed up to April 30, 2015. Eight studies, containing 4,286 patients, were analyzed. In the grouping analysis, among esophageal squamous-cell carcinoma patients, current and former smokers, compared to those who have never smoked, seemed to have a poorer prognosis (HR = 1.41, 95% CI 1.22–1.64, and HR = 1.35, 95% CI 0.92–1.97, resp.). In the subgroup analysis, adverse effects on current smoker compared with never smoker were also observed in China and the other countries (HR = 1.5, 95% CI 1.18–1.92, and HR = 1.36, 95% CI 1.12–1.65, resp.). In the group that ever smoked, we could not get a similar result. No significantly increased risk was found in esophageal adenocarcinoma patients compared to the squamous-cell histology ones. In the smoking intensity analysis, heavy smoking was associated with poor survival in esophageal squamous-cell carcinoma. Our pooled results supported the existence of harmful effects of smoking on survival after esophagus cancer diagnosis

Morphological diversity of single neurons in molecularly defined cell types.

Dendritic and axonal morphology reflects the input and output of neurons and is a defining feature of neuronal types1,2, yet our knowledge of its diversity remains limited. Here, to systematically examine complete single-neuron morphologies on a brain-wide scale, we established a pipeline encompassing sparse labelling, whole-brain imaging, reconstruction, registration and analysis. We fully reconstructed 1,741 neurons from cortex, claustrum, thalamus, striatum and other brain regions in mice. We identified 11 major projection neuron types with distinct morphological features and corresponding transcriptomic identities. Extensive projectional diversity was found within each of these major types, on the basis of which some types were clustered into more refined subtypes. This diversity follows a set of generalizable principles that govern long-range axonal projections at different levels, including molecular correspondence, divergent or convergent projection, axon termination pattern, regional specificity, topography, and individual cell variability. Although clear concordance with transcriptomic profiles is evident at the level of major projection type, fine-grained morphological diversity often does not readily correlate with transcriptomic subtypes derived from unsupervised clustering, highlighting the need for single-cell cross-modality studies. Overall, our study demonstrates the crucial need for quantitative description of complete single-cell anatomy in cell-type classification, as single-cell morphological diversity reveals a plethora of ways in which different cell types and their individual members may contribute to the configuration and function of their respective circuits

Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial

Background Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population. Methods AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921. Findings Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [<1%]; p=0·038) at 6 months. Interpretation Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke

A simplified morphological classification scheme for pyramidal cells in six layers of primary somatosensory cortex of juvenile rats

The majority of neurons in the neocortex are excitatory pyramidal cells (PCs). Many systematic classification schemes have been proposed based the neuronal morphology, the chemical composition, and the synaptic connectivity, etc. Recently, a cortical column of primary somatosensory cortex (SSC) has been reconstruction and functionally simulated (Markram et al., 2015). Putting forward from this study, here we proposed a simplified classification scheme for PCs in all layers of the SSC by mainly identifying apical dendritic morphology based on a large data set of 3D neuron reconstructions. We used this scheme to classify three types in layer 2, two in layer 3, three in layer 4, four in layer 5, and six types in layer 6. These PC types were visually distinguished and confirmed by quantitative differences in their morphometric properties. The classes yielded using this scheme largely corresponded with PC classes that were defined previously based on other neuronal and synaptic properties such as long-range projects and synaptic innervations, further validating its applicability. Therefore, the morphology information of apical dendrites is sufficient for a simple scheme to classify a spectrum of anatomical types of PCs in the SSC. Keywords: Somatosensory cortex, Cortical layers, Cell types, Pyramidal cells, Dendrites, Apical dendrite

A comprehensive review on phytochemistry, pharmacology, and flavonoid biosynthesis of Scutellaria baicalensis

Context: Scutellaria baicalensis Georgi (Lamiaceae) is a popular medicinal plant. Its roots are used as the famous traditional Chinese medicine Huang-Qin, which is recorded in Chinese Pharmacopoeia, European Pharmacopoeia, and British Pharmacopoeia. Objective: This review comprehensively summarizes research progress in phytochemistry, pharmacology, and flavonoid biosynthesis of S. baicalensis. Methods: English and Chinese literature from 1973 to March 2018 was collected from databases including Web of Science, SciFinder, PubMed, Elsevier, Baidu Scholar (Chinese), and CNKI (Chinese). Scutellaria baicalensis, chemical constituents, phytochemistry, biological activities, and biosynthesis were used as the key words. Results: A total of 126 small molecules (1–126) and 6 polysaccharides have been isolated from S. baicalensis. The small molecules can be classified into four structural types, namely, free flavonoids, flavonoid glycosides, phenylethanoid glycosides, and other small molecules. Extracts of S. baicalensis and its major chemical constituents have been reported to possess anti-viral, anti-tumor, anti-bacterial, antioxidant, anti-inflammatory, hepatoprotective, and neuroprotective activities. Key steps in the biosynthetic pathways of Scutellaria flavonoids have also been summarized. Conclusions: This article could be helpful for researchers who are interested in the chemical constituents, bioactivities, biosynthesis, and clinical applications of S. baicalensis

An Update on Renal Artery Denervation and Its Clinical Impact on Hypertensive Disease

Hypertension is a globally prevalent condition, with a heavy clinical and economic burden. It is the predominant risk factor for premature cardiovascular and cerebrovascular disease, and is associated with a variety of clinical disorders including stroke, congestive cardiac failure, ischaemic heart disease, chronic renal failure, and peripheral arterial disease. A significant subset of hypertensive patients have resistant hypertensive disease. In this group of patients, catheter-based renal artery denervation has emerged as a potential therapy, with favourable clinical efficacy and safety in early trials. Additional benefits of this therapy are also being identified and include effects on left ventricular remodeling, cardiac performance, and symptom status in congestive cardiac failure. Utility of renal denervation for the management of resistant hypertension, however, has become controversial since the release of the Symplicity HTN-3 trial, the first large-scale blinded randomised study investigating the efficacy and safety of renal artery denervation. The aim of this paper is to evaluate the history, utility, and clinical efficacy of renal artery denervation technology, including an in-depth appraisal of the current literature and principal trials