Danggui Sini decoction alleviates oxaliplatin-induced peripheral neuropathy by regulating gut microbiota and potentially relieving neuroinflammation related metabolic disorder.

BACKGROUND: Danggui Sini decoction (DSD), a traditional Chinese medicine formula, has the function of nourishing blood, warming meridians, and unblocking collaterals. Our clinical and animal studies had shown that DSD can effectively protect against oxaliplatin (OXA)-induced peripheral neuropathy (OIPN), but the detailed mechanisms remain uncertain. Multiple studies have confirmed that gut microbiota plays a crucial role in the development of OIPN. In this study, the potential mechanism of protective effect of DSD against OIPN by regulating gut microbiota was investigated. METHODS: The neuroprotective effects of DSD against OIPN were examined on a rat model of OIPN by determining mechanical allodynia, biological features of dorsal root ganglia (DRG) as well as proinflammatory indicators. Gut microbiota dysbiosis was characterized using 16S rDNA gene sequencing and metabolism disorders were evaluated using untargeted and targeted metabolomics. Moreover the gut microbiota mediated mechanisms were validated by antibiotic intervention and fecal microbiota transplantation. RESULTS: DSD treatment significantly alleviated OIPN symptoms by relieving mechanical allodynia, preserving DRG integrity and reducing proinflammatory indicators lipopolysaccharide (LPS), IL-6 and TNF-α. Besides, DSD restored OXA induced intestinal barrier disruption, gut microbiota dysbiosis as well as systemic metabolic disorders. Correlation analysis revealed that DSD increased bacterial genera such as Faecalibaculum, Allobaculum, Dubosiella and Rhodospirillales_unclassified were closely associated with neuroinflammation related metabolites, including positively with short-chain fatty acids (SCFAs) and sphingomyelin (d18:1/16:0), and negatively with pi-methylimidazoleacetic acid, L-glutamine and homovanillic acid. Meanwhile, antibiotic intervention apparently relieved OIPN symptoms. Furthermore, fecal microbiota transplantation further confirmed the mediated effects of gut microbiota. CONCLUSION: DSD alleviates OIPN by regulating gut microbiota and potentially relieving neuroinflammation related metabolic disorder.

Copper-Catalyzed Regio- and Stereoselective Three-Component Coupling of Allenyl Ethers with gem-Dichlorocyclobutenones and B2pin2.

The three-component coupling method for regio- and stereoselective difunctionalization of allenes with allenyl ethers, bis(pinacolato)diboron, and gem-dichlorocyclobutenones as electrophiles was reported, yielding a variety of highly functionalized cyclobutenone products tethering with an alkenylborate fragment. The polysubstituted cyclobutenone products also underwent diverse transformations.

Copper-Catalyzed Enantioselective Hydrosilylation of Allenes to Access Axially Chiral (Cyclohexylidene)ethyl Silanes.

A novel strategy of copper-catalyzed regio- and enantioselective hydrosilylation of 4-substituted vinylidenecyclohexanes with silanes was developed. In this protocol, various allenes and silanes were used to afford the corresponding (cyclohexylidene)ethyl silanes in moderate to high yields with good enantioselectivities.

Copper-Catalyzed Regiodivergent and Enantioselective Hydrosilylation of Allenes.

A copper-catalyzed regiodivergent hydrosilylation of a wide range of simple allenes is reported. Linear and branched allylsilanes were formed by judicious choice of solvents. Furthermore, branched allylsilanes were obtained with high enantioselectivity (up to 97% enantiomeric excess) with the aid of a C2-symmetric bisphosphine ligand in the unprecedented asymmetric allene hydrosilylation.

Microbial Oligosaccharides with Biomedical Applications.

Microbial oligosaccharides have been regarded as one of the most appealing natural products attributable to their potent and selective bioactivities, such as antimicrobial activity, inhibition of α-glucosidases and lipase, interference of cellular recognition and signal transduction, and disruption of cell wall biosynthesis. Accordingly, a handful of bioactive oligosaccharides have been developed for the treatment of bacterial infections and type II diabetes mellitus. Given that naturally occurring oligosaccharides have increasingly gained recognition in recent years, a comprehensive review is needed. The current review highlights the chemical structures, biological activities and divergent biosynthetic origins of three subgroups of oligomers including the acarviosine-containing oligosaccharides, saccharomicins, and orthosomycins.

Synthesis of Structurally Diverse Allylsilanes via Copper-Catalyzed Regiodivergent Hydrosilylation of 1,3-Dienes.

Unprecedented copper-catalyzed regiodivergent hydrosilylation reactions of substituted 1,3-dienes with hydrosilanes have been developed. The 1,2- and 1,4-hydrosilylations of 1-(hetero)aryl-substituted 1,3-dienes were highly selectively controlled via variation of the catalytic systems. Meanwhile, the 1,4-hydrosilylation reaction of 2-aryl-substituted 1,3-dienes with diphenylsilane was also successfully realized for the first time. These methods provide convenient and efficient approaches for the synthesis of structurally diverse allylsilanes.

Copper-Catalyzed Chemoselective Silylative Cyclization of 2,2'-Diethynylbiaryl Derivatives.

In this protocol, copper-catalyzed diverse silylative carbocyclization reactions of 2,2'-diethynylbiaryl derivatives with silaboronate were reported. Three new and novel types of domino reactions for the copper-catalyzed transformation of silaboronate were discovered. The corresponding cyclobuta[l]phenanthrene, bis((silyl)methyl)phenanthrene, and silyl-substituted exocyclic diene products were chemoselectively formed with high efficiency.

Synthesis of Enynic and Allenic Orthoesters via Defluoromethoxylation of 2-Trifluoromethyl-1,3-enynes.

In this protocol, the chemoselective defluoromethoxylation reactions of 2-trifluoromethyl-1,3-enynes were developed. The enynic and allenic orthoesters were selectively produced in good to excellent yields via multiple substitution processes under mild reaction conditions, respectively. The enynic orthoester products were proved capable of acting as efficient "platform molecules" to access various functionalized allenyl compounds.

Acylated Aminooligosaccharides from the Yellow Sea Streptomyces sp. HO1518 as Both α-Glucosidase and Lipase Inhibitors.

Three new acylated aminooligosaccharide (1-3), along with five known congeners (4-8), were isolated from the marine-derived Streptomyces sp. HO1518. Their structures were fully elucidated by extensive spectroscopic analysis, mainly based on 1D-selective and 2D TOCSY, HSQC-TOCSY, and HRESIMS spectrometry measurements, and by chemical transformations. All of the compounds were evaluated for their α-glucosidase and pancreatic lipase inhibitory activities. Among the isolates, D6-O-isobutyryl-acarviostatin II03 (3) and D6-O-acetyl-acarviostatin II03 (8), sharing acarviostatin II03-type structure, showed the most potent α-glucosidase and lipase inhibitory effects, far stronger than the antidiabetic acarbose towards α-glucosidase and almost equal to the anti-obesity orlistat towards lipase in vitro. This is the first report on inhibitory activities against the two major digestive enzymes for acylated aminooligosaccharides. The results from our investigation highlight the potential of acylated aminooligosaccharides for the future development of multi-target anti-diabetic drug.

Copper-Catalyzed Anti-Markovnikov Hydrosilylation of Terminal Alkynes.

A copper-catalyzed anti-Markovnikov hydrosilylation of alkynes with PhSiH3 was reported. This reaction represents a notable and efficient example on copper-catalyzed hydrosilylatioin of alkynes, which shows excellent recognition between the terminal and internal triple bonds. Various (hetero)aromatic and aliphatic substituted terminal alkynes underwent this reaction to afford the (E)-vinylsilanes in high yields and with excellent regioselectivity.

Anlotinib or platinum-pemetrexed as second-line therapy in EGFR T790M-negative lung cancer.

BACKGROUND: Clinical management of T790M-negative patients after first-line epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) treatment failure is controversial. Anlotinib is a novel multi-target TKI for tumor angiogenesis and tumor cell proliferation, and it has been approved as a thirdline or beyond treatment for advanced non-small cell lung cancer (NSCLC). The impact of anlotinib as a second-line therapy compared with platinum-pemetrexed chemotherapy in T790M-negative patients after first-line EGFR-TKIs failed remains unclear. METHODS: In this retrospective cohort study, we reviewed 20 patients who were given anlotinib and 42 patients who received platinum-pemetrexed chemotherapy as a control after first-line EGFR-TKIs therapy progression. All the patients were confirmed to be T790M-negative using the cobas EGFR Mutation Test. The primary end point included progression-free survival (PFS) time, objective response rate (ORR) and disease control rate. RESULTS: The duration of PFS was significantly longer in the platinum-pemetrexed group than in the anlotinib group (median, 4.5 vs. 3.0 months; HR, 1.972; 95% CI, 1.078 to 3.607; P=0.021). The response rate was significantly better in the platinum-pemetrexed group (30.9%) than that in the anlotinib group (15%), and disease control rate (DCR) of both groups was 70% and 83%, respectively. All the adverse events in anlotinib group appeared to be manageable. CONCLUSIONS: Anlotinib was less effective than platinum-pemetrexed chemotherapy in T790M-negative NSCLC patients after disease progression with first-line EGFR-TKIs therapy failure.

Palladium-Catalyzed Cycloaromatization/Alkylation of o-(Alkynyl)styrenes.

A Pd(II)-catalyzed mild and highly regioselective 6-endo cyclization/alkylation reaction of o-(alkynyl)styrenes with simple allylic alcohols has been developed. Under mild reaction conditions, the vinyl palladium species generated in situ after cyclization could insert a C-C double bond of allylic alcohol through a cross-coupling reaction and led to the formation of (alkyl)naphthalenes. This cascade cross-coupling reaction represents a direct and atom economic method for the construction of functionalized naphthalene derivatives in moderate to good yields.

Copper-catalyzed regiodivergent 1,4- and 1,6-conjugate silyl addition to diendioates: access to functionalized allylsilanes.

A copper-catalyzed regioselective 1,4- and 1,6-conjugate addition of a silyl reagent to diendioates was established. Various 1,4- and 1,6-protosilylation products were obtained in good yields and with high regioselectivity via tuning the ligands used in the reactions. This protocol has provided a simple and efficient method for the synthesis of multisubstituted functionalized allylsilanes.

De novo MET amplification promotes intrinsic resistance to first-generation EGFR tyrosine kinase inhibitors.

First-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) could induce dramatic tumor responses in non-small-cell lung cancer patients with EGFR-activating mutations. However, a small proportion of patients have no tumor response on initial EGFR TKI treatment with an activating EGFR mutation and the primary resistance mechanism is not well understood. Here, we report the patient with primary dual MET/EGFR mutation treated with icotinib shows a disease progression, but the chest computed tomography shows the mass has significantly shrunk after 3 weeks of single-agent crizotinib. These suggest that de novo MET amplification could be a potential mechanism of intrinsic resistance to first-generation EGFR TKI.

Characteristics of cardiopulmonary exercise testing of patients with borderline mean pulmonary artery pressure.

BACKGROUND: Pulmonary hypertension patients with mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg had impaired cardiopulmonary exercise testing (CPET). Borderline mean pulmonary pressures (boPAP; 21-24 mm Hg) represent early pulmonary vasculopathy. The CPET characteristics of boPAP are a matter of discussion. We aimed to determine the CPET profile of such borderline hemodynamics. METHODS: A matched case-control study was conducted on consecutive boPAP patients at the Shanghai Pulmonary Hospital between Jan 2012 and Jan 2017. Hemodynamics, echocardiography, the pulmonary function test (PFT) and CPET parameters were compared between boPAP patients and normal mPAP patients which were matched 1:1 by sex and age. Conditional logistic regression analysis was performed to determine the efficacy of CPET in detecting boPAP. RESULTS: A total of 48 patients underwent RHC and CPET (24 Normal, 24 boPAP). There were no differences in the demographics, echocardiography and PFT. BoPAP patients had significantly decreased VO2 at the anaerobic threshold and peak VO2 /kg (858.4 ± 246.5 mL/min vs 727.9 ± 228.0 mL/min, P = 0.037; 21.1 ± 6.4 mL/min/kg vs. 15.5 ± 5.6 mL/min/kg, P = 0.001, respectively). Significant differences were not observed in ventilation efficiency. A trend of impaired oxygen pulse and submaximal exercise tolerance were observed in boPAP patients. Conditional logistical regression analysis revealed the risk of boPAP increased by 2.493 (95% confident interval: 1.388 to 4.476, P = 0.002) with every 5 mL/min/kg decrease in peak VO2 /kg. CONCLUSIONS: Patients with boPAP have a greater prevalence of exercise intolerance, a trend of impaired oxygen pulse and submaximal exercise tolerance.

Highly Substituted Benzophenone Aldehydes and Eremophilane Derivatives from the Deep-Sea Derived Fungus Phomopsis lithocarpus FS508.

Five new benzophenone derivatives named tenellones D⁻H (1⁻5), sharing a rare naturally occurring aldehyde functionality in this family, and a new eremophilane derivative named lithocarin A (7), together with two known compounds (6 and 8), were isolated from the deep marine sediment-derived fungus Phomopsis lithocarpus FS508. All of the structures for these new compounds were fully characterized and established on the basis of extensive spectroscopic interpretation and X-ray crystallographic analysis. Compound 5 exhibited cytotoxic activity against HepG-2 and A549 cell lines with IC50 values of 16.0 and 17.6 µM, respectively.

Palladium-catalyzed silaborative carbocyclizations of 1,6-diynes.

An addition/cyclization reaction of 1,6-diynes was developed for the synthesis of highly substituted 1,2-dialkylidenecycloalkanes. In this work, 1,6-diynes reacted with (dimethylphenylsilyl)pinacol-borane in the presence of a palladium catalyst to afford 1,2-dialkylidenecycloalkanes bearing silyl and boryl groups with a (Z,Z)-configuration in good to excellent yields. Moreover, the corresponding products could be easily converted into other synthetically useful compounds. This protocol provides an efficient and practical method of heteroelement-element linkage addition to the unsaturated 1,6-diynes.

Hypoxia promotes mitochondrial glutamine metabolism through HIF1α-GDH pathway in human lung cancer cells.

Drug-resistance is common in human lung cancer therapy. Hypoxia remarkably contributes to drug-resistance in lung cancer but the underlying mechanism remains elusive. Here we demonstrate that hypoxia-induced glutamine metabolism is involved in drug resistance in lung cancer cells. Hypoxia increases glutamine up-take, glutamate to α-ketoglutarate flux and the generation of ATP in lung cancer cells by up-regulating the expression of glutamate dehydrogenase (GDH). Hypoxia-induced expression of GDH relies on the up-regulation of HIF1α but not HIF2α. HIF1α binds the promoter of GDH and promotes the transcription of GDH gene in lung cancer cells. Finally, we show that GDH represses cisplatin-induced cell apoptosis and repression of colony formation, indicating that GDH contributes to drug-resistance in lung cancer cells. In conclusion, HIF1α-GDH pathway regulates glutamine metabolism and ATP production upon hypoxia stress and contributes to drug-resistance in human lung cancer cells.

Elective versus therapeutic neck dissection in node-negative oral cancer: Evidence from five randomized controlled trials.

The aim of this study was to compare the outcomes of elective neck dissection (END) with that of a more conservative approach comprising of observation plus therapeutic neck dissection for nodal relapse (OBS), by conducting a meta-analysis of randomized controlled trials (RCTs) that compare these two surgical approaches in patients. RCTs conducted prior to May 2015 were identified from electronic databases such as MEDLINE EMBASE and Cochrane Library. Reference lists within the retrieved articles were used as secondary reference sources. Disease-free survival (DFS) and overall survival (OS) were the primary outcome measures. Five RCTs with a combined subject population of 779 patients were included. Meta-analysis of these 5 RCTs showed that DFS in END group was higher than that in the OBS group with a significant inter-group difference (Risk Ratio [RR]:1.33; 95% Confidence Interval [CI] 1.06, 1.66); P=0.01; five trials, 779 participants]. However, there was a significant statistical heterogeneity among the studies (I-squared=56%, P=0.06). Four studies had reported on OS. Meta-analysis of these 4 RCTs revealed a higher OS in the END group as compared to that that in the OBS group with a significant inter-group difference (RR: 1.18; 95% CI 1.07, 1.29); P=0.0009; four trials, 708 participants]. The statistical heterogeneity of these 4 studies is small (I-squared=14%, P=0.32). The results of this meta-analysis suggest that END at the time of resection of the primary tumor confers a DFS and OS benefit in patients with clinically node-negative oral cancer.

The Harmonic Scalpel versus Conventional Hemostasis for Neck Dissection: A Meta-Analysis of the Randomized Controlled Trials.

OBJECTIVE: Neck dissection is the most definitive and effective treatment for head and neck cancer. This systematic review aims to compare the efficacy and surgical outcomes of neck dissection between the harmonic scalpel and conventional surgical techniques and conduct a quantitative meta-analysis of the randomized trials. METHODS: Randomized controlled trials (RCTs) were identified from the major electronic databases (MEDLINE, EMBASE and Cochrane Library) using the keywords ''harmonic scalpel'' and ''neck dissection,'' and a quantitative meta-analysis was conducted. The operative time and intraoperative bleeding were the primary outcome measures, and other parameters assessed included the drainage fluid volume and length of hospital stay. RESULTS: Seven trials that met the inclusion criteria included 406 neck dissection cases (201 in the harmonic scalpel group). Compared with conventional surgical techniques, the HS group had an operative time that was significantly reduced by 29.3 minutes [mean difference: -29.29; 95% CI = (-44.26, -14.32); P=0.0001], a reduction in intraoperative bleeding by 141.1 milliliters [mean difference: -141.13; 95% CI = (-314.99, 32.73); P=0.11], and a reduction in drainage fluid volume by 64.9 milliliters [mean difference: -64.86; 95% CI = (-110.40, -19.32); P=0.005] , but it is not significant after removal of studies driving heterogeneity. There was no significant difference in the length of the hospital stay [mean difference: -0.21; 95% CI = (-0.48, 0.07); P=0.14]. CONCLUSION: This systematic review showed that using the harmonic scalpel for neck dissection significantly reduces the operative time and drainage fluid volume and that it is not associated with an increased length of hospital stay or perioperative complications. Therefore, the harmonic scalpel method is safe and effective for neck dissection. However, the statistical heterogeneity was high. Further studies are required to substantiate our findings.