Microbiota modulate Doxorubicin induced cardiotoxicity.

Chemotherapy has several adverse effects to patients, some of which are life-threatening. We hypothesized that Doxorubicin induced microbiome imbalance and intestinal damage may contribute to Doxorubicin induced cardiac dysfunction. Male adult (2-3 months) C57BL/6 mice were administered 3 mg/kg, 5 mg/kg, 7.5 mg/kg,15 mg/kg, 20 mg/kg doses of Doxorubicin. Echocardiography was performed at 7 and 14 days after Doxorubicin administration. 16S rRNA amplicon sequencing was used to characterize microbiome changes. Fecal microbiota transplantation (FMT) was performed to evaluate the role of the microbiota on Doxorubicin induced cardiac dysfunction. Doxorubicin dose dependently increases mortality rate and induces cardiac dysfunction. 5 mg/kg-Doxorubicin significantly induces decreased left ventricular ejection fraction (LVEF) and fraction shortening (FS) as well as increased cardiac fibrosis, inflammation and oxidative stress respond without increasing mortality. 5 mg/kg-Doxorubicin induces significant decreased colorectum length, increased loss of goblet cells, numbers of ulcers and infiltration of lymphocyte clusters and decreased tight junction protein ZO-1, as well as increased plasma endotoxin level measured by ELISA assay. 16S rRNA microbiota analysis shows that Doxorubicin-induced microbiota dysbiosis with decreased community richness compared with normal control mice. FMT to Doxorubicin-5 mg treated mice significantly improved cardiac function by increasing LVEF and FS as well as decreased perivascular and interstitial fibrosis; increased colorectum length, decreased the loss of goblet cells,infiltration of lymphocyte clusters,the number of ulcers and plasma endotoxin level; improved microbiota composition, function and diversity with increased abundance of Alloprevotella, Prevotellaceae_UCG-001 and Rikenellaceae_RC9_gut_group. We find that normal fecal transplantation improves cardiac function, decreases gut damage and alter microbiota composition induced by Doxorubicin. The microbiota appears to contribute to heart-gut interaction.

A "Traceless" Directing Group Enables Catalytic SN2 Glycosylation toward 1,2-cis-Glycopyranosides.

Generally applicable and stereoselective formation of 1,2-cis-glycopyranosidic linkage remains a long sought after yet unmet goal in carbohydrate chemistry. This work advances a strategy to this challenge via stereoinversion at the anomeric position of 1,2-trans glycosyl ester donors. This SN2 glycosylation is enabled under gold catalysis by an oxazole-based directing group optimally tethered to a leaving group and achieved under mild catalytic conditions, in mostly excellent yields, and with good to outstanding selectivities. The strategy is also applied to the synthesis of oligosaccharides.

Homogeneous Gold-Catalyzed Oxidation Reactions.

Homogeneous gold catalysis has experienced extraordinary development since the dawn of this millennium. Oxidative gold catalysis is a vibrant and fertile subfield and has over the years delivered a diverse array of versatile synthetic methods of exceptional value to synthetic practices. This review aims to cover this topic in a comprehensive manner. The discussions are organized by the mechanistic aspects of the metal oxidation states and further by the types of oxidants or oxidizing functional groups. Synthetic applications of oxidative gold catalysis are also discussed.

Non-Diazo C-H Insertion Approach to Cyclobutanones through Oxidative Gold Catalysis.

Cyclobutanones are synthetically versatile compounds that often require extensive effort to access. Herein, we report a facile synthesis of cyclobutanones based on the C(sp3 )-H insertion chemistry of oxidatively generated gold carbenes. Various cyclobutanones were obtained in synthetically useful yields from substrates with minimal structural prefunctionalization. This discovery reveals new synthetic utilities of gold-catalyzed oxidative transformations of alkynones.

VEGI Improves Outcomes in the Early Phase of Experimental Traumatic Brain Injury.

Excessive expression of vascular endothelial growth factor (VEGF) is a common cause of blood-brain barrier (BBB) breakdown that triggers severe complications following traumatic brain injury (TBI). It has been shown that inhibition of VEGF activities may attenuate cerebral edema in pathological conditions. Vascular endothelial growth inhibitor (VEGI; also known as TNFSF15), a cytokine produced largely by vascular endothelial cells, is capable of downregulating VEGF expression and inhibiting VEGF receptor-2 (VEGFR2) activation. In this study we found that TBI can cause breakdown of BBB and sharp increases of VEGF/VEGI and Angpt2/Angpt1 ratios in the injured tissues. VEGI treatment resulted in a marked decrease of BBB permeability and concomitant restoration of normal ratios of VEGF/VEGI and Angpt2/Angpt1. Consistently, alleviated edema, decreased neuron cell death, and improved neurological functions were observed when the experimental animals were treated with VEGI in the early phase of TBI. Our findings suggest that administration of VEGI recombinant protein at early phases of TBI is beneficial to stabilization of the disease conditions.

Multifaceted roles of pericytes in central nervous system homeostasis and disease.

Pericytes, the mural cells surrounding microcirculation, are gaining increasing attention for their roles in health and disease of the central nervous system (CNS). As an essential part of the neurovascular unit (NVU), pericytes are actively engaged in interactions with neighboring cells and work in synergy with them to maintain homeostasis of the CNS, such as maintaining the blood-brain barrier (BBB), regulating cerebral blood flow (CBF) and the glymphatic system as well as mediating immune responses. However, the dysfunction of pericytes may contribute to the progression of various pathologies. In this review, we discuss: (1) origin of pericytes and different pericyte markers; (2) interactions of pericytes with endothelial cells (ECs), astrocytes, microglia, oligodendrocytes, and neurons; (3) physiological roles of pericytes in the CNS; (4) effects of pericytes in different CNS diseases; (5) relationship of pericytes with extracellular vesicles (EVs) and microRNAs (miRs); (6) recent advances in pericytes studies and future perspective.

Gold-catalyzed synthesis of α-D-glucosides using an o-ethynylphenyl ß-D-1-thioglucoside donor.

A gold-catalyzed glucosylation method using an o-ethynylphenyl ß-D-1-thioglucoside as donor is described. The reaction proceeds in a mostly SN2 pathway. A series of α-D-glucosides are obtained in good yields and with up to 19:1 α-selectivity.

Silver-catalyzed stereoselective formation of glycosides using glycosyl ynenoates as donors.

A silver-catalyzed glycosylation reaction employing readily accessible and stable glycosyl ynenoates is developed. This reaction is mostly high yielding and exhibits varying levels of stereoinversion at the anomeric position. Compared to established and versatile Yu's gold catalysis, this chemistry features the use of substantially cheaper AgNTf2.

Electrical stimulation improved cognitive deficits associated with traumatic brain injury in rats.

Introduction: Cognitive deficits associated with traumatic brain injury (TBI) reduce patient quality of life. However, to date, there have been no effective treatments for TBI-associated cognitive deficits. In this study, we aimed to determine whether electrical stimulation (ES) improves cognitive deficits in TBI rats. Methods: Rats were randomly divided into three groups: the Sham control group, electrical stimulation group (ES group), and No electrical stimulation control group (N-ES group). Following fluid percussion injury, the rats in the ES group received ES treatment for 3 weeks. Potent cognitive function-relevant factors, including the escape latency, time percentage in the goal quadrant, and numbers of CD34+ cells, von Willebrand Factor+ (vWF +) vessels, and circulating endothelial progenitor cells (EPCs), were subsequently assessed using the Morris water maze (MWM) test, immunohistochemical staining, and flow cytometry. Results: Compared with the rats in the N-ES group, the rats in the ES group exhibited a shorter escape latency on day 3 (p = .025), day 4 (p = .011), and day 5 (p = .003), as well as a higher time percentage in the goal quadrant (p = .025) in the MWM test. After 3 weeks of ES, there were increased numbers of CD34+ cells (p = .008) and vWF + vessels (p = .000) in the hippocampus of injured brain tissue in the ES group compared with those in the N-ES group. Moreover, ES also significantly increased the number of EPCs in the peripheral blood from days 3 to 21 after TBI in the ES group (p < .05). Conclusions: Taken together, these findings suggest that ES may improve cognitive deficits induced by TBI, and this protective effect may be a result, in part, of enhanced angiogenesis, which may be attributed to the increased mobilization of EPCs in peripheral blood.

Erythropoietin regulates immune/inflammatory reaction and improves neurological function outcomes in traumatic brain injury.

Introduction: Traumatic brain injury (TBI) remains a leading cause of disability and death among young people in China. Unfortunately, no specific pharmacological agents to block the progression of secondary brain injury have been approved for clinical treatment. Recently, neuroprotective effects of erythropoietin (EPO) have been demonstrated in addition to its principal function in erythropoiesis, and hence it is viewed as a potential drug for TBI. In this study, we have investigated the neuroprotective effects of EPO associated with immune/inflammatory modulation in a mouse experimental TBI model. Methods: EPO (5000 U/kg body weight, i.p.) was injected at 1 hr, 1, 2, and 3 days after TBI, and its effect on cognitive function, brain edema, immune/inflammatory cells including regulatory T cells (Tregs), neutrophils, CD3+ T cells, and microglia, cytokines including interleukin-10 (IL-10), transforming growth factor-ß (TGF-ß), interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) were evaluated at different time points after treatment. Results: EPO treatment significantly decreased brain edema and improved cognitive function when compared to Saline-treated mice (p < .05). EPO treatment also significantly increased Tregs level in spleen and injured brain tissue as well as significantly reduced the infiltration and activation of immune/inflammatory cells (neutrophils, CD3+T cells, and microglia) in the injured hemisphere compared to Saline-treated control animals (p < .05). In addition, ELISA analysis demonstrated that EPO treatment increased the expression of anti-inflammatory cytokine IL-10, but decreased the expression of proinflammatory cytokine IL-1ß and TNF-α in the injured brain tissue (p < .05). Conclusions: These findings suggest that EPO could improve neurological and cognitive functional outcomes as well as regulate immune/inflammatory reaction in TBI.

Au-Catalysed oxidative cyclisation.

The two main strategies of gold-catalysed oxidative cyclisation are discussed in this tutorial. The first one employs nucleophilic oxidants as either internal or external nucleophiles. The inherently weak O-heteroatom bond in the oxidant enables the versatile reactivities of the initial gold-promoted adduct of the oxidant to alkyne, including its fragmentation into a highly reactive α-oxo gold carbene intermediate. The second features external oxidant-powered Au(i)/Au(iii) catalysis, where the metal oxidation state changes during the catalytic cycle. These strategies have been applied toward the development of a variety of valuable synthetic transformations.

Intramolecular Insertions into Unactivated C(sp³)-H Bonds by Oxidatively Generated ß-Diketone-α-Gold Carbenes: Synthesis of Cyclopentanones.

Generation of reactive α-oxo gold carbene intermediates via gold-catalyzed oxidation of alkynes has become an increasing versatile strategy of replacing hazardous diazo carbonyl compounds with benign and readily available alkynes in the development of efficient synthetic methods. However, one of the hallmarks of metal carbene/carbenoid chemistry, i.e., insertion into an unactivated C(sp(3))-H bond, has not be realized. This study reveals for the first time that this highly valuable transformation can be readily realized intramolecularly by oxidatively generated ß-diketone-α-gold carbenes using ynones as substrates. Substrate conformation control via the Thorpe-Ingold effect is the key design feature that enables generally good to excellent efficiencies, and synthetically versatile cyclopentanones including spiro-, bridged, and fused bicyclic ones can be readily accessed.

Enantioselective oxidative gold catalysis enabled by a designed chiral P,N-bidentate ligand.

A newly developed P,N-bidentate ligand enables enantioselective intramolecular cyclopropanation by a reactive α-oxo gold carbene intermediate generated in situ. The ligand design is based on our previously proposed structure (with a well-organized triscoordinated gold center) of the carbene intermediate in the presence of a P,N-bidentate ligand. A C2-symmetric piperidine ring was incorporated in the ligand as the nitrogen-containing moiety. A range of racemic transformations of α-oxo gold carbene intermediates have been developed recently, and this new class of chiral ligands could enable their modification for asymmetric synthesis, as demonstrated in this study.

Synthesis-enabled probing of mitosene structural space leads to improved IC50 over mitomycin C.

A DNA crosslinking approach, which is distinct but related to the double alkylation by mitomycin C, involving a novel electrophilic spiro-cyclopropane intermediate is hypothesized. Rational design and substantial structural simplification permitted the expedient chemical synthesis and rapid discovery of MTSB-6, a mitomycin C analogue which is twice as potent as mitomycin C against the prostate cancer cells. MTSB-6 shows improvements in its selective action against noncancer prostate cells over mitomycin C. This hypothesis-driven discovery opens novel yet synthetically accessible mitosene structural space for discovering more potent and less toxic therapeutic candidates.

Ruthenium-catalyzed oxidative transformations of terminal alkynes to ketenes by using tethered sulfoxides: access to ß-lactams and cyclobutanones.

The oxidation of in situ generated Ru vinylidenes to ketenes is realized with tethered sulfoxides. The result is a Ru-catalyzed oxidative transformation of terminal alkynes to highly valuable ketenes. Moreover, the ketenes generated here were shown to undergo characteristic ketene [2+2] cycloaddition reactions with tethered alkenes and external imines, yielding synthetically versatile bicyclic cyclobutanones and ß-lactams, respectively.

One-pot synthesis of fused pyrroles through a key gold-catalysis-triggered cascade.

A two-step, one-pot synthesis of fused pyrroles is realized by firstly condensing an N-alkynylhydroxammonium salt with a readily enolizable ketone under mild basic conditions and then subjecting the reaction mixture to a gold catalyst, which triggers a cascade reaction involving a facile initial [3.3]-sigmatropic rearrangement of the gold-catalysis product, that is, an N,O-dialkenylhydroxamine. The reaction provides a facile access to polycyclic pyrroles in moderate to good yields.

Synthesis of pinacol arylboronates from aromatic amines: a metal-free transformation.

A metal-free borylation process based on Sandmeyer-type transformation using arylamines derivatives as the substrates has been developed. Through optimization of the reaction conditions, this novel conversion can be successfully applied to a wide range of aromatic amines, affording borylation products in moderate to good yields. Various functionalized arylboronates, which are difficult to access by other methods, can be easily obtained with this metal-free transformation. Moreover, this transformation can be followed by Suzuki-Miyaura cross-coupling without purification of the borylation products, which enhances the practical usefulness of this method. A possible reaction mechanism involving radical species has been proposed.

Gold(III)-catalyzed direct acetoxylation of arenes with iodobenzene diacetate.

AuCl(3)-catalyzed direct acetoxylation of electron-rich aromatic compounds has been achieved with iodobenzene diacetate as the acetoxylation reagent.

New developments in aromatic halogenation, borylation, and cyanation.

Several green procedures have been developed for synthesizing functionalized aromatics: i) AuCl(3)-catalyzed halogenation of aromatic compounds, including aryl boronates; ii) Fe(2)O(3)-catalyzed direct aromatic C-H bond borylation; iii) Pd-catalyzed direct cyanation of indoles; iv) direct conversion of arylamines to pinacol boronates.