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We report the efficient syntheses of chiral tetrahydroindole pyrazolinones by the asymmetric [3 + 2] cascade cyclizations (indolizations) of simple aniline derivatives with pyrazolinone ketimines as 2C synthons. The chiral phosphoric-acid-catalyzed system uses a concerted π-π interaction/dual H-bond control strategy to catalytically direct the asymmetric aniline, which undergoes a highly chemo-, regio-, and enantioselective [3 + 2] cascade annulation, furnishing a series of optically active tetra-hydroindole pyrazolinones with two contiguous chiral aza-quaternary carbon centers in excellent yields with excellent enantioselectivities. This method features a relatively broad substrate scope for amines and 2-naphthylamines and highlights the emerging value of direct chiral indolizations from simple amine sources in organic synthesis.

In this contribution, we thoroughly investigated the ring-opening alternating copolymerization (ROAC) of cyclic anhydride and epoxide by using commercially available alkali metal carboxylates (AMCs...

Macrophages play an important role in the immune microenvironment during bone healing, and sequential macrophage phenotypic transition could achieve superior osteogenic outcomes. Microcrystalline bioactive glasses (MCBGs) with osteoimmunomodulatory effects show potential in bone tissue regeneration. Zinc (Zn) has been approved to coordinate innate and adaptive immunity. Therefore, in this study, different amounts of ZnO were incorporated into microcrystalline bioactive glass to improve its immunomodulatory ability. The effect of Zn-MCBG ionic extracts on macrophage transition was studied, and the 5Zn-MCBG extracts could orchestrate sequential M1-to-M2 macrophage transition and promote the expression of proinflammatory and anti-inflammatory genes and cytokine expression to induce human bone marrow stromal cells (hBMSCs) osteogenic differentiation in vitro. Macroporous Zn-MCBG scaffolds containing mesopores were fabricated and showed good cell adhesion and feasible apatite formation when immersed in SBF in vitro. Furthermore, a rat calvarial defect model was used to confirm that the Zn-MCBG scaffold could modulate macrophage phenotypic transition and create a desirable osteogenic microenvironment to promote osteogenesis in vivo.

A cobalt-catalyzed regio- and enantioselective γ-amination of β,γ-unsaturated N-acylpyrazoles that delivers the corresponding γ-amination products in good regio- and enantioselectivity has been established. Moreover, the nitrogen-containing compounds could be easily synthesized. DFT calculations have been provided to explain regio- and enantioselectivity for this γ-amination. The chiral γ-amination products were readily converted into the chiral γ-amino acid derivatives.

Infections are the leading cause of failure of osteogenic material implantation. Antibiotic treatment, treatment with bone cement, or collagen sponge placement can result in drug resistance and difficulties in operation. To address this, gellan gum (GG) was selected in this study and prepared as an injectable hydrogel containing chlorhexidine (CHX) and nanohydroxyapatite (nHA) that overcomes these intractable problems. Scanning electron microscopy and micro-computed tomography revealed a three-dimensional polymeric network of the hydrogel. The hydrogel had excellent biocompatibility, as detected by cell counting kit-8 and Live/Dead assay. Bone marrow mesenchymal stem cells could be encapsulated into the network, showing that the structure was suitable for cell growth. Additionally, loading the hydrogel with nHA improved its mechanical, biodegradable, and osteogenic properties. Quantitative alkaline phosphatase and Alizarin Red S staining validated its osteogenic ability. Furthermore, antibacterial activity assessment showed that the hydrogel loaded with 50 μg/mL CHX inhibited Enterococcus faecalis in a concentration-dependent manner. Thus, we report an injectable GG-based hydrogel with superior antibacterial effect against E. faecalis and osteogenesis, which holds promise for treating infectious bone defects caused by refractory periradicular periodontitis.

Huntington’s disease (HD) is one of main neurodegenerative diseases, characterized by striatal atrophy, involuntary movements, and motor incoordination. Ginsenoside Rg1 (Rg1), an active ingredient in ginseng, possesses a variety of neuroprotective effects with low toxicity and side effects. In this study, we investigated the potential therapeutic effects of Rg1 in a mouse model of HD and explored the underlying mechanisms. HD was induced in mice by injection of 3-nitropropionic acid (3-NP, i.p.) for 4 days. From the first day of 3-NP injection, the mice were administered Rg1 (10, 20, 40 mg·kg −1 , p.o .) for 5 days. We showed that oral pretreatment with Rg1 alleviated 3-NP-induced body weight loss and behavioral defects. Furthermore, pretreatment with Rg1 ameliorated 3-NP- induced neuronal loss and ultrastructural morphological damage in the striatum. Moreover, pretreatment with Rg1 reduced 3-NP- induced apoptosis and inhibited the activation of microglia, inflammatory mediators in the striatum. We revealed that Rg1 exerted neuroprotective effects by suppressing 3-NP-induced activation of the MAPKs and NF-κΒ signaling pathways in the striatum. Thus, our results suggest that Rg1 exerts therapeutic effects on 3-NP-induced HD mouse model via suppressing MAPKs and NF-κΒ signaling pathways. Rg1 may be served as a novel therapeutic option for HD.

From an aqueous extract of “tian ma” (the steamed and dried rhizomes of Gastrodia elata), ten new compounds gastrodibenzins A−D (1−4) and gastrotribenzins A−F (5−10), along with known analogues (11−20), having structure features coupling between two and three p-hydroxybenzyl-derived units via carbon- and/or ether-bonds, were isolated and characterized by spectroscopic data analysis. Meanwhile, the new compounds 5a, 6a, 8a, 22, and 23, as well as the known derivatives 13a, 14a, 15, 17−21, 24, 25, and p-hydroxybenzyl aldehyde were isolated and identified from a refluxed aqueous solution of p-hydroxybenzyl alcohol. Methylation of 5a and 6a in methanol and ethylation of 6a, 8a, 13a, and 14a in ethanol produced 5 and 6 and 7, 8, 13, and 14, respectively. using ultra-performance liquid chromatography high-resolution electrospray ionization mass spectrometry (UPLC-HRESIMS) analysis of the refluxed solutions of p-hydroxybenzyl alcohol and the refluxed extracts of the fresh G. elata rhizome and “tian ma” extracts indicated consistent production and variation of the dimeric and trimeric derivatives of p-hydroxybenzyl alcohol upon extracting solvents and refluxing time. In various assays, the dimeric and trimeric derivatives showed more potent activities than p-hydroxybenzyl alcohol itself and gastrodin, which are the main known active constituents of “tian ma”. These results revealed for the first time that the more effective dimers and trimers can be produced through condensation of the co-occurring p-hydroxybenzyl alcohol during processing and decocting of the G. elata rhizomes, demonstrating insights into medicinal chemistry behind application protocols of traditional Chinese medicines. Graphic Abstract

Ruthenium(II)-catalyzed ortho-C-H alkylation of naphthylamines with diazo compounds for the synthesis of 2,2-disubstituted π-extended 3-oxindoles has been developed. The method represents the first example of C-H alkylation via carbenoid insertion in water as a sustainable solvent. The procedure includes an inexpensive ruthenium catalyst as well as aqueous media and results in the release of benign N2. The π-extended 3-oxindole products exhibit favorable antitumor properties and remarkable fluorescent properties in aqueous solution for fluorescent imaging.

The critical role of mitochondrial dysfunction in the pathological mechanisms of neurodegenerative disorders, particularly Parkinson's disease (PD), is well established. Compelling evidence indicates that Parkinson's proteins (e.g., α-synuclein, Parkin, PINK1, DJ-1, and LRRK2) are associated with mitochondrial dysfunction and oxidative stress in PD. Significantly, there is a possible central role of alpha-synuclein (α-Syn) in the occurrence of mitochondrial dysfunction and oxidative stress by the mediation of different signaling pathways. Also, tau, traditionally considered as the main component of neurofibrillary tangles, aggregates and amplifies the neurotoxic effects on mitochondria by interacting with α-Syn. Moreover, oxidative stress caused by mitochondrial dysfunction favors assembly of both α-Syn and tau and also plays a key role in the formation of protein aggregates. In this review, we provide an overview of the relationship between these two pathological proteins and mitochondrial dysfunction in PD, and also summarize the underlying mechanisms in the interplay of α-Syn aggregation and phosphorylated tau targeting the mitochondria, to find new strategies to prevent PD processing.

Objective To explore the ultrastructure characteristics of patients with dampness-heat of Pi (Spleen)-Wei (Stomach) syndrome (DHPW) and Pi-qi deficiency syndrome (PQD), both of which are Helicobacter pylori (Hp)-correlated gastric diseases (HPCG), and implicate a helpful hint for the clinical microcosmic syndrome differentiation. Methods Fourteen gastric mucosa samples from 6 chronic gastritis (CG) and 6 active peptic ulcer (including 8 DHPW, 4 PQD) as well as 2 healthy volunteers were collected and tested for Hp infection. The ultrastructure of gastric mucosa was observed under the transmission electron microscope (TEM). Results Among 14 gastric mucosa samples, 8 of them were Hp positive (6 DHPW and 2 PQD), which were all accordance with the results screened by supermicro-pathological method. Under TEM, the normal gastric mucosa, with tidy microvilli and abundant in mucus granules, mitochondria and rough endoplasmic reticulum distributed evenly, and with smooth nucleus membrane. But in those specimens of DHPW with Hp infection, microvilli were presented with burr shape. Especially, those samples from dampness-heat syndrome with predominant heat type (DHSH) patients were more obvious, with microvilli damaged, mitochondria concentrated and distributed in disorder, secretory tubule extended. In dampness-heat syndrome with predominant dampness type (DHSD) patients, mucus granules aggregated obviously, mitochondria swelled and blurred, and rough endoplasmic reticulum crowded. For 2 samples of DHPW without Hp infection, their microvilli were intact, with mitochondria increased and gathered but well-distributed, and secretory tubule extended mildly. In 2 PQD patients with Hp positive, the specimens of microvilli were sparse, and their mucus granules and mitochondria were decreased, with fractured crests and vacuole, secretory tubules extension to nucleus membrane, and rough endoplasmic reticulum extension in a pool-like way, and nucleus condensed. The 2 samples from PQD patients without Hp infection were characterized with intact microvilli, decreased mitochondria, fractured crest and extended rough endoplasmic reticulum in a pool-like way. Conclusion It's obviously different in ultrastructure of DHPW and PQD patients under TEM, which may give a helpful hint for the microcosmic syndrome differentiation of HPCG.

Parkinson’s disease (PD) is a multifactorial disorder characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies (LBs) consisting of misfolded α-synuclein protein. The etiology of PD is still not clear but systemic inflammation is proved to trigger and exacerbate DA neurons degeneration. Toll-like receptor 4 (TLR4) is a pattern-recognition receptor (PRR) and plays a major role in promoting the host immune. TLR4-mediated signal pathways induce the release of many inflammatory cytokines. It is reasonable to hypothesize that TLR4 is the mediator in microglia contributing to the damage of DA neurons in the SNpc. In this study, we evaluated the role of TLR4 in the chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/probenecid mouse model. Both TLR4-deficient and wild-type (WT) mice were injected with probenecid (250 mg/kg, i.p.) followed by injection of MPTP (25 mg/kg, s.c.) every 4 days for 10 times. From D43 to D47, the behavioral performance in pole test and wire hang test was assessed. Then the mice were euthanized, and SN and striatum were dissected out for biochemical tests. We showed that compared with MPTP-treated WT mice, TLR4 deficiency significantly attenuated MPTP-induced motor deficits and TH-protein expression reduction in SNpc and striatum, suppressed MPTP-induced α-synuclein abnormality and neuroinflammation mediated through oxidative stress, glial activation, NF-κB and the NLRP3 inflammasome signaling pathways. These findings highlight the neuroprotective effect of TLR4-pathways in the chronic MPTP-induced PD mouse model.

Nonbiaryl N-C atropisomer is an important structural scaffold, which is present in natural products, medicines and chiral ligands. However the direct enantioselective C-H amination to access optically pure N-C atropisomer is still difficult and rare. Here we report a π-π interaction and dual H-bond concerted control strategy to develop the chiral phosphoric acids (CPAs) catalyzed direct intermolecular enantioselective C-H amination of N-aryl-2-naphthylamines with azodicarboxylates as amino sources for the construction of atroposelective naphthalene-1,2-diamines. This type of N-C atropisomers is stabilized by intramolecular hydrogen bond and the method features a broad range of substrates, high yields and ee values, providing a strategy to chirality transfer via the modification of N-C atropisomers., Atropisomers with a chiral C-N axis are useful for natural products synthesis and as ligands in asymmetric catalysis. Here, the authors reportt a π-π interaction and dual H-bond concerted control strategy in enantioselective C-H amination affording configurationally stable N-C atropisomers.

A simple and efficient protocol for para-selective C–H amination of 1-naphthylamide derivatives under silver catalysis is described. This reaction system could proceed without the help of directing group and a broad range of substrates were proved to be well tolerated. In addition, control experiments suggested that this reaction might not proceed via a single-electron-transfer process.

A kind of annular uranium nitride (UN) fuel suitable for lead-cooled fast reactor applications has been designed in this study. The design is directly targeting two main issues of UN fuel: severe swelling and thermal decomposition of UN fuel at high temperatures. A performance analysis program based on FORTRAN programming language has been developed for UN fuel in fast reactors. The program contains heat transfer, fuel stress-strain analysis, cladding stress-strain analysis, fission gas release and fuel-cladding mechanical interaction (FCMI) modules, etc. Extensive code verification has been performed by comparing simulation results obtained with the code and those obtained via the COMSOL Multiphysics platform. Preliminary code validation has been conducted as well by comparing code simulation results with experimental data. The results showed that this program could predict the fuel temperature, stress-strain, and displacement of UN fuel during reactor operation with a reasonable accuracy.

Diversiform ways of intercellular communication are vital links in maintaining homeostasis and disseminating physiological states. Among intercellular bridges, tunneling nanotubes (TNTs) discovered in 2004 were recognized as potential pharmacology targets related to the pathogenesis of common or infrequent neurodegenerative disorders. The neurotoxic aggregates in neurodegenerative diseases including scrapie prion protein (PrPSc), mutant tau protein, amyloid-beta (Aβ) protein, alpha-synuclein (α-syn) as well as mutant Huntington (mHTT) protein could promote TNT formation via certain physiological mechanisms, in turn, mediating the intercellular transmission of neurotoxicity. In this review, we described in detail the skeleton, the formation, the physicochemical properties, and the functions of TNTs, while paying particular attention to the key role of TNTs in the transport of pathological proteins during neurodegeneration.

Current treatments for Parkinson's disease (PD) are mainly dopaminergic drugs. However, dopaminergic drugs are only symptomatic treatments and limited by several side effects. Recent studies into drug development focused on emerging new molecular mechanisms, including nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, nuclear receptor-related 1 (Nurr1), adenosine receptor A2, nicotine receptor, metabotropic glutamate receptors (mGluRs), and glucocerebrosidase (GCase). Also, immunotherapy and common pathological mechanisms shared with Alzheimer's Disease (AD) and diabetes have attracted much attention. In this review, we summarized the development of preclinical and clinical studies of novel drugs and the improvement of dopaminergic drugs to provide a prospect for PD treatment.

The Chinese tree shrew (TS) has many unique advantages that make it suitable for use as an experimental animal model for human disease including moderate body size, low cost of feeding, short reproductive cycle and lifespan, and close phylogenetic relationship to primates. Our previous studies have shown that TS treated with the mitochondrial inhibitor MPTP displayed classic Parkinsonian symptoms. Additionally, the structure of TS alpha-synuclein (α-syn) is highly homologous to that found in humans. Previous studies have concluded that misfolded, fibrillar α-syn is a hallmark of α-synucleinopathies. In this study, we examined the distribution and expression levels of α-syn in different TS brain regions. We also obtained recombinant TS α-syn protein to study its aggregation and cytotoxic properties in primary neurons. Our results showed that α-syn was expressed in numerous different brain regions in TS but was most abundant in the hippocampus and midbrain. The recombinant α-syn of TS displayed straight fibrils when incubated for 72 h in vitro, which is very similar to human α-syn. When exposed to primary neurons, the TS and human α-syn fibrils led to cytotoxicity and Lewy-like pathology. Our findings indicated that TS could be a potential animal model to study the pathology of α-synucleinopathies.

Poly(ester-b-ether)s, a kind of meaningful and potentially bio-based block copolymer, are typically synthesized via ring-opening polymerization (ROP) of cyclic esters initiated by the pre-prepared polyether macroinitiator. However, a multi-step procedure is required in this traditional method. Herein, we detailed a one-step selective copolymerization process of mixed monomers to precisely prepare poly(ester-b-ether) block copolymers, which could minimize the additional catalytic processes and organic reagents of the multi-step procedure. The strategy enables ring-opening alternating copolymerization (ROAC) of anhydrides with epoxides and ROP of epoxides sequentially in a closed system. Organic Lewis pairs were utilized to catalyze the selective copolymerization and were easily removed from the reaction system which avoided the metal residues in the copolymers. Regioselective and living copolymerization is realized by using cooperative organocatalysts, yielding the poly(ester-b-ether) with a controlled monomer sequence, high isotacticity and predictable molecular weight (MW). The optimized organocatalysis exhibits broad monomer adaptability and allows fabricating structurally diverse poly(ester-b-ether)s. Epimerization was suppressed even when tricyclic and bicyclic anhydrides were used, which enables the synthesis of stereoregular block copolymers. Significantly, well-defined block copolymers based on renewable succinic anhydride were achieved. A tandem copolymerization is also performed by using lactide as an external trigger which could switch the selective copolymerization to lactide polymerization. The study provides a new route to the facile synthesis of poly(ester-b-ether) block copolymers using a metal-free catalytic system.

Parkinson's disease (PD) is a multi-factorial neurodegenerative disease. Abnormal α-synuclein protein aggregate and sustained microglia activation contribute to the pathogenic processes of PD. However, the relationship between α-synuclein and microglia-mediated neuroinflammation remains unclear. We purified α-synuclein after overexpression in Escherichia coli and then used it to stimulate BV-2 cells or primary microglia cells from wild type or toll-like receptor 4 (TLR4)-defective mice. Enzyme linked immunosorbent assay (ELISA) and real-time PCR results confirmed that α-synuclein could enhance the production of tumor necrosis factor α (TNF-α) through TLR4 activation. Western blotting results confirmed the involvement of the TLR4/PI3K/AKT/GSK3β signal pathway in the inflammatory response. Nuclear factor kappa B (NF-κB) could translocate to the nucleus, promoting the expression of TNF-α when stimulated by α-synuclein in BV-2 cells. Nurr1 suppressed the production of TNF-α via interaction with NF-κB/p65 and inhibiting its nuclear translocation. In addition, both NF-κB and Nurr1 appeared to be regulated by the TLR4-mediated signal pathway. Our work demonstrated that TLR4 recognized α-synuclein and activated downstream signaling mechanisms leading to the release of pro-inflammatory mediators that are contra-balanced by Nurr1 expression. In conclusion, Nurr1 is a novel participant in the neuroinflammation stimulated by α-synuclein, thus the regulation of Nurr1 may be a novel neuroprotective target for PD treatment.

A one-step procedure for the self-switchable block copolymerization of monomer mixtures of epoxides, cyclic anhydrides, and lactide (LA) was developed by using simple organocatalysts without an external stimulus. This multicomponent polymerization bridges two catalytic cycles involving ring-opening alternating copolymerization of epoxides with anhydrides and ring-opening polymerization (ROP) of LA, in which the presence/absence of anhydrides in mixed feedstocks switched the ROP of LA off/on. The self-switchable terpolymerization showed distinct noncoordinating and living nature, as well as perfect chemoselectivity. Different combinations of epoxides, anhydrides, and initiators enabled the generation of a variety of new block polyester polyols.

In general, enantioselective C-H functionalization of N-monosubstituted anilines is a highly challenging task owing to the competitive chemoselective N-H bond insertion reactions. In this paper, we reported a direct highly chemo-, site-, and enantioselective para C-H aminoalkylation of N-monosubstituted aniline derivatives with isatin-derived ketimines in the presence of chiral phosphoric acids (CPAs) and offered a practical strategy for para asymmetric C-H functionalization of anilines containing N-H bonds.

A simple and highly active catalytic process for ring-opening alternating copolymerization (ROAC) of cyclic anhydrides and epoxides still remains a key challenge. Herein, we have described an effective group of versatile and low-toxic zinc dicarbyl/amine Lewis pairs for the ROAC. The facile route showed a high catalytic activity (TOF ≤ 210 h−1 at 110 °C) and perfectly alternating selectivity (>99%). An unexpected highly regioselective ring-opening of asymmetric epoxides (PO, ECH and SO) was also achieved by the combination of zinc alkyls (or aryls) and amines. Of note, deprotonation side reaction of α-H of anhydrides with organic bases was uncovered, and subsequently was inhibited by using nonpolar solvents and Lewis acid/base pairs. Thus, an array of polyesters was synthesized by the coupling of various anhydrides (PA, CHA, SA and NA) and epoxides (CHO, PO, ECH and SO) using the same Lewis pairs. Furthermore, variable temperature 1H NMR spectral and MALDI TOF MS analyses were performed to understand the possible mechanism and microstructure. The experimental results indicated that zwitterionic alkoxide and carboxylate intermediates alternately formed to enhance the ester repeat units in chain initiation and propagation. This work provides a simple and green catalytic strategy to prepare diversified polyesters from the ROAC process of cyclic anhydrides and epoxides with considerable catalytic activity and alternating selectivity.

A metal-free, highly regioselective and stereoregular ring-opening alternating copolymerization (ROAC) of monosubstituted epoxides with tricyclic anhydrides remains a challenge in the advancement of polyester synthesis. Herein, we described an effective group of organic dual catalysts for the ROAC, exhibiting a high catalytic activity (the highest TOF = 330 h−1 at 110 °C), narrow polydispersity (PDI 99%) in a controlled manner. The ROAC of a variety of monosubstituted epoxides and tricyclic anhydrides was carried out under mild conditions. Of importance is the fact that highly regioselective insertion of epoxides has been realized by simple and metal-free catalysts in the ROAC, where the highest regioselectivity is up to 98% for aliphatic epoxides and glycidyl ethers at 80 °C. Styrene oxide bearing electron-withdrawing phenyl also showed a good regioselectivity of 78%. Besides, the complete suppression of epimerization and transesterification was achieved even at high conversion for a variety of tricyclic anhydrides. Furthermore, block and gradient copolymers were synthesized by the sequential addition strategy and one-pot terpolymerization. Accordingly, a green, regioselective and stereoregular fabrication of functional polyesters was realized for the first time by a metal-free process.

Parkinson's disease (PD) is the prevalent neurodegenerative disorder characterized by the degeneration of the nigrostriatal neurons. Dynamin-related protein 1 (Drp1) is a key regulator mediating mitochondrial fission and affecting mitophagy in neurons. It has been reported that the inhibition of Drp1 may be beneficial to PD. However, the role of Drp1 and mitophagy in PD remains elusive. Therefore, in this research, we investigated the role of Drp1 and the underlying mechanisms in the mice model of PD. We used the dynasore, a GTPase inhibitor, to inhibit the expression of Drp1. We found that inhibition of Drp1 could ameliorate the motor deficits and the expression of tyrosine hydroxylase in the mice of the PD model. But Drp1 inhibition did not affect mitochondria number and morphological parameters. Moreover, suppression of Drp1 up-regulated the mitochondrial expressions of PINK1 and Parkin while not affected the expressions of NIX and BNIP3. Conclusively, our findings suggest that the inhibition of Drp1 ameliorated the mitochondrial ultrastructure at least via regulating PINK1 and Parkin in the mice of the PD model. This study also implicates that inhibition of Drp1 might impact mitophagy and recover mitochondrial homeostasis in PD.

The novel bibenzyl compound 2-[4-hydroxy-3-(4- hydroxyphenyl) benzyl]-4-(4- hydroxyphenyl) phenol (20C) plays a neuroprotective role in vitro, but its effects in vivo have not yet been elucidated. In this study, we estimated the efficacy of 20C in vivo using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/p) mouse model from behavior, dopamine, and neuron and then the possible mechanisms for these effects were further investigated. The experimental results showed that 20C improved behavioral deficits, attenuated dopamine depletion, reduced dopaminergic neuron loss, protected the blood-brain barrier (BBB) structure, ameliorated α-synuclein dysfunction, suppressed glial activation, and regulated both nuclear factor-κB (NF-κB) signaling and the NOD-like receptor protein (NLRP) 3 inflammasome pathway. Our results indicated that 20C may prevent neurodegeneration in the MPTP/p mouse model by targeting α-synuclein and regulating α-synuclein-related inflammatory responses, including BBB damage, glial activation, NF-κB signaling, and the NLRP3 inflammasome pathway.

SiC foam ceramic reinforced aluminum matrix composites (SFCAMCs) were prepared by squeeze casting aluminum alloy (Al–23Si) into the SiC foam ceramic with different pore sizes, and the corrosion behavior of the SFCAMCs was studied in NaCl solutions. Static immersion corrosion tests were conducted at 20 °C, 50 °C and 80 °C, respectively. Corrosion morphology and products were analyzed by scanning electron microscope, energy dispersive system and X-ray diffraction. It was found that the corrosion rate of SFCAMCs increases as the temperature rising, and the bigger pore size of SiC foam ceramic reinforcement, the better corrosion resistance of SFCAMCs.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model remains the most commonly used animal model of Parkinson's disease (PD). There are three MPTP-treatment schemes: acute, subacute and chronic. Considering the advantages of the period and similarity to PD, the subacute model was often chosen to assess the validity of new candidates, but the changes caused by the subacute MPTP treatment and the appropriate positive control for this model remain to be further confirmed. The aim of this study was: to estimate the value of the subacute MPTP mouse model in aspects of behavioral performance, biochemical changes and pathological abnormalities, and to find effective positive drugs. Male C57BL/6 mice were injected with MPTP (30 mg·kg−1·d−1, ip) for 5 consecutive days. Three days before MPTP injection, the mice were orally administered selegiline (3 mg·kg−1·d−1), pramipexole (3 mg·kg−1·d−1), or medopar (100 mg·kg−1·d−1) for 18 days. Behavioral performance was assessed in the open field test, pole test and rotarod test. Neurotransmitters in the striatum were detected using HPLC. Protein levels were measured by Western blot. Pathological characteristics were examined by immunohistochemistry. Ultrastructure changes were observed by electron microscopy. The subacute MPTP treatment did not induce evident motor defects despite severe injuries in the dopaminergic system. Additionally, MPTP significantly increased the α-synuclein levels and the number of astrocytes in the striatum, and destroyed the blood-brain barrier (BBB) in the substantia nigra pars compacta. Both selegiline and pramipexole were able to protect the mice against MPTP injuries. We conclude that the subacute MPTP mouse model does not show visible motor defects; it is not enough to evaluate the validity of a candidate just based on behavioral examination, much attention should also be paid to the alterations in neurotransmitters, astrocytes, α-synuclein and the BBB. In addition, selegiline or pramipexole is a better choice than medopar as an effective positive control for the subacute MPTP model.

Objectives Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe complication of systemic nitrogen-containing bisphosphonate (N-BP) administration, which leads to osteonecrosis, pain, and infection. Despite much effort, effective remedies are yet to be established. This study aimed to investigate potential recovery effect of borate bioactive glass (BBG) in vitro and in vivo. Methods The effect of BBG on zoledronate-treated bone marrow mesenchymal cells (BMSCs) and human umbilical vein endothelial cells (HUVECs) was explored by cell counting kit-8, EdU assay, flow cytometry, alkaline phosphatase staining, alizarin red staining, angiogenesis experiment, and real-time quantitative polymerase chain reaction. The preventive effect of BBG on zoledronate-induced osteonecrosis of the jaw in rat model was examined by micro-CT, HE staining, and immunohistochemistry. Results Exposure of BBG to BMSCs and HUVECs increased cell proliferation and restored their osteogenesis and angiogenesis potential in vitro. The BRONJ lesions were satisfactorily repaired and bone mineral density, bone volume/tissue volume, trabecula number, OCN-positive cells, and CD31-positive cells were increased in the BBG-treated groups compared with saline-treated groups. Conclusions Exposure of BMSCs and HUVECs to BBG restores osteogenesis and angiogenesis inhibited by zoledronate. BBG successfully restores extraction socket healing of BRONJ in rat model.

A single biomineralization of demineralized dentin is significant to restore the demineralized dentin due to dental caries or erosion. In recent years, meaningful progress has been made regarding the mechanisms involved in the biomineralization of dentin collagen. Concepts changing from the classical ion-based crystallization to non-classical particle-based crystallization, inspired a different strategy to infiltrate the demineralized dentin collagen. The remarkable discovery was the report of liquid-like amorphous calcium phosphate as nanoprecursor particles to carbonated hydroxyapatite. The non-collagenous proteins and their analogues are widely investigated, for their key role in controlling mineralization during the process of crystal nucleation and growth. The in-depth studies of the gap zone provided significant improvements in our understanding of the structure of collagen and of the intrafibrillar remineralization of collagen fibrils. The collagen is not a passive substrate as previously supposed, and the active role of guiding nanoprecursor infiltration and mediating its nucleation has been demonstrated. Furthermore, recovery of mechanical properties has been evaluated to determine the effectiveness of dentin remineralization. Finally, the problems regarding the origin formation of the calcium phosphate that is deposited in the collagen, and the exact interactions between the non-collagenous proteins, amorphous calcium phosphate and collagen are still unclear. We reviewed the importance of these findings in enriching our understanding of dentin biomineralization, while addressing certain limitations that are inherent to in vitro studies.

Seven flavonoid dimers, biflavocochins A-G, together with six known compounds were isolated from the red resins of Dracaena cochinchinensis (Chinese dragon's blood). Their structures were elucidated based on extensive spectroscopic analysis. The absolute configurations of 1-7 was assigned by experimental and quantum chemical calculated ECD spectra, and that of 4 was further established by X-ray diffraction analysis using Cu Kα radiation. Compounds 1-3 are novel dimers of homoisoflavonoid and dihydrochalcone with a unique dibenzopyran ring. Compounds 2, 6, 7 exhibited moderate PTP1B inhibitory activities in an enzyme assay. Compound 1 showed neuroprotective effect on serum deficiency-induced cellular damage in PC12 cells.

An efficient and convenient method enabling direct amination of unactivated methylene C(sp3)–H bonds to form C–N bonds with azodiformates as amino source is described. This method highlights the emerging strategy of unactivated methylene as versatile functional groups in organic synthesis and provides a strategy to construct functionalized C–N bonds for the synthesis of complex molecules.

Parkinson's disease (PD) is characterized by α-synuclein accumulation, dopaminergic neuron loss and inflammation. α-Synuclein can be secreted by neurons and activate microglia to different degrees. Excessive microglial activation can increase the production of tumor necrosis factor alpha (TNF-α), interleukin-1-β (IL-1β), interleukin-6 (IL-6), interferon-γ (INF-γ), inducible nitric oxide synthase (iNOS), reactive oxygen species (ROS) and nitric oxide (NO), and can also enhance microglial phagocytosis and migration as well as lymphocyte infiltration. Pathological α-synuclein and microglial activation can potentiate each other, leading to the loss of dopaminergic neurons and accelerated PD degeneration. This review will mainly describe the profiles of α-synuclein-activated microglia, with particular emphasis on the signaling cascades involved in this process.

Disruption of blood-brain barrier (BBB) and subsequent edema are major contributors to the pathogenesis of ischemic stroke, and the current clinical therapy remains unsatisfied. Chemokine-like factor 1 (CKLF1), as a novel C-C chemokine, plays important roles in immune response. The expression of CKLF1 increased after focal cerebral ischemia and inhibition of CKLF1 activity showed neuroprotective effect by alleviating infiltration of neutrophil and neuron apoptosis in cerebral ischemia. However, few studies have focused on the role of CKLF1 on BBB integrity. The objective of present study was to investigate the role of CKLF1 on BBB integrity by applying anti-CKLF1 antibodies in rat focal cerebral ischemia and reperfusion model. Brain water content, Evans blue leakage and the expression of aquaporin-4 (AQP-4), matrix metalloproteinase-9 (MMP-9), Zonula Occludens-1 (ZO-1) and Occludin were measured. After treatment with anti-CKLF1 antibody, brain water content and Evans blue leakage in ipsilateral hemisphere were decreased in a dose-dependent manner at 24h after reperfusion, but not changed in contralateral hemisphere. Anti-CKLF1 antibody reduced the expression of AQP-4 and MMP-9, and upregulated the expression of ZO-1 and Occludin. These results suggest that CKLF1 is involved in BBB disruption after reperfusion. Inhibition of CKLF1 protects against cerebral ischemia by maintaining BBB integrity, possibly via inhibiting the expression of AQP-4 and MMP-9, and increasing the expression of tight junction protein.

Our preliminary study shows that a bibenzyl compound isolated from Gastrodia elata, 2-[4-hydroxy-3-(4-hydroxybenzyl)benzyl]-4-(4-hydroxybenzyl)phenol (designated 20C), protects PC12 cells against H2O2-induced injury. In this study we investigated whether 20C exerted neuroprotective action in a cell model of Parkinson's disease. A cell model of Parkinson's disease was established in PC12 cells by exposure to rotenone (4 μmol/L) for 48 h. Cell viability and apoptosis were assessed, and intracellular ROS level and the mitochondrial membrane potential (MMP) were detected. The expression of apoptosis-related proteins Bax, Bcl-2, cytochrome c, cleaved caspase-3, and oxidative stress-related proteins Nrf2, HO-1 and NQO1 were examined using Western blotting. The mRNA levels of HO-1 and NQO1 were determined with RT-PCR. The nuclear translocation of Nrf2 was observed with immunofluorescence staining. Treatment with rotenone significantly increased the number of apoptotic cells, accompanied by marked increases in the Bax/Bcl-2 ratio, cytochrome c release and caspase-3 activation. Rotenone also increased ROS accumulation, reduced MMP, and increased the nuclear translocation of Nrf2 as well as the mRNA and protein levels of the Nrf2 downstream target genes HO-1 and NQO1 in PC12 cells. Co-treatment with 20C (0.01–1 μmol/L) dose-dependently attenuated rotenone-induced apoptosis and oxidative stress in PC12 cells. Nrf2 knockdown by siRNA partially reversed the protective effects of 20C in rotenone-treated PC12 cells. The bibenzyl compound 20C protects PC12 cells from rotenone-induced apoptosis, at least in part, via activation of the Nrf2/ARE/HO-1 signaling pathway.

The low denitrification effect on constructed wetlands (CWs) treating low carbon to nitrogen ratio (C/N) wastewater was a problem. In this study, a novel coupled system by installing CW and biofilm-electrode reactor (CW-BER) was developed. In this system, the heterotrophic and autotrophic denitrifying bacteria all played their roles in denitrification process. The system was investigated systematically with simulated wastewater at different C/Ns, electric current intensities (I), hydraulic retention times (HRTs), and pH. Results showed that the optimum running conditions were C/N=0.75-1, I=15 mA, HRT=12 h, and pH=7.5. The highest removal efficiency of NO3-N and TN at the best conditions was respectively 63.03% and 98.11% for CW-BER. Also, the TN and NO3-N enhancive removal efficiency of CW-BER was 23.26% and 24.20%, respectively. No residual organic carbon source was detected in final effluent at the best parameters.

In this work, SnO2 nanoparticles (NPs) were grown in-situ on g-C3N4 nanosheets using a microwave-assisted hydrothermal method. The resulting nanocomposite formed heterojunctions with useful photocatalytic properties. The morphology and chemical structure of the g-C3N4/SnO2 were thoroughly characterized. UV–vis and photoluminescence results revealed g-C3N4/SnO2 heterojunction with strong light adsorption and enhanced efficient separation of electron-hole pairs, respectively. These properties provided an excellent photocatalytic efficiency of the g-C3N4/SnO2 catalysts towards Rhodamine B degradation under UV and visible light irradiation, which were 100% and 98.5%, respectively, after 4 h of exposure to light. Such efficient materials could be used for future degradation of organic dyes under solar light. In addition, these composite materials could be applied to environmentally friendly photocatalysis reaction.

Olfactory bulb, as one of sensory organs opening to the outside, is susceptible to toxic environment and easy to deteriorate. Recent studies in Parkinson’s disease (PD) patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys have shown that abnormal α-synuclein is accumulated in the olfactory glomeruli, suggesting that the lesions of PD are not only confined to the substantia nigra (SN) but also located in the olfactory bulb. Thus, olfactory bulb might be the region of onset in PD pathogenesis and a targeted region for diagnosis and treatment of PD. However, the relationship between olfactory bulb and pathogenesis of PD remains unclear. In the present study, we investigated the inflammatory pathological alterations in olfactory bulb and the underlying mechanisms in chronic MPTP mice. Mice were treated with MPTP/P, i.e., MPTP (25 mg/kg, s.c.) plus probenecid (250 mg/kg, i.p.) every 4 days, for ten times. The mice displayed typical parkinsonian syndrome. Then we examined their olfactory function and the pathologic changes in olfactory bulb. The mice showed obvious olfactory dysfunction in a buried pellet test. Immunohistochemical studies revealed that tyrosine hydroxylase (TH) protein levels were significantly decreased, whereas abnormal α-synuclein was significantly increased in the olfactory bulbs. Furthermore, the olfactory bulbs in MPTP/P-treated mice showed significantly increased levels of interleukin-1β (IL-1β), caspase-1, glial fibrillary acidic protein (GFAP), Toll receptor 4 (TLR4), phosphorylation of p65, as well as activated molecules of NOD-like receptor protein 3 (NLRP3) that were associated with neuroinflammation. Our results demonstrate that MPTP/P-caused olfactory bulb damage might be related to NLRP3-mediated inflammation.

A Rh(III)-catalyzed cascade [3 + 2] annulation of N-phenoxyacetamides with propiolates under mild conditions using the internal oxidative O-N bond as the directing group has been achieved. This catalytic system provides a regio- and stereoselective access to benzofuran-2(3 H)-ones bearing exocyclic enamino motifs with exclusive Z configuration selectivity, acceptable to good yields and good functional group compatibility. Mechanistic investigations by experimental and density functional theory studies suggest that a consecutive process of C-H functionalization/isomerization/lactonization is likely to be involved in the reaction.

The calcined layered double hydroxide (CLDH)-alginate hydrogel beads were synthesized by embedding CLDH into alginate hydrogel beads. The beads were used to remove p-nitrophenol (PNP) and p-aminophenol (PAP) from aqueous solution. The structure and composition of CLDH-alginate hydrogel beads were characterized by scanning electron microscopy (SEM) with energy dispersive spectroscopy (EDS), elemental mapping, transmission electron microscope (TEM), X-ray powder diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, BET, and X-ray photoelectron spectroscopy (XPS). The adsorption kinetic, isothermal, thermodynamic properties and adsorption mechanism of PNP and PAP on CLDH-alginate hydrogel beads were studied. The results demonstrated that the adsorption kinetic data fitted the pseudo-second-order model well with the correlation coefficients (R2) of 0.9975 and 0.9995 for PNP and PAP, respectively. The isothermal data followed the Freundlich equation, and the values of R2 for PNP and PAP were 0.9728 and 0.9946, respectively. The adsorption processes were feasible, spontaneous, and endothermic. The adsorption mechanism was predominated by anionic exchange and hydrogen bonding for PNP and hydrogen bonding for PAP, which was evidenced by the results of adsorption experiments, characterization of FTIR and XPS, and theoretical calculation. Furthermore, the CLDH-alginate hydrogel beads can be separated easily due to their larger particle size. This will provide convenience in practice application.

Tunable diode laser absorption spectroscopy (TDLAS) provides a reliable method for detection of methane in coal mine. To study the influence of temperature and pressure on methane concentration detection, 1653.7 nm was selected as the center wavelength of methane according to the HITRAN database (explain what is this database), and then methane online detection system was designed using long path reflection structure detection technology combined with wavelength modulation and harmonic. The standard methane concentrations of 50.0, 99.8 and 200.0 ppm were adopted to study the influence of different temperature and pressure on the methane concentration within the range of −5 to 50 °C and 0–75 kPa. The results indicated that with the increase of temperature, methane concentration gradually decreased at the same pressure. Simultaneously, with the increase of pressure, the methane concentration also gradually decreased at the same temperature. Based on the above results, the temperature and pressure effects of different concentrations were combined to obtain the correction formula. The feasibility of the formula was verified by correcting the methane concentration at different temperatures and pressures. The corrected maximum relative error was 2%, which greatly improves the measurement accuracy and enables the system to meet the needs of methane detection during coal mine production.

Three triterpene saponins, nototronesides A-C (1-3), possessing an unprecedented 6/6/9 fused tricyclic tetranordammarane core, were isolated from the leaves of Panax notoginseng. Their structures were elucidated on the basis of spectroscopic data, and the structure of sapogenin (1a) was further confirmed by X-ray crystallography. The existence of 1-3 adds a new dimension to the diversity of the triterpene family. Moreover, compound 2 showed a moderate neuroprotective effect on serum deficiency-induced cellular damage in PC12 cells.

Parkinson's disease (PD) is a progressive degenerative disease of the nervous system, which is characterized by movement disorders, such as static tremor, rigidity, and bradykinesia in advanced patients. Gastrointestinal (GI) dysfunction, such as gastric dysmotility, constipation, and anorectic dysfunction, is common non-motor symptom in the early stage of PD. The progression of PD includes the degenerative loss of dopaminergic (DA) neurons and aggregation of α-synuclein in the substantia nigra (SN). Interestingly, both of them are also present in the enteric nervous system (ENS) of PD patients. In this review, we describe the relationship between non-motor symptoms particularly GI dysfunction and the pathogenesis of PD, aiming to show the powerful evidences about the prion-like propagation of α-synuclein and support the hypothesis of gut-brain axis in PD. We then summarize the mechanism of the gut-brain axis and confirm α-synuclein as a potential target for drug design or new clinical treatment.

The mechanism for ring-opening polymerization (ROP) of lactide catalyzed by Zn(C6F5)2–organic superbase Lewis pairs was investigated in the present work. Common organic superbases 4-dimethylaminopyridine (DMAP), 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (MesNHC), 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), and 7-methyl-1,5,7-triazabicyclo[4.4.0]decane-5-ene (MTBD) were selected as the Lewis bases to work cooperatively with Zn(C6F5)2. It was demonstrated that less sterically bulky DMAP could coordinate with the zinc atom and form classical Lewis acid–base adducts (CLA), whereas frustrated Lewis pairs (FLP) were obtained when bulky MTBD and DBU were used. Investigation into the polymerization behavior of lactide showed that the frustrated Lewis pair Zn(C6F5)2/MTBD exhibited much higher activity in the polymerization of lactide and much lower temperature dependence compared with the Lewis adduct Zn(C6F5)2/DMAP. Furthermore, there is a direct relationship between polymerization activity and the degree of “frustration”. The initiation reaction was further explored by in situ NMR at variable temperature. The interactions between Zn(C6F5)2 and the organic base in both CLA and FLP would be impaired at high temperature, and lactide was activated electronically by coordination to the Lewis acid Zn(C6F5)2. In addition, NMR and MALDI-TOF analyses showed that the active species are zwitterionic species, in which each chain end bears one amine and one Zn(C6F5)2 moiety, respectively, and Zn(C6F5)2 associated with the amine closely. Based on these results, a possible mechanism involving bifunctional activation was proposed. Further kinetic studies showed that increasing the reaction temperature and solvent polarity can significantly enhance the chain initiation rate. These experimental results also demonstrated that the polymerization was initiated through the proposed mechanism.