Asymmetric Hydrogenation of Racemic 2-Substituted Indoles via Dynamic Kinetic Resolution: An Easy Access to Chiral Indolines Bearing Vicinal Stereogenic Centers.

The asymmetric hydrogenation (AH) of N-unprotected indoles is a straightforward, yet challenging method to access biologically interesting NH chiral indolines. This method has for years been limited to 2/3-monosubstituted or 2,3-disubstituted indoles, which produce chiral indolines bearing endocyclic chiral centers. Herein, we have reported an innovative Pd-catalyzed AH of racemic α-alkyl or aryl-substituted indole-2-acetates using an acid-assisted dynamic kinetic resolution (DKR) process, affording a range of structurally fascinating chiral indolines that contain exocyclic stereocenters with excellent yields, diastereoselectivities, and enantioselectivities. Mechanistic studies support that the DKR process relies on a rapid interconversion of each enantiomer of racemic substrates, leveraged by an acid-promoted isomerization between the aromatic indole and nonaromatic exocyclic enamine intermediate. The reaction can be performed on a gram scale, and the products can be derivatized into non-natural ß-amino acids via facile debenzylation and amino alcohol upon reduction.

Chiral Cpx Rhodium(III)-Catalyzed Enantioselective Aziridination of Unactivated Terminal Alkenes.

Chiral cyclopentadienyl-rhodium(III) Cpx Rh(III) catalysis has been demonstrated to be competent for catalyzing highly enantioselective aziridination of challenging unactivated terminal alkenes and nitrene sources. The chiral Cpx Rh(III) catalysis system exhibited outstanding catalytic performance and wide functional group tolerance, yielding synthetically important and highly valuable chiral aziridines with good to excellent yields and enantioselectivities (up to 99 % yield, 93 % ee). This protocol presents a novel and effective strategy for synthesizing enantioenriched aziridines from simple alkenes. Various transformations were performed on the aziridine products, illustrating the versatility and synthetic potential of this protocol for constructing highly functionalized compounds.

Catalytic Asymmetric Cascade Dearomatization of Indoles via a Photoinduced Pd-Catalyzed 1,2-Bisfunctionalization of Butadienes.

Photoinduced Pd-catalyzed bisfunctionalization of butadienes with a readily available organic halide and a nucleophile represents an emerging and attractive method to assemble versatile alkenes bearing various functional groups at the allylic position. However, enantiocontrol and/or diastereocontrol in the C-C or C-X bond-formation step have not been solved due to the open-shell process. Herein, we present a cascade asymmetric dearomatization reaction of indoles via photoexcited Pd-catalyzed 1,2-biscarbonfunctionalization of 1,3-butadienes, wherein asymmetric control on both the nucleophile and electrophile part is achieved for the first time in photoinduced bisfunctionalization of butadienes. This method delivers structurally novel chiral spiroindolenines bearing two contiguous stereogenic centers with high diastereomeric ratios (up to >20 : 1 dr) and good to excellent enantiomeric ratios (up to 97 : 3 er). Experimental and computational studies of the mechanism have confirmed a radical pathway involving excited-state palladium catalysis. The alignment and non-covalent interactions between the substrate and the catalyst were found to be essential for stereocontrol.

Palladium-Catalyzed Chemo- and Regioselective C-H Bond Functionalization of Phenols with 1,3-Dienes.

Chemo- and site-selective functionalization of phenols offers a rapid strategy for the synthesis of phenol derivatives with diverse structures. Herein, we report a Pd-catalyzed regioselective C-H bond allylic alkylation of phenols with 1,3-dienes, which has precision reactivity at the ortho C-H bond of 2-naphthols, 1-naphthols, and electron-rich phenols. The reaction is accelerated by a diphosphine ligand, does not need any other additive, and features broad substrate scope and good chemo- and regioselectivity. In addition, we have also investigated the asymmetric variant, and the product could be achieved in up to 55% ee.

The association of air pollutants with hospital outpatient visits for child and adolescence psychiatry in Shenzhen, China.

BACKGROUND: Although exposure to ambient air pollution has been associated with mental disorder, little is known about its potential effects on children and adolescents, especially in Chinese population. We aimed to reveal the relationship of air pollutants with hospital outpatient visits for child and adolescence psychiatry (HOVCAP) in Shenzhen. METHODS: A case-crossover study based on time-series data was applied, and a distributed lag non-linear model (DLNM) was used to evaluate the non-linear and delayed effects of 4 major air pollutants (NO2, PM2.5, SO2 and O3) on HOVCAP. Least absolute shrinkage and selection operator (LASSO) regression was used to control the multicollinearity between covariates and to filter variables. RESULT: A total of 94,660 cases aged 3-18 were collected from 2014 to 2019 in the Mental Health Center of Shenzhen. Results of pollutants at mode value (M0) showed that in the single lag effect result, when the average daily concentration of NO2 at 24 µg/m3, there was a significant effect on HOVCAP over lag 1, lag 4 and lag 5, respectively. The cumulative RR of NO2 M0 value to the outpatient visits were 1.438 (1.137-1.818) over lag 0-2, 1.454 (1.120-1.887) over lag 0-3, 1.466 (1.084-1.982) over lag 0-4, 1.680 (1.199-2.354) over lag 0-5, 1.993 (1.369-2.903) over lag 0-6, and 2.069 (1.372-3.119) over lag 0-7. However, PM2.5, SO2, O3 were not associated with HOVCAP over neither single lag effects nor cumulative effects. The RR values both shown an increase either when NO2 increases by 10 units or when the maximum concentration of NO2 is reached. CONCLUSION: Our study suggests that exposure to the normal air quality of NO2 in Shenzhen may associated with the risk of HOVCAP. However, PM2.5, SO2, O3 were not associated with HOVCAP.

Impact of tectoridin on the pharmacokinetics of florfenicol via targeting cytochrome P450 and P-glycoprotein of rats.

Belamcanda chinensis (L.) DC, commonly used with florfenicol in Chinese veterinary clinics for respiratory tract infections, contains the major effective isoflavone, tectoridin (TEC). This study aimed to investigate the impact of TEC co-administration on the pharmacokinetics of florfenicol in vivo.Male rats received oral TEC (50 mg/kg BW) or sterile water for seven days, followed by a single oral dose of florfenicol (25 mg/kg BW) on the 8th day. Non-compartmental methods analysed the pharmacokinetics of florfenicol, while real-time reverse transcription polymerase chain reaction (RT-PCR), Western blot, and immunohistochemical analyses measured expression levels of cytochrome P450 (CYP) isoforms in the liver and P-glycoprotein (P-gp) in the jejunum.TEC significantly decreased florfenicol's AUC(0-∞), MRT(0-∞), t1/2z, Vz/F, and Cmax by 24.75%, 18.43%, 55.47%, 43.05%, and 19.48%, while increasing CLz/F by 33.33%. TEC also up-regulated hepatic CYP1A2 and CYP3A1 mRNA expression, as well as intestinal MDR1, by 1.39-fold, 1.85-fold, and 1.65-fold. This coincided with a respective increase in protein expression by 1.37-fold, 1.39-fold, and 1.43-fold.These findings suggest that TEC-induced alterations in the pharmacokinetics of florfenicol may be attributed to increased CYP and P-gp expression. Further investigations are warranted to understand the implications of these findings on the clinical effectiveness of florfenicol in veterinary practice.

A novel modified McLaughlin surgery for treating locked chronic posterior shoulder dislocation.

BACKGROUND: Posterior shoulder dislocation is an uncommon orthopaedics injury and is frequently missed or misdiagnosed, accounting for 2%-4% of all shoulder dislocations, and is associated with the reverse Hill-Sachs lesion. Once posterior shoulder dislocation develops into a chronic disease, it will bring a lot of trouble to the treatment, especially in repairing the humeral defects. Surgical strategies are also developing and innovating to deal with this injury, including transfer of subscapularis tendon or lesser tubercle, humeral rotational osteotomy, autogenous bone graft or allograft. Shoulder replacement seems to be the ultimate and only option when the injury becomes irreparable, although some studies have shown unsatisfactory follow-up results. Considering no gold-standard treatment for locked posterior shoulder dislocation, we described a novel modified McLaughlin procedure for locked chronic posterior shoulder dislocation and evaluated the functional outcomes. METHODS: This study included five locked chronic posterior shoulder dislocation patients with an associated reverse Hill-Sachs lesion, in which the compression surface covered 30-40% of the humeral head. The mean period from injury to receiving surgery was 11.6 weeks (6-24 weeks). All five patients underwent the modified McLaughlin procedure, mainly divided into three steps, including open reduction, transfer of the partial lesser tuberosity and artificial bone to repair the reverse Hill-Sachs defects. The kernel technique was to fix the transferred tuberosity with two lag screws and strengthen it with two Ethibond sutures. The Constant-Murley score (CMS), the range of shoulder motion and the complications were recorded to assess and compare the functional situation of the shoulder postoperatively and postoperatively. RESULTS: After an average of 19.8 months (12-30) of follow-up, the mean CMS improved to 85.8 ± 4.9 (79-91) compared with 46.0 ± 4.5 (40-52) preoperatively, which showed a significant difference (p = 0.001). In the final follow-up, all five patients showed no symptoms of shoulder instability, and there was no pain or limited activity in daily life, thus all patients were satisfied with the results. CONCLUSION: Repairing the reverse Hill-Sachs lesion by transferring the partial lesser tuberosity combined with artificial bone fixed by lag screws and sutures can ensure shoulder stability and provide pain relief and good function in patients with locked chronic posterior shoulder dislocation associated with the humeral head defect.

Pollution characteristics and microbial community succession of a rural informal landfill in an arid climate.

Informal landfills pose potential threats to the environment and human health due to the lack of anti-seepage measures. However, little research has been conducted on the distribution of pollutants in informal landfill sites situated in arid climates, as well as the underlying interaction mechanisms between environmental factors and microbial structure. In this study, we sought to investigate the pollution characteristics and microbial community succession of the landfill in northern China. The results revealed that heavy metals in the landfill showed poor mobility and migration. The lower layers of the garbage samples had higher water-soluble contents of heavy metals compared to the upper layers. The landfill-derived dissolved organic matter (DOM) was found to originate from microbial production, and four fluorescent components were identified, including fulvic acid-like substances, humus-like substances, and protein-like components. Fluorescence intensity and humification degree increased with increasing depth. The microbial diversity and richness decreased with sampling depth. The most abundant phyla in the samples were Proteobacteria, unidentified_Bacteria, Bacteroidota, Firmicutes, Myxococcota, Gemmatimonadota, Actinobacteria, and Deinococcota. As the sampling depth increased, Proteobacteria decreased, while Bacteroidota and Firmicutes showed a remarkable increase, with little variation observed in the other phyla. The partial least-squares path model (PLS-PM) results indicated that pH had the most significant effect on microbial abundance and diversity (direct effect value = -5.560), while DOM and heavy metals had the opposite effect, with direct effects of 1.838 and 3.231, respectively. DOM was identified as the driving factor for the variation in other environmental factors. The redundancy analysis (RDA) showed that the dominant genera were greatly influenced by Cu, humic-like substances, and protein-like substances. Among them, Bacillus, Alcanivorax, Devosia, and Chryseolinea may play important roles in the remediation of landfills. Our study not only gains a deeper understanding of the pollution risk of informal landfills in arid climates, but also provides a scientific basis for the future treatment and restoration of contaminated sites associated with landfills.

Xanthones from securidaca inappendiculata antagonizes the anti-rheumatic effect of methotrexate by inhibiting reduced folate carrier 1.

BACKGROUND: The first-line anti-rheumatic drug methotrexate (MTX) is used in the combination. Because of the unpredictable adverse reactions, optimization of relevant regimens is necessary and meaningful. This study aimed to study the possible interaction between Securidaca inappendiculate Hassk. Derived xanthones and MTX. METHODS: We established adjuvant-induced arthritis (AIA) model, which was treated with MTX and MTX + xanthone-rich fraction (XRF). The clinical efficacy was evaluated by histopathological examination, and LC-MS was used to monitor the blood concentration of MTX. Western blotting and immunohistochemistry were used to detect protein expression. In vitro, we assessed the activity of related transporters by cellular uptake assay based on HEK-293T cells. RESULTS: Compared with MTX-treated rats, inflammation in the immunized rats in the MTX + XRF group was obvious, indicating that XRF antagonized the anti-rheumatic effect of MTX. Meanwhile, XRF reduced liver and kidney injuries caused by MTX in addition to MTX. Results from immunohistochemical and nappendiculat assays suggested that XRF may reduce uptake of MTX by down-regulating reduced folate carrier 1 (RFC1). CONCLUSION: This study indicated that XRF could reduce the plasma concentration of MTX by inhibiting the expression of RFC1, antagonize the therapeutic effect of MTX on AIA rats, and reduce its oral bioavailability. The combination of S. inappendiculate and MTX should be further optimized to achieve the goal of increasing efficiency and reducing toxicity.

The Effect of α7nAChR Signaling on T Cells and Macrophages and Their Clinical Implication in the Treatment of Rheumatic Diseases.

Rheumatoid arthritis (RA) is one of the most common autoimmune disease and until now, the etiology and pathogenesis of RA is not fully understood, although dysregulation of immune cells is one of the leading cause of RA-related pathological changes. Based on current understanding, the priority of anti-rheumatic treatments is to restore immune homeostasis. There are several anti-rheumatic drugs with immunomodulatory effects available nowadays, but most of them have obvious safety or efficacy shortcomings. Therefore, the development of novel anti-rheumatic drugs is still in urgently needed. Cholinergic anti-inflammatory pathway (CAP) has been identified as an important aspect of the so-called neuro-immune regulation feedback, and the interaction between acetylcholine and alpha 7 nicotinic acetylcholine receptor (α7nAChR) serves as the foundation for this signaling. Consistent to its immunomodulatory functions, α7nAChR is extensively expressed by immune cells. Accordingly, CAP activation greatly affects the differentiation and function of α7nAChR-expressing immune cells. As a result, targeting α7nAChR will bring profound therapeutic impacts on the treatment of inflammatory diseases like RA. RA is widely recognized as a CD4+ T cells-driven disease. As a major component of innate immunity, macrophages also significantly contribute to RA-related immune abnormalities. Theoretically, manipulation of CAP in immune cells is a feasible way to treat RA. In this review, we summarized the roles of different T cells and macrophages subsets in the occurrence and progression of RA, and highlighted the immune consequences of CAP activation in these cells under RA circumstances. The in-depth discussion is supposed to inspire the development of novel cell-specific CAP-targeting anti-rheumatic regimens.

Self-powered topological insulator Bi2Te3/Ge heterojunction photodetector driven by long-lived excitons transfer.

Due to the wide spectral absorption and ultrafast electron dynamical response under optical excitation, topological insulator (TI) was proposed to have appealing application in next-generation photonic and optoelectronic devices. Whereas, the bandgap-free speciality of Dirac surface states usually leads to a quick relaxation of photoexcited carriers, making the transient excitons difficult to manipulate in isolated TIs. Growth of TI Bi2Te3/Ge heterostructures can promote the specific lifetime and quantity of long-lived excitons, offering the possibility of designing original near-infrared optoelectronic devices, however, the construction of TI Bi2Te3/Ge heterostructures has yet to be investigated. Herein, the high-quality Bi2Te3/Ge heterojunction with clear interface was prepared by physical vapor deposition strategy. A significant photoluminescence quenching behaviour was observed by experiments, which was attributed to the spontaneous excitation transfer of electrons at heterointerface via theoretical analysis. Then, a self-powered heterostructure photodetector was fabricated, which demonstrated a maximal detectivity of 1.3 × 1011Jones, an optical responsivity of 0.97 A W-1, and ultrafast photoresponse speed (12.1µs) under 1064 nm light illumination. This study offers a fundamental understanding of the spontaneous interfacial exciton transfer of TI-based heterostructures, and the as-fabricated photodetectors with excellent performance provided an important step to meet the increasing demand for novel optoelectronic applications in the future.

Position of Biphenyl Group Turning the Structure and Photophysical Property of D-π- π -A Prototype Fluorescent Material.

Three novel D-π-π-A prototype compounds, namely, (E)-2-(3-([1,1'-biphenyl]-2-yl)-1-(9H-fluoren-2-yl)allylidene)malononitri-le (2-BAM), (E)-2-(3-([1,1'-biphenyl]-3-yl)-1-(9H-fluoren-2-yl)allylidene)malononitri-le (3-BAM), and (E)-2-(3-([1,1'-biphenyl]-4-yl)-1-(9H-fluoren-2-yl)allylidene)malononitri-le (4-BAM) were synthesized. Furthermore, the structures and photophysical properties of three compounds were compared. Molecules of 2-BAM were packed into a 1D column structure with H-aggregation. However, both of 3-BAM and 4-BAM were packed into 3D layer structures with J-aggregation, respectively. Although all three compounds showed highly twisted molecular geometries, their respective molecular packing and intermolecular interactions were different. Because of the differences in electronic structures of molecules, three compounds displayed different emission behaviors in solid and dilute solution states. This study indicated that changing the position of biphenyl groups is an effective way for turning the structures and photophysical properties of such D-π-π-A prototype fluorescent materials.

Algicidal interaction between Paenibacillus polymyxa MEZ6 and microalgae.

AIMS: Algicidal bacteria can be used for control of harmful algal bloom and extraction of algal bioproducts based on their algae-lysing activities. This work investigated the algae-lysing activity of a newly isolated algicidal bacterium, Paenibacillus polymyxa strain MEZ6 and its possible mechanisms. METHODS AND RESULTS: Algicidal bacteria were isolated from soil samples collected at the university campus. Co-inoculation tests identified that one isolate, MEZ6, can rapidly kill eukaryotic algae including Chlamydomonas reinhardtii, Tribonema minus, Haematococcus pluvialis, and Chlorella ellipsoidea. The strain was determined as Paenibacillus polymyxa MEZ6 based on 16S rRNA gene sequence and genome comparisons. The algicidal activity was detected in both living cells and cell-free supernatant of spent culture medium, suggesting cell-cell contact is not required for algicidal activity. Strain MEZ6 was less active towards cyanobacterial strains compared to algae. Genomic sequence and comparative proteomic analyses were performed to explore the possible algicidal mechanisms of the strain. Differentially expressed protein analysis identified a number of proteins related to polysaccharides degradation and antimicrobial secondary metabolite biosynthesis that may be involved in the algicidal activity of MEZ6. CONCLUSION: Paenibacillus polymyxa MEZ6 is a newly discovered gram-positive algicidal bacterial strain with high lytic activity towards several algal species. SIGNIFICANCE AND IMPACT OF THE STUDY: Our study extends the understanding of the versatile characters of Paenibacillus polymyxa and sheds new insights into its application in algae biotechnology.

Highly Enantioselective Synthesis of N-Unprotected Unnatural α-Amino Acid Derivatives by Ruthenium-Catalyzed Direct Asymmetric Reductive Amination.

An unprecedented highly enantioselective Ru-catalyzed direct asymmetric reductive amination of α-keto amides with ammonium salts has been disclosed, efficiently offering valuable enantioenriched N-unprotected unnatural α-amino acid derivatives bearing a broad range of aryl or alkyl α-substituents. This protocol features easily accessible substrates, good functional-group tolerance and excellent enantiocontrol, making it a good complementary approach to the known methods. Moreover, this method is also applicable to the preparation of N-unprotected unnatural α-amino acid derivatives containing an additional stereogenic center at the ß-position through a dynamic kinetic resolution (DKR) process. Convenient transformations of the obtained products into chiral N-unprotected unnatural α-amino acids, drug intermediates, peptides, and organocatalysts/ligands further showcase the utility of this method.

Direct reductive amination of ketones with ammonium salt catalysed by Cp*Ir(III) complexes bearing an amidato ligand.

A series of half-sandwich Ir(III) complexes 1-6 bearing an amidato bidentate ligand were conveniently synthesized and applied to the catalytic Leuckart-Wallach reaction to produce racemic α-chiral primary amines. With 0.1 mol% of complex 1, a broad range of ketones, including aryl ketones, dialkyl ketones, cyclic ketones, α-keto acids, α-keto esters and diketones, could be transformed to their corresponding primary amines with moderate to excellent yields (40%-95%). Asymmetric transformation was also attempted with chiral Ir complexes 3-6, and 16% ee of the desired primary amine was obtained. Despite the unsatisfactory enantio-control achieved so far, the current exploration might stimulate more efforts towards the discovery of better chiral catalysts for this challenging but important transformation.

Intravenously injected lidocaine or magnesium improves the quality of early recovery after laparoscopic cholecystectomy: A randomised controlled trial.

BACKGROUND: Previous data show that lidocaine or magnesium has unique characteristics of stress inhibition and antiinflammation. OBJECTIVE: We aimed to observe the effects of lidocaine or magnesium on the quality of recovery (QoR) after laparoscopic cholecystectomy. DESIGN: Single-centre, prospective, randomised, double-blind study. SETTING: The Affiliated Hospital of Xuzhou Medical University from March 2019 to October 2019. PATIENTS: One hundred and fourteen patients scheduled for laparoscopic cholecystectomy. INTERVENTION: The enrolled patients were randomly divided into three groups. Lidocaine (group L), magnesium sulphate (group M) or 0.9% saline (group C) was administered intravenously 10 min before induction. MAIN OUTCOME MEASURES: The quality of recovery 15 (QoR-15) score, the Hospital Anxiety and Depression Scale (HADS), and the Numerical Rating Scale (NRS) score were selected. The usage of propofol and remifentanil, haemodynamic parameters, anaesthesia recovery parameters and adverse events were also evaluated. RESULTS: The QoR-15 scores for group L (132.0) and group M (134.0) were 6 and 8 points higher than that of group C (126.0) on POD1 (postoperative day 1) (adjP < 0.05). However, the decrease of QoR-15 in Group L is less than the minimal clinically important difference (8).The NRS scores on POD1 in group C 3, were higher than other two groups (adjP < 0.05). The dosage of remifentanil in group L was lower than other two groups (adjP < 0.05).The physical independence of group L and group M and physical comfort of group M were improved compared with group C. CONCLUSION: The results show that magnesium sulphate improved the QoR through improving physical comfort and physical independence in patients after laparoscopic cholecystectomy. However, lidocaine had limited effects on QoR under current conditions. TRIAL REGISTRATION: ChiCTR1800019092 (www.chictr.org.cn). CLINICAL TRIAL NUMBER AND REGISTRY URL: The study was registered in the Chinese Clinical Trials Register (ChiCTR1800019092) https://www.chictr.org.cn.

Direct catalytic asymmetric synthesis of α-chiral primary amines.

α-Chiral primary amines are one among the most valuable and versatile building blocks for the synthesis of numerous amine-containing pharmaceuticals and natural compounds. They also serve as chiral ligands or organo-catalysts for asymmetric catalysis. However, most of the existing chemocatalytic methods toward enantiopure primary amines rely on multistep manipulations on N-substituted substrates, which are not ideally atom-economical and cost-effective. Among the catalytic methods including the asymmetric transformations of the pre-prepared or in situ formed NH imines, biomimetic chemocatalysis inspired by enzymatic transaminations has recently emerged as an appealing and straightforward method to access chiral primary amines. This tutorial review highlights the state-of-the-art catalytic methods for the direct asymmetric synthesis of α-chiral primary amines and demonstrates their utility in the construction of molecular complexities, which may attract extensive attention and inspire applications in synthetic and medicinal chemistry.

Chemokine receptor CXCR4 activates the RhoA/ROCK2 pathway in spinal neurons that induces bone cancer pain.

BACKGROUND: Chemokine receptor CXCR4 has been found to be associated with spinal neuron and glial cell activation during bone cancer pain. However, the underlying mechanism remains unknown. Furthermore, the RhoA/ROCK2 pathway serves as a downstream pathway activated by CXCR4 during bone cancer pain. We first validated the increase in the expressions of CXCR4, p-RhoA, and p-ROCK2 in the spinal dorsal horn of a well-characterized tumor cell implantation-induced cancer pain rat model and how these expressions contributed to the pain behavior in tumor cell implantation rats. We hypothesized that spinal blockade of the CXCR4-RhoA/ROCK2 pathway is a potential analgesic therapy for cancer pain management. METHODS: Adult female Sprague-Dawley rats (body weight of 180-220 g) and six- to seven-week old female Sprague-Dawley rats (body weight of 80-90 g) were taken. Ascitic cancer cells were extracted from the rats (body weight of 80-90 g) with intraperitoneally implanted Walker 256 mammary gland carcinoma cells. Walker 256 rat mammary gland carcinoma cells were then injected (tumor cell implantation) into the intramedullary space of the tibia to establish a rat model of bone cancer pain. RESULTS: We found increased expressions of CXCR4, p-RhoA, and p-ROCK2 in the neurons in the spinal cord. p-RhoA and p-ROCK2 were co-expressed in the neurons and promoted by overexpressed CXCR4. Intrathecal delivery of CXCR4 inhibitor Plerixafor (AMD3100) or ROCK2 inhibitor Fasudil abrogated tumor cell implantation-induced pain hypersensitivity and tumor cell implantation-induced increase in p-RhoA and p-ROCK2 expressions. Intrathecal injection of stromal-derived factor-1, the principal ligand for CXCR4, accelerated p-RhoA expression in naive rats, which was prevented by postadministration of CXCR4 inhibitor Plerixafor (AMD3100) or ROCK2 inhibitor Fasudil. CONCLUSIONS: Collectively, the spinal RhoA/ROCK2 pathway could be a critical downstream target for CXCR4-mediated neuronal sensitization and pain hypersensitivity in bone cancer pain, and it may serve as a potent therapeutic target for pain treatment.

A familial cluster, including a kidney transplant recipient, of Coronavirus Disease 2019 (COVID-19) in Wuhan, China.

In December 2019, an outbreak of COVID-19 occurred in Wuhan, China, and spread to the whole of China and to multiple countries worldwide. Unlike SARS and MERS, where secondary transmission mostly occurred in hospital settings, COVID-19 transmission occurs in large numbers within families. Herein we report three cases of a familial cluster with one family member being a kidney transplant recipient. The initial clinical symptoms of COVID-19 in these three patients were the same, but their progression was different. Based on the severity of clinical symptoms, chest computer tomography findings and SARS-Cov-2 RNA test results, we admitted the husband to the respiratory intensive care unit (RICU) and used a treatment consisting of immunosuppressant reduction/cessation and low dose methylprednisolone-based therapy, and his wife to the respiratory isolation ward. In contrast, the son received in-home isolation and home-based care. All three family members made a full recovery.

Crocin Alleviates Pain Hyperalgesia in AIA Rats by Inhibiting the Spinal Wnt5a/ß-Catenin Signaling Pathway and Glial Activation.

At present, most of the drugs have little effect on the pathological process of rheumatoid arthritis (RA). Analgesia is an important measure in the treatment of RA and is also one of the criteria to determine the therapeutic effects of the disease. Some studies have found that crocin, a kind of Chinese medicine, can effectively alleviate pain sensitization in pain model rats, but the mechanism is not clear. Emerging evidence indicates that crocin may inhibit the metastasis of lung and liver cancer cells from the breast by inhibiting Wnt/ß-catenin and the Wnt signaling pathway is closely related to RA. Wnt5a belongs to the Wnt protein family and was previously thought to be involved only in nonclassical Wnt signaling pathways. Recent studies have shown that Wnt5a has both stimulatory and inhibitory effects on the classical Wnt signaling pathway, and so, Wnt5a has attracted increasing attention. This study demonstrated that crocin significantly increased the mechanical thresholds of adjuvant-induced arthritis (AIA) rats, suggesting that crocin can alleviate neuropathic pain. Crocin significantly decreased the levels of pain-related factors and glial activation. Foxy5, activator of Wnt5a, inhibited the above effects of crocin in AIA rats. In addition, intrathecal injection of a Wnt5a inhibitor significantly decreased hyperalgesia in AIA rats. This research shows that crocin may alleviate neuropathic pain in AIA rats by inhibiting the expression of pain-related molecules through the Wnt5a/ß-catenin pathway, elucidating the mechanism by which crocin relieves neuropathic pain and provides a new way of thinking for the treatment of AIA pain.