Stereodivergent, Kinetically Controlled Isomerization of Terminal Alkenes via Nickel Catalysis.

Because internal alkenes are more challenging synthetic targets than terminal alkenes, metal-catalyzed olefin mono-transposition (i.e., positional isomerization) approaches have emerged to afford valuable E- or Z- internal alkenes from their complementary terminal alkene feedstocks. However, the applicability of these methods has been hampered by lack of generality, commercial availability of precatalysts, and scalability. Here, we report a nickel-catalyzed platform for the stereodivergent E/Z-selective synthesis of internal alkenes at room temperature. Commercial reagents enable this one-carbon transposition of terminal alkenes to valuable E- or Z-internal alkenes via a Ni-H-mediated insertion/elimination mechanism. Though the mechanistic regime is the same in both systems, the underlying pathways that lead to each of the active catalysts are distinct, with the Z-selective catalyst forming from comproportionation of an oxidative addition complex followed by oxidative addition with substrate and the E-selective catalyst forming from protonation of the metal by the trialkylphosphonium salt additive. In each case, ligand sterics and denticity control stereochemistry and prevent over-isomerization.

Anti-Glioma Effects of Ligustilide or n-Butylphthalide on Their Own and the Synergistic Effects with Temozolomide via PI3K/Akt Signaling Pathway.

Background: Ligustilide (LIG) and n-butylphthalide (NBP) have neuroprotective effects in cerebral ischemia; however, their roles in gliomas are not well-known.This study aimed to explore the anti-glioma effects of LIG and NBP individually and the synergistic effects of temozolomide (TMZ) via the PI3K/Akt Signaling Pathway. Materials and Methods: Cytotoxicity of LIG and NBP alone and in combination with TMZ in U251 cells was determined using the CCk-8. The effect of compounds alone or in combination on cell migration was detected using the wound healing assay, and the invasion was evaluated by transwell assays, respectively. Cell apoptosis was quantified by flow cytometry and the changed expressions of proteins were detected by Western blotting. Results: The results showed that LIG and NBP significantly inhibited the growth of U251 cells at concentrations of 4-10 µg/mL and 1.5-6 µg/mL in a dose-dependent manner (p<0.05, p<0.01). The combination of 20 µg/mL TMZ with LIG in the concentration range of 4-10 µg/mL or with NBP of 0.5-6 µg/mlachieved synergistic effect towardsU251 cells. LIG and NBP, alone or in combination with TMZ, markedly inhibited cell invasion (p< 0.001) and enhanced apoptosis (p< 0.05). The combination of TMZ with LIG or NBP markedly inhibited cell migration (p< 0.001). Western blot analysis showed that LIG, NBP, and TMZ, alone and in combination, significantly decreased the expression of Bcl-2, p-PI3K, and p-Akt, and increased the expression of Bax. Conclusion: Both LIG and NBP exert anti-glioma effects on their own through the PI3K/Akt pathway and enhance TMZ-mediated anti-glioma efficiency via the same pathway.

Revised Mechanism of C(sp3)-C(sp3) Reductive Elimination from Ni(II) with the Assistance of a Z-Type Metalloligand.

Reductive elimination is a key step in Ni-catalyzed cross-couplings. Compared with processes that proceed from Ni(III) or Ni(IV) intermediates, C(sp3)-C(sp3) reductive eliminations from Ni(II) centers are challenging due to the weak oxidizing ability of Ni(II) species. In this report, we present computational evidence that supports a mechanism in which Zn coordination to the nickel center as a Z-type ligand accelerates reductive elimination. This Zn-assisted pathway is found to be lower in energy compared with direct reductive elimination from a σ-coordinated Ni(II) intermediate, providing new insights into the mechanism of Ni-catalyzed cross-coupling with organozinc nucleophiles. Mayer bond order, Hirshfield charge, Laplacian of the electron density, orbital, and interaction region indicator analyses were conducted to elucidate details of the reductive elimination process and characterize the key intermediates. Theoretical calculations indicate a significant Z-type Ni-Zn interaction that reduces the electron density around the Ni center and accelerates reductive elimination. This mechanistic study of reductive elimination in Ni(0)-catalyzed conjunctive cross-couplings of aryl iodides, organozinc reagents, and alkenes is an important case study of the involvement of Zn-assisted reductive elimination in Ni catalysis. We anticipate that the novel Zn-assisted reductive elimination mode may extend to other cross-coupling processes and explain the unique effectiveness of organozinc nucleophiles in many instances.

Structurally Diverse Bench-Stable Nickel(0) Pre-Catalysts: A Practical Toolkit for In Situ Ligation Protocols.

A flurry of recent research has centered on harnessing the power of nickel catalysis in organic synthesis. These efforts have been bolstered by contemporaneous development of well-defined nickel (pre)catalysts with diverse structure and reactivity. In this report, we present ten different bench-stable, 18-electron, formally zero-valent nickel-olefin complexes that are competent pre-catalysts in various reactions. Our investigation includes preparations of novel, bench-stable Ni(COD)(L) complexes (COD=1,5-cyclooctadiene), in which L=quinone, cyclopentadienone, thiophene-S-oxide, and fulvene. Characterization by NMR, IR, single-crystal X-ray diffraction, cyclic voltammetry, thermogravimetric analysis, and natural bond orbital analysis sheds light on the structure, bonding, and properties of these complexes. Applications in an assortment of nickel-catalyzed reactions underscore the complementary nature of the different pre-catalysts within this toolkit.

A Sterically Tuned Directing Auxiliary Promotes Catalytic 1,2-Carbofluorination of Alkenyl Carbonyl Compounds.

The site-selective palladium-catalyzed three-component coupling of unactivated alkenyl carbonyl compounds, aryl- or alkenylboronic acids, and N-fluorobenzenesulfonimide is described herein. Tuning of the steric environment on the bidentate directing auxiliary enhances regioselectivity and facilitates challenging C(sp3 )-F reductive elimination from a PdIV intermediate to afford 1,2-carbofluorination products in moderate to good yields.

Application of protective weight-bearing in osteonecrosis of the femoral head: A systematic review and meta-analysis of randomized controlled trials and observational studies.

Background: The aim of this systematic review and meta-analysis was to estimate the efficacy and prognostic value of protective weight-bearing for ONFH. Methods: The authors searched the PubMed, EMBASE and Cochrane Library databases, up to February 25, 2022. RCTs and observational studies on conservative treatment, including the use of crutches, for skeletally mature patients with ONFH and written in English were included. Outcomes were the total hip arthroplasty (THA) rate, collapse rate, Hip Harris score (HHS) and visual analog scale (VAS) score. Cochrane Review Manager Software 5.4 and Stata 15.1 were used to perform the statistical analyses. Results: A total of 14 studies involving 813 patients (1,025 hips) were included in this meta-analysis. The results showed that the THA rate, collapse rate, HHS and VAS scores in the protective weight-bearing group were not significantly different from those in the surgical group. In the protective weight-bearing group, the results showed that the THA rate was 40%, 8% in ARCO stage II, 37% in ARCO stage III, and the collapse rate was 46%. The mean HHS and VAS score was 80.86 and 1.00, respectively. The HHS score at the 3-, 6-, 12-, and 24-month follow-up was 79.93, 83.94, 85.94, and 96.09 points, respectively, whereas the VAS score at the 6- and 12-month follow-up was 2.20 and 1.29, respectively. Conclusion: Protective weight bearing could achieve satisfactory results in terms of THA rate, collapse rate, HHS and VAS scores. Protective weight-bearing allows most precollapse patients to preserve the hip but also allows postcollapse patients to delay THA or hip-preserving surgery. The effects and prognosis of protective weight-bearing in the short or mid-term are noninferior to surgical hip preservation and are a viable alternative option for osteonecrosis of the femoral head.

Sepsis-induced AKI: From pathogenesis to therapeutic approaches.

Sepsis is a heterogenous and highly complex clinical syndrome, which is caused by infectious or noninfectious factors. Acute kidney injury (AKI) is one of the most common and severe complication of sepsis, and it is associated with high mortality and poor outcomes. Recent evidence has identified that autophagy participates in the pathophysiology of sepsis-associated AKI. Despite the use of antibiotics, the mortality rate is still at an extremely high level in patients with sepsis. Besides traditional treatments, many natural products, including phytochemicals and their derivatives, are proved to exert protective effects through multiple mechanisms, such as regulation of autophagy, inhibition of inflammation, fibrosis, and apoptosis, etc. Accumulating evidence has also shown that many pharmacological inhibitors might have potential therapeutic effects in sepsis-induced AKI. Hence, understanding the pathophysiology of sepsis-induced AKI may help to develop novel therapeutics to attenuate the complications of sepsis and lower the mortality rate. This review updates the recent progress of underlying pathophysiological mechanisms of sepsis-associated AKI, focuses specifically on autophagy, and summarizes the potential therapeutic effects of phytochemicals and pharmacological inhibitors.

Recent Advances in the Emerging Therapeutic Strategies for Diabetic Kidney Diseases.

Diabetic kidney disease (DKD) is one of the most common causes of end-stage renal disease worldwide. The treatment of DKD is strongly associated with clinical outcomes in patients with diabetes mellitus. Traditional therapeutic strategies focus on the control of major risk factors, such as blood glucose, blood lipids, and blood pressure. Renin-angiotensin-aldosterone system inhibitors have been the main therapeutic measures in the past, but the emergence of sodium-glucose cotransporter 2 inhibitors, incretin mimetics, and endothelin-1 receptor antagonists has provided more options for the management of DKD. Simultaneously, with advances in research on the pathogenesis of DKD, some new therapies targeting renal inflammation, fibrosis, and oxidative stress have gradually entered clinical application. In addition, some recently discovered therapeutic targets and signaling pathways, mainly in preclinical and early clinical trial stages, are expected to provide benefits for patients with DKD in the future. This review summarizes the traditional treatments and emerging management options for DKD, demonstrating recent advances in the therapeutic strategies for DKD.

Directed, nickel-catalyzed 1,2-alkylsulfenylation of alkenyl carbonyl compounds.

We report a regioselective, nickel-catalyzed syn-1,2-carbosulfenylation of non-conjugated alkenyl carbonyl compounds with alkyl/arylzinc nucleophiles and tailored N-S electrophiles. This method allows the simultaneous installation of a variety of C(sp3) and S(Ar) (or Se(Ar)) groups onto unactivated alkenes, which complements previously developed 1,2-carbosulfenylation methodology in which only C(sp2) nucleophiles are compatible. A bidentate directing auxiliary controls regioselectivity, promotes high syn-stereoselectivity with a variety of E- and Z-internal alkenes, and enables the use of an array of electrophilic sulfenyl (and seleno) electrophiles. Among compatible electrophiles, those with N-alkyl-benzamide leaving groups were found to be especially effective, as determined through comprehensive structure-reactivity mapping.

Electrophilic Sulfur Reagent Design Enables Directed syn-Carbosulfenylation of Unactivated Alkenes.

A multi-component approach to structurally complex organosulfur products is described via the nickel-catalyzed 1,2-carbosulfenylation of unactivated alkenes with organoboron nucleophiles and tailored organosulfur electrophiles. The key to the development of this transformation is the identification of a modular N-alkyl-N-(arylsulfenyl)arenesulfonamide family of sulfur electrophiles. Tuning the electronic and steric properties of the leaving group in these reagents controls pathway selectivity, favoring three-component coupling and suppressing side reactions, as examined via computational studies. The unique syn-stereoselectivity differs from traditional electrophilic sulfenyl transfer processes involving a thiiranium ion intermediate and arises from the directed arylnickel(I) migratory insertion mechanism, as elucidated through reaction kinetics and control experiments. Reactivity and regioselectivity are facilitated by a collection of monodentate, weakly coordinating native directing groups, including sulfonamides, alcohols, amines, amides, and azaheterocycles.

Predicting Collapse in Osteonecrosis of the Femoral Head Using a New Method: Preserved Angles of Anterior and Lateral Femoral Head.

BACKGROUND: Femoral head collapse (FHC) is associated with a poor prognosis in osteonecrosis of the femoral head (ONFH). Preserved angles (PAs), including the lateral preserved angle (LPA), the anterior preserved angle (APA) and the combined preserved angle (CPA), can be used to quantify the extent of femoral head necrosis and predict the risk of femoral head collapse. The purpose of this retrospective cohort study was to assess the efficacy of these preserved angles in the prediction of femoral head collapse using plain radiographs. METHODS: Patients with ONFH treated conservatively between January 2010 and January 2019 were analyzed retrospectively to assess the risk of FHC. A logistic regression model was used to evaluate the independent prognostic factors associated with FHC, including age, sex, etiology, onset of symptom, The Japanese Investigation Committee classification, and PAs (LPA, APA, and CPA). RESULTS: A total of 137 patients, with 180 hips, had follow-up of at least two years and were included. During the follow-up period, FHC occurred in 89 hips (49.44%) after the initial diagnosis. Multivariable analysis indicated that CPA (odds ratio [OR] = 0.95; 95%CI = 0.93-0.97; P < 0.01) was a stronger predictor of femoral head collapse compared with the Japanese Investigation Committee classification (OR = 2.40, 95%CI = 0.92-6.25; P > 0.01). The receiver operating characteristic and survival curve analyses revealed that the predictive cutoff point for the CPA was 118.7° (sensitivity = 96.70%, specificity = 79.78%, log-rank test: P < 0.01). CONCLUSIONS: Assessment of preserved angles on plain radiographs is a simple method to quantify the extent of lateral and anterior necrosis of the femoral head. Specifically, CPA has a potential value in predicting femoral head collapse.

Arthroplasty vs proximal femoral nails for unstable intertrochanteric femoral fractures in elderly patients: A systematic review and meta-analysis.

BACKGROUND: Proximal femoral nails (PFNs) are the most common method for the treatment of unstable intertrochanteric femoral fractures (IFFs), but postoperative bed rest is required. There is a large amount of blood loss during the operation. Osteoporosis in elderly patients may cause nonunion of fractures and other complications. Arthroplasty can give patients early weight bearing and reduce financial burden, but whether it can replace PFNs remains controversial. AIM: To compare the clinical outcomes of arthroplasty and PFNs in the treatment of unstable IFFs in elderly patients. METHODS: A search was conducted in the PubMed, Embase, and Cochrane Library databases and included relevant articles comparing arthroplasty and PFN. The search time was limited from January 1, 2005 to November 1, 2020. Two investigators independently screened studies, extracted data and evaluated the quality according to the inclusion and exclusion criteria. According to the research results, the fixed effect model or random effect model were selected for analysis. The following outcomes were analyzed: Harris Hip score, mortality, complications, operation time, blood loos, hospital stay, weight-bearing time, fracture classification and type of anesthesia. RESULTS: We analyzed four randomized controlled trials that met the requirements. A total of 298 patients were included in these studies. According to the AO/OTA classification, there are 20 A1 types, 136 A2 types, 42 A3 types and 100 unrecorded types. Primary outcome: The Harris Hip Score at the final follow-up of the PFN group was higher [mean difference (MD): 9.01, 95% confidence interval (CI): 16.57 to 1.45), P = 0.02]. There was no significant difference between the two groups in the rate of overall mortality [risk ratio (RR): 1.44, P = 0.44] or the number of complications (RR: 0.77, P = 0.05). Secondary outcomes: blood loss of the arthroplasty group was higher (MD: 241.01, 95% CI: 43.06-438.96, P = 0.02); the operation time of the PFN group was shorter (MD: 23.12, 95%CI: 10.46-35.77, P = 0.0003); and the length of hospital stay of the arthroplasty group was shorter [MD: 0.97, 95% CI: 1.29 to 0.66), P < 0.00001]. There was no difference between the two groups in the type of anesthesia (RR: 0.99). There were only two studies recording the weight-bearing time, and the time of full weight bearing in the arthroplasty group was significantly earlier. CONCLUSION: Compared with PFN, arthroplasty can achieve weight bearing earlier and shorten hospital stay, but it cannot achieve a better clinical outcome. Arthroplasty cannot replace PFNs in the treatment of unstable IFFs in elderly individuals.

Immobilization of Escherichia coli cells harboring a nitrilase with improved catalytic properties though polyethylenemine-induced silicification on zeolite.

In the chemical-biological synthesis route of gabapentin, immobilized Escherichia coli cells harboring nitrilase are used to catalyze the biotransformation of intermediate 1-cyanocyclohexaneacetonitile to 1-cyanocyclohexaneacetic acid. Herein, we present a novel cell immobilization method, which is based on cell adsorption using 75 g/L Escherichia coli cells and 6 g/L zeolite, cell crosslinking using 3 g/L polyethylenemine and biomimetic silicification using 18 g/L hydrolyzed tetramethylorthosilicate. The constructed "hybrid biomimetic silica particles (HBSPs)" with core-shell structure showed a specific activity of 147.2 ± 2.3 U/g, 82.6 ± 2.8% recovery of nitrilase activity and a half-life of 19.1 ± 1.9 h at 55 °C. 1-Cyanocyclohexaneacetonitrile (1.0 M) could be completely hydrolyzed by 50 g/L of HBSPs at pH 7.5, 35 °C in 4 h, providing 92.1 ± 3.2% yield of 1-cyanocyclohexaneacetic acid. In batch reactions, the HBSPs could be reused for 13 cycles and maintained 79.9 ± 4.1% residual activity after the 10th batch, providing an average product yield of 92.6% in the first 10 batches with a productivity of 619.3 g/L/day. In addition, multi-layer structures consisting of silica coating and polyethylenemine/glutaraldehyde crosslinking were constructed to enhance the mechanical strength of immobilized cells, and the effects of coating layers on the catalytic properties of immobilized cells was discussed.

Directed Markovnikov hydroarylation and hydroalkenylation of alkenes under nickel catalysis.

We report a full account of our research on nickel-catalyzed Markovnikov-selective hydroarylation and hydroalkenylation of non-conjugated alkenes, which has yielded a toolkit of methods that proceed under mild conditions with alkenyl sulfonamide, ketone, and amide substrates. Regioselectivity is controlled through catalyst coordination to the native Lewis basic functional groups contained within these substrates. To maximize product yield, reaction conditions were fine-tuned for each substrate class, reflecting the different coordination properties of the directing functionality. Detailed kinetic and computational studies shed light on the mechanism of this family of transformations, pointing to transmetalation as the turnover-limiting step.

Modular synthesis of non-conjugated N-(quinolin-8-yl) alkenyl amides via cross-metathesis.

We report a direct and modular method to access non-conjugated alkenyl amides containing the 8-aminoquinoline (AQ) directing auxiliary and related groups via cross-metathesis. In this way, readily available, AQ-containing, terminal ß,γ-unsaturated amides can be coupled with various terminal alkenes to furnish internal alkene products that are otherwise difficult to prepare. The value of this family of products stems from their ability to participate in a number of directed alkene functionalization reactions.

Application of Physical Examination Data on Health Analysis and Intelligent Diagnosis.

Analysis and diagnosis according to the collected physical data are an important part in the physical examination. Through the data analysis of the physical examination results and expert diagnoses, the physical condition of a specific physical examination unit can be achieved which may guide individual health development. However, in general, the application of physical examination data is insufficient in most of the current physical examination organizations. Therefore, in the present study, statistical analysis and intelligent diagnosis were applied to maximize the utilization of physical examination data. The physical examination data collected from different departments of Dalian University of Technology were statistically analyzed and then synthesized for stimulating the thinking mode and knowledge framework of medical experts by a learning model on machine, resulting in the construction of an intelligent physical examination diagnosis method with 93.4% accuracy confirmed by experts. In conclusion, a potential artificial intelligence model of psychical examination data on health analysis and intelligent diagnosis was established, which may become more and more accurate with data accumulation in the near future.

Ni-Catalyzed 1,2-Diarylation of Alkenyl Ketones: A Comparative Study of Carbonyl-Directed Reaction Systems.

A nickel-catalyzed 1,2-diarylation of alkenyl ketones with aryl iodides and arylboronic esters is reported. Ketones with a variety of substituents serve as effective directing groups, offering high levels of regiocontrol. A representative product is diversified into a wide range of useful products that are not readily accessible via existing 1,2-diarylation reactions. Preliminary mechanistic studies shed light on the binding mode of the substrate, and Hammett analysis reveals the effect of electronic factors on initial rates.

A Transient Directing Group Strategy Enables Enantioselective Multicomponent Organofluorine Synthesis.

The vicinal fluorofunctionalization of alkenes represents an expedient strategy for converting feedstock olefins into valuable fluorinated molecules and as such has garnered significant attention from the synthetic community; however, current methods remain limited in terms of scope and selectivity. Here we report the site-selective palladium-catalyzed three-component coupling of alkenylbenzaldehydes, arylboronic acids, and N-fluoro-2,4,6-trimethylpyridinium hexafluorophosphate facilitated by a transient directing group. The synthetically enabling methodology constructs vicinal stereocenters with excellent regio-, diastereo-, and enantioselectivities, forging products that map onto bioactive compounds.

Melanization induced by Heliothis virescens ascovirus 3h promotes viral replication.

Melanization is an important innate immune defense mechanism of insects, which can kill invading pathogens. Most pathogens, for their survival and reproduction, inhibit the melanization of the host. Interestingly, our results suggested that after infection with Heliothis virescens ascovirus 3h (HvAV-3h), the speed of melanization in infected Spodoptera exigua larval hemolymph was accelerated and that the phenoloxidase (PO) activity of hemolymph in larvae infected with HvAV-3h increased significantly (1.20-fold at 96 hpi, 1.52-fold at 120 hpi, 1.23-fold at 144 hpi, 1.12-fold at 168 hpi). The transcription level of the gene encoding S. exigua prophenoloxidase-1 (SePPO-1 gene) was upregulated dramatically in the fat body during the middle stage of infection. In addition, when melanization was inhibited or promoted, the replication of HvAV-3h was inhibited or promoted, respectively. In conclusion, infection with HvAV-3h can markedly induce melanization in the middle stage of infection, and melanization is helpful for HvAV-3h viral replication.