Atom Transfer Radical Coupling Enables Highly Enantioselective Carbo-Oxygenation of Alkenes with Hydrocarbons.

The selective functionalization of C(sp3)-H bonds has emerged as a transformative approach for streamlining synthetic routes, offering remarkable efficiency in the preparation and modification of complex organic molecules. However, the direct enantioselective transformation of hydrocarbons to medicinally valuable chiral molecules remains a significant challenge that has yet to be addressed. In this study, we adopt an atom transfer radical coupling (ATRC) strategy to achieve the asymmetric functionalization of C(sp3)-H bonds in hydrocarbons. This approach involves intermolecular H atom transfer (HAT) between a hydrocarbon and an alkoxy radical, leading to the formation of a carbon-centered radical. The resulting radical adds to alkenes, generating a new radical species that is intercepted by a chiral copper-mediated C-O bond coupling. By employing this method, we can directly access valuable chiral lactones bearing a quaternary stereocenter with high efficiency and excellent enantioselectivity. Importantly, ATRC exhibits great potential as a versatile platform for achieving stereoselective transformations of hydrocarbons.

Palladium-Catalyzed Branch- and Z-Selective Allylic C-H Amination with Aromatic Amines.

Allylamines are important building blocks in the synthesis of bioactive compounds. The direct coupling of allylic C-H bonds and commonly available amines is a major synthetic challenge. An allylic C-H amination of 1,4-dienes has been accomplished by palladium catalysis. With aromatic amines, branch-selective allylic aminations are favored to generate thermodynamically unstable Z-allylamines. In addition, more basic aliphatic cyclic amines can also engage in the reaction, but linear dienyl allylic amines are the major products.

Bioequivalence study of two formulations of terazosin hydrochloride capsule in healthy Chinese subjects under fasting and fed conditions.

OBJECTIVE: This study was conducted to assess the pharmacokinetic and safety profiles between a new oral formulation of terazosin hydrochloride capsule compared with the brand-name drug. MATERIALS AND METHODS: A randomized, open-label, single-dose, 2-period crossover study under fasting or fed conditions was conducted in healthy Chinese subjects. 24 individuals were selected, respectively. Each subject was randomized at the beginning to receive a 2-mg capsule of the test or the reference terazosin during the first period and then received the alternate formulation during the second period following a 1-week washout period. Blood samples were collected at pre-dose and up to 60 hours after administration. Plasma terazosin was quantified by a validated LC-MS/MS method. RESULTS: 48 healthy subjects were enrolled, and 47 completed the study. Cmax, AUC0-t, and AUC0-∞ were similar and the 90% CIs for the geometric mean ratios of these parameters between the two groups were all bounded within the predefined bioequivalence criterion of 80 - 125% under both fasting and fed conditions. Throughout the study period, a total of 30 treatment-emergent adverse events (TEAEs) were reported under fasting condition. 35 TEAEs were observed under fed conditions. No serious adverse event was observed. CONCLUSION: The test and reference formulations of terazosin were bioequivalent and well tolerated under both fasting and fed conditions.

Asymmetric Allylic C-H Alkylation of Allyl Ethers with 2-Acylimidazoles.

An asymmetric allylic C-H alkylation of allyl ethers has been established by chiral phosphoramidite-palladium catalysis, affording a wide variety of functionalized chiral 2-acylimidazoles in moderate to high yields and with high levels of enantioselectivity. Moreover, this protocol could be applied to a concise asymmetric synthesis of a tachykinin receptor antagonist.

Nucleophile Coordination Enabled Regioselectivity in Palladium-Catalyzed Asymmetric Allylic C-H Alkylation.

Branched selectivity in asymmetric allylic C-H alkylation is enabled by using 2-acylimidazoles as nucleophiles in the presence of a chiral phosphoramidite-palladium catalyst. A wide range of terminal alkenes, including 1,4-dienes and allylarenes, are nicely tolerated and provide chiral 2-acylimidazoles in moderate to high yields and with high levels of regio-, and enantio-, and E/Z-selectivities. Mechanistic studies using density-functional theory calculations suggest a nucleophile-coordination-enabled inner-sphere attack mode for the enantioselective carbon-carbon bond-forming event.

Palladium-Catalyzed Asymmetric Aminohydroxylation of 1,3-Dienes.

A PdII -catalyzed asymmetric aminohydroxylation of 1,3-dienes with N-tosyl-2-aminophenols was developed by making use of a chiral pyridinebis(oxazoline) ligand. The highly regioselective reaction provides direct and efficient access to chiral 3,4-dihydro-2H-1,4-benzoxazines in high yield and enantioselectivity (up to 96:4 e.r.). The reaction employs readily available N-tosyl-2-aminophenols as a unique aminohydroxylation reagent and is complementary to known asymmetric aminohydroxylation methods.

Transcriptomic analysis of Pak Choi under acute ozone exposure revealed regulatory mechanism against ozone stress.

BACKGROUND: Ground-level ozone (O3) is one of the major air pollutants, which cause oxidative injury to plants. The physiological and biochemical mechanisms underlying the responses of plants to O3 stress have been well investigated. However, there are limited reports about the molecular basis of plant responses to O3. In this study, a comparative transcriptomic analysis of Pak Choi (Brassica campestris ssp. chinensis) exposed to different O3 concentrations was conducted for the first time. RESULTS: Seedlings of Pak Choi with five leaves were exposed to non-filtered air (NF, 31 ppb) or elevated O3 (E-O3, 252 ppb) for 2 days (8 h per day, from 9:00-17:00). Compared with plants in the NF, a total of 675 differentially expressed genes (DEGs) were identified in plants under E-O3, including 219 DEGs with decreased expressions and 456 DEGs with increased expressions. Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that O3 stress invoked multiple cellular defense pathways to mitigate the impaired cellular integrity and metabolism, including 'glutathione metabolism', 'phenylpropanoid biosynthesis', 'sulfur metabolism', 'glucosinolate biosynthesis', 'cutin, suberine and wax biosynthesis' and others. Transcription factors potentially involved in this cellular regulation were also found, such as AP2-ERF, WRKY, JAZ, MYB etc. Based on the RNA-Seq data and previous studies, a working model was proposed integrating O3 caused reactive oxygen burst, oxidation-reduction regulation, jasmonic acid and downstream functional genes for the regulation of cellular homeostasis after acute O3 stress. CONCLUSION: The present results provide a valuable insight into the molecular responses of Pak Choi to acute O3 stress and the specific DEGs revealed in this study could be used for further functional identification of key allelic genes determining the O3 sensitivity of Pak Choi.

[Expressions of JNK and p-JNK in advanced prostate cancer and their clinical implications].

OBJECTIVE: To investigate the expressions of JNK and p-JNK in advanced prostate cancer (PCa) and benign prostatic hyperplasia (BPH) and their implications. METHODS: Using immunohistochemistry, we detected the expressions of JNK and p-JNK proteins in 40 cases of paraffin wax-embedded PCa and 21 cases of BPH tissues and analyzed their relationships with advanced PCa and BPH as well as with the pathologic features of advanced PCa. RESULTS: Statistically significant differences were not found in the positive expression rate of the JNK protein between BPH and PCa (42.86% vs 52.50%, P>0.05), non-metastatic and metastatic PCa (53.85% vs 51.85%, P >0.05), Gleason ≤7 and Gleason >7 (58.82% vs 47.82%, P >0.05), PSA ≤20 µg/L and PSA >20 µg/L (57.14% vs 51.52%, P >0.05), or survival >5 yr and survival ≤5 yr (60.00% vs 45.00%, P >0.05), nor in the expression level of p-JNK between BPH and PCa (33.33% vs 35.00%, P >0.05), non-metastatic and metastatic PCa (30.77% vs 37.03%, P >0.05), Gleason ≤7 and Gleason >7 (35.29% vs 34.78%, P >0.05), or PSA ≤20 µg/L and PSA >20 µg/L (43.75% vs 10.93%, P >0.05). However, the expression of p-JNK was significantly higher in the survival >5 yr than in the survival ≤5 yr group of the PCa patients (50.00% vs 20.00%, P <0.05). CONCLUSIONS: PCa patients with highly expressed p-JNK have a longer survival time and the high positive rate of p-JNK is associated with the prognosis of PCa.

[Expressions of ERK and p-ERK in advanced prostate cancer].

OBJECTIVE: To investigate the expressions of extracellular signal-regulated kinase (ERK) and p-ERK in benign and malignant prostate tissues, and whether it can be used as a marker for the prognosis of advanced prostate cancer (PCa). METHODS: Using immunohistochemical Envision, we detected the expressions of ERK1/2 and p-ERK1/2 in 20 cases of benign prostatic hyperplasia (BPH) and 40 cases of advanced PCa and analyzed their correlation with PCa metastasis, Gleason score, PSA level, and prognosis. RESULTS: The expression of ERK1/2 was remarkably higher in the advanced PCa than in the BPH cases (82.5% vs 55%, P<0.05), which was not associated with cancer metastasis, Gleason score, PSA level, or survival time of the patients with advanced PCa, and so was that of p-ERK1/2 (75.0% vs 35%, P<0.05), which was not associated with the Gleason score or PSA level of the PCa patients, either. The expression rates of p-ERK in the metastasis, non-metastasis, survival >5 yr, and survival ≤ 5 yr groups were 61.9%, 89.5%, 57.9%, and 90.5%, respectively, with statistically significant differences among these groups (P<0.05). CONCLUSIONS: ERK1/2 and p-ERK1/2 proteins are highly expressed in advanced PCa and p-ERK1/2 is associated with the metastasis and prognosis of advanced PCa.

[Intervention effects of Zuoguiwan containing serum on osteoblast through ERK1/2 and Wnt/ß-catenin signaling pathway in models with kidney-Yang-deficiency, kidney-Yin-deficiency osteoporosis syndromes].

To clarify the effects of Zuoguiwan containing serum on osteoblast proliferation and alkaline phosphatase(ALP) expression and its effects on the expression of ß-catenin, ERK1, ERK2 mRNA and protein of osteoblast through ERK1/2, Wnt/ß-catenin signaling pathway in models with osteoporosis(OP) kidney-Yang-deficiency, osteoporosis(OP) kidney-Yin-deficiency syndrome. Rat osteoporosis models were established by ovariectomy surgery, and 10 weeks after surgery, hydrocortisone was injected and thyroxine was administered by intragastric administration to establish OP kidney-Yang-deficiency rat model, and OP kidney-Yin-deficiency rat model. Osteoblasts were obtained from 24 h newborn rat skull and were identified by alkaline phosphatase and alizarin red staining. Zuoguiwan containing serum of OP, OP kidney-Yang-deficiency, and OP kidney-Yin-deficiency, as well as the blank serum were used to intervene the osteoblast, and the cells proliferation was detected by MTS. ELISA assay was used to detect ALP expression. RT-PCR assay was used to detect the mRNA expression of ERK1, ERK2, ß-catenin and protein expression levels were detected by Western blot. The results showed that Zuoguiwan containing serum in OP kidney-Yin-deficiency model had stronger effect than OP kidney-Yang-deficiency in promoting osteoblast proliferation, ALP expression, osteoblast ERK1/2, Wnt/ß-catenin signaling pathway related factors ß-catenin, ERK1, ERK2 mRNA and protein expression levels. This was consistent with the TCM theory of "Zuoguiwan nourishes kidney Yin", providing a scientific basis for the clinical and dialectical treatment of osteoporosis. Zuoguiwan could regulate the proliferation and differentiation of bone cells by ERK1/2 and Wnt/ß-catenin signaling pathway, which may be one of the mechanisms of Zuoguiwan for the prevention of osteoporosis.

Pollen Coat Proteomes of Arabidopsis thaliana, Arabidopsis lyrata, and Brassica oleracea Reveal Remarkable Diversity of Small Cysteine-Rich Proteins at the Pollen-Stigma Interface.

The pollen coat is the outermost domain of the pollen grain and is largely derived from the anther tapetum, which is a secretory tissue that degenerates late in pollen development. By being localised at the interface of the pollen-stigma interaction, the pollen coat plays a central role in mediating early pollination events, including molecular recognition. Amongst species of the Brassicaceae, a growing body of data has revealed that the pollen coat carries a range of proteins, with a number of small cysteine-rich proteins (CRPs) being identified as important regulators of the pollen-stigma interaction. By utilising a state-of-the-art liquid chromatography/tandem mass spectrometry (LC-MS/MS) approach, rich pollen coat proteomic profiles were obtained for Arabidopsis thaliana, Arabidopsis lyrata, and Brassica oleracea, which greatly extended previous datasets. All three proteomes revealed a strikingly large number of small CRPs that were not previously reported as pollen coat components. The profiling also uncovered a wide range of other protein families, many of which were enriched in the pollen coat proteomes and had functions associated with signal transduction, cell walls, lipid metabolism and defence. These proteomes provide an excellent source of molecular targets for future investigations into the pollen-stigma interaction and its potential evolutionary links to plant-pathogen interactions.

Redox-Neutral 1,4-Dicarbonfunctionalization of 1,3-Butadiene by Merging Photoredox and Nickel Catalysis.

The diverse functionalization of 1,3-butadiene provides wide applicability toward the synthesis of abundant and useful allylic compounds. Here, we describe a three-component and redox-neutral assembly of readily available C═X compounds, 1,3-butadiene, and various nucleophiles by merging photoredox and nickel catalysis, enabling the rapid synthesis of structurally diverse homoallyl amines and homoallylic alcohols.

PD-1 inhibitor plus anlotinib for metastatic castration-resistant prostate cancer: a real-world study.

Management and treatment of terminal metastatic castration-resistant prostate cancer (mCRPC) remains heavily debated. We sought to investigate the efficacy of programmed cell death 1 (PD-1) inhibitor plus anlotinib as a potential solution for terminal mCRPC and further evaluate the association of genomic characteristics with efficacy outcomes. We conducted a retrospective real-world study of 25 mCRPC patients who received PD-1 inhibitor plus anlotinib after the progression to standard treatments. The clinical information was extracted from the electronic medical records and 22 patients had targeted circulating tumor DNA (ctDNA) next-generation sequencing. Statistical analysis showed that 6 (24.0%) patients experienced prostate-specific antigen (PSA) response and 11 (44.0%) patients experienced PSA reduction. The relationship between ctDNA findings and outcomes was also analyzed. DNA-damage repair (DDR) pathways and homologous recombination repair (HRR) pathway defects indicated a comparatively longer PSA-progression-free survival (PSA-PFS; 2.5 months vs 1.2 months, P = 0.027; 3.3 months vs 1.2 months, P = 0.017; respectively). This study introduces the PD-1 inhibitor plus anlotinib as a late-line therapeutic strategy for terminal mCRPC. PD-1 inhibitor plus anlotinib may be a new treatment choice for terminal mCRPC patients with DDR or HRR pathway defects and requires further investigation.

Interleukin-37 promotes DMBA/TPA skin cancer through SIGIRR-mediated inhibition of glycolysis in CD103+DC cells.

Interleukin 37 (IL-37), a member of the IL-1 family, is considered a suppressor of innate and adaptive immunity and, hence is a regulator of tumor immunity. However, the specific molecular mechanism and role of IL-37 in skin cancer remain unclear. Here, we report that IL-37b-transgenic mice (IL-37tg) treated with the carcinogenic 7,12-dimethylbenzoanthracene (DMBA)/12-o-tetradecylphorbol-13-acetate (TPA) exhibited enhanced skin cancer and increased tumor burden in the skin by inhibiting the function of CD103+ dendritic cells (DCs). Notably, IL-37 induced rapid phosphorylation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), and via single immunoglobulin IL-1-related receptor (SIGIRR), inhibited the long-term Akt activation. Specifically, by affecting the SIGIRR-AMPK-Akt signaling axis, which is related to the regulation of glycolysis in CD103+DCs, IL-37 inhibited their anti-tumor function. Our results show that a marked correlation between the CD103+DC signature (IRF8, FMS-like tyrosine kinase 3 ligand, CLEC9A, CLNK, XCR1, BATF3, and ZBTB46) and chemokines C-X-C motif chemokine ligand 9, CXCL10, and CD8A in a mouse model with DMBA/TPA-induced skin cancer. In a word, our results highlight that IL-37 as an inhibitor of tumor immune surveillance through modulating CD103+DCs and establishing an important link between metabolism and immunity as a therapeutic target for skin cancer.

Effect of ischemia preconditioning on renal ischemia/reperfusion injury in rats.

OBJECTIVE: To study the effect of ischemia preconditioning (IP) on renal ischemia/reperfusion (I/R)-associated functional injury and expression of renal adhesion molecules in rats. MATERIALS AND METHODS: The ischemia preconditioning plan adopted in this experiment involved renal warm ischemia for 6 min. and blood flow for 4 min., repeated four times. The Wistar rat kidneys used for warm ischemia preconditioning were subjected to 60 min of renal warm ischemia followed by reperfusion. The rat kidneys with ischemia/reperfusion were compared with the ischemia preconditioning group to observe rat renal function and changes in the expression of renal adhesion molecules ICAM-1, P-Selectin, and E-Selectin. RESULTS: The expression of rat renal adhesion molecules (ICAM-1, P-Selectin, and E-Selectin) with ischemia preconditioning was significantly lower than that of the ischemia/reperfusion group. Serum creatinine was significantly lower than that in the ischemia/reperfusion group after 48 hours. CONCLUSIONS: Ischemia preconditioning has a protective effect on renal function. Reduced expression of renal adhesion molecules is likely a mechanism involved in the observed protection.

[Spectrum of gene deletion in 471 children with α-thalassemia].

OBJECTIVE: To study the distribution of common α-thalassemia gene deletion in children. METHODS: Blood cell analysis was performed on children who visited the clinic of the Foshan Women and Children's Hospital. Blood samples (2 mL, EDTA anticoagulant) was collected from children with MCV<82 fl for analysis of α-thalassemia gene using the GAP-PCR method. RESULTS: MCV<82 fl was found in 1341 children. Of the 1341 children, 471 (35.1%) were diagnosed with α-thalassemia. The prevalence of α-thalassemia increased with increasing age. --SEA was a major type of α-thalassemia gene deletion (75.3%), followed by -a3.7 (17.0%) and -a4.2 (7.7%) in the 471 patients. The top three genotypes were --SEA/aa (73.2%), aa/-a3.7 (12.5%) and --SEA/-a3.7 (5.5%). CONCLUSIONS: Genetic testing is necessary for the diagnosis of α-thalassemia in children with MCV<82 fl. --SEA is a common type of α-thalassemia gene deletion, and -SEA/aa is a common gene type of α-thalassemia in the subjects of this study.

Experimental Study on Danggui Shaoyao San Improving Renal Fibrosis by Promoting Autophagy.

Renal fibrosis could lead to chronic kidney disease (CKD) developing into the end-stage with its pathological manifestation is the deposition of extracellular matrix (ECM). Danggui Shaoyao San (DSS) is one of the widely used herbal formulas in ancient China, which has been proven to have efficacy in the treatment of CKD. The experiment employed TGF-ß1 to stimulate the NRK-52E cells to establish a renal fibrosis model. With rapamycin (RAPA) used as the positive control, we detected the expression of fibronectin (FN), caspase-3, and autophagy-related proteins in the NRK-52E cells treated with DSS by Western blot and immunofluorescence assay. In order to further verify autophagy-promoting effects of DSS, we adopted 3-MA to inhibit autophagy. The experiment has found that DSS can lower the protein levels of FN and caspase-3 in the NRK-52E cells induced by TGF-ß1. After TGF-ß1 stimulation, the expression of LC3 II/I and Beclin 1 has decreased, and the protein levels of mTOR and p62 have increased. Consistent with rapamycin, DSS has significantly reduced these effects of TGF-ß1. It has also been found that DSS can increase the expression of LC3 II/I and Beclin 1 proteins and can reduce the level of mTOR in cells treated with 3-MA, suggesting that DSS can promote autophagy. In conclusion, DSS has been proved to reduce the apoptosis and fibrosis of NRK-52E cells induced by TGF-ß1, which may be achieved by promoting autophagy.

Research on electroacupuncture parameters for knee osteoarthritis based on data mining.

BACKGROUND: Knee osteoarthritis, a common degenerative joint disease, has been widely treated by electroacupuncture in recent years. However, there are too many parameters of the treatment currently, resulting in various applications in clinical practice. This study aims to summarize the optimal stimulation parameters of electroacupuncture for knee osteoarthritis in clinical studies by applying data mining techniques. METHODS: Four databases including Pubmed, Cochrane Library, Embase, and Web of Science were searched for clinical studies on electroacupuncture treating knee osteoarthritis from 2012 to 2021. A database was established by Microsoft Excel 2020 and analyzed by R Version 4.1.1. RESULTS: Forty-six articles were included according to the established criteria. The most used electroacupuncture stimulation parameters were 0.30 mm × 40 mm needle, continuous wave, low frequency of current (mainly 2 Hz), stimulation duration for 30 min per treatment, and frequency of treatment for once a day. Eighteen acupoints were mentioned and the most used ones include Dubi (ST35), Liangqiu (ST34), Neixiyan (EX-LE4), Xuehai (SP10), Yanglingquan (GB34), and Yinlingquan (SP9), and those most generally used acupoints are closely arranged on the Stomach Channel of Foot Yangming. Cluster analysis showed two groups, one for obligatory acupoints and one for adjunctive ones. The association analysis showed the most supported acupoint pair was Liangqiu (ST34) and Xuehai (SP10). CONCLUSIONS: Continuous wave, low frequency of current (2 Hz), 30-min stimulation, and local acupoint selection are frequently used for electroacupuncture treating knee osteoarthritis. Due to the limitations of this study, further research and more standardized, multi-centered, and large-sample clinical trials should be conducted to provide more convincing evidence.

Improvements in Brazed-Joint Properties of Silicon Nitride and Titanium Alloys Using Laser-Induced Microscale Rice Leaf Structures.

Si3N4 ceramics with a microscale rice leaf structure (MRLS) and titanium alloy were connected via brazing, and the influence of the surface microstructure on the ceramic connection was analyzed. MRLS fabrication is an efficient and high-degree-of-freedom method that can be used to change a material's surface morphology and wettability. The MRLS was obtained at a laser power of 110 W, with line spacings of 100 and 50 µm. The laser-treated surface included nanoparticles and micro particles, exhibiting a coral-like structure after agglomeration. When the MRLS was used to braze the titanium alloy, no defects were observed at the brazing interface, and the formation was excellent. Throughout the brazed joint, the MRLS remained intact and formed a strong metallurgical bond with the brazing filler metal. A finite element analysis was performed to study the cross-sectional morphology after joint fracture; from the load-time curve, it was found that the MRLS on the surface not only helped improve the mechanical occlusion and brazing area at the interface, but also helped generate compressive stress on the Si3N4 side. Crack propagation was hindered, thereby increasing the joint strength.

Fabrication of Metallic Superhydrophobic Surfaces with Tunable Condensate Self-Removal Capability and Excellent Anti-Frosting Performance.

Laser fabrication of metallic superhydrophobic surfaces (SHSs) for anti-frosting has recently attracted considerable attention. Effective anti-frosting SHSs require the efficient removal of condensed microdroplets through self-propelled droplet jumping, which is strongly influenced by the surface morphology. However, detailed analyses of the condensate self-removal capability of laser-structured surfaces are limited, and guidelines for laser processing parameter control for fabricating rationally structured SHSs for anti-frosting have not yet been established. Herein, a series of nanostructured copper-zinc alloy SHSs are facilely constructed through ultrafast laser processing. The surface morphology can be properly tuned by adjusting the laser processing parameters. The relationship between the surface morphologies and condensate self-removal capability is investigated, and a guideline for laser processing parameterization for fabricating optimal anti-frosting SHSs is established. After 120 min of the frosting test, the optimized surface exhibits less than 70% frost coverage because the remarkably enhanced condensate self-removal capability reduces the water accumulation amount and frost propagation speed (<1 µm/s). Additionally, the material adaptability of the proposed technique is validated by extending this methodology to other metals and metal alloys. This study provides valuable and instructive insights into the design and optimization of metallic anti-frosting SHSs by ultrafast laser processing.