Metal- and light-free decarboxylative direct C-H alkylation of heteroarenes at room temperature.

This study reports a metal- and light-free decarboxylative C-H alkylation of heteroarenes at room temperature. The reaction generates various primary, secondary, and tertiary alkyl radicals and functionalizes seven different privileged scaffolds widely present in bioactive molecules. During this process, one equivalent of hypervalent iodine(III) carboxylates (HICs) plays dual roles as an alkyl radical precursor and an oxidant.

Unicompartmental knee arthroplasty combined with posterior cruciate ligament reconstruction: a case report.

BACKGROUND: In this study, we present the unique case of a patient with knee osteoarthritis (OA) of the medial compartment and posterior cruciate ligament (PCL) deficiency who underwent simultaneous medial unicompartmental knee arthroplasty (UKA) and PCL reconstruction. CASE PRESENTATION: A 49-year-old male patient presented with a 1-year history of pain and instability in the left knee. The patient had previously experienced a trauma-related injury to the PCL of the left knee that was left untreated. Imaging and physical examination confirmed the presence of left medial knee OA along with PCL rupture. To address these issues, the patient underwent UKA combined with PCL reconstruction. The patient's Lysholm score was 47 before surgery and 81 three months after surgery, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score was 29 before surgery and 18 three months after surgery, and the International Knee Documentation Committee (IKDC) subjective score was 56.3 before surgery and 74.7 three months after surgery. Six months after surgery, the patient's gait returned to normal, and he was able to jog. CONCLUSION: This case report presents the first instance of UKA combined with PCL reconstruction and introduces a novel treatment approach for patients suffering from medial knee OA and ligament injury.

Synthesis and antitumor activity of erysolin and its metabolites.

Erysolin and its two metabolites which were found in blood, ERY-GSH and ERY-NAC, were synthesized by alkylation, amination, isothiocyanation and oxidation reactions from 1-bromo-4-chlorobutane and sodium methyl mercaptide. The reaction temperature, time, feed ratios and purification method were also optimized. The synthesis method was simple, green, safe and low-cost. Erysolin, ERY-GSH and ERY-NAC showed good antitumor activities against MCF-7, HeLa, HepG2, A549 and SW480 cells, which suggested that the antitumor mechanism of erysolin can also be clarified from its metabolites in addition to itself.

Antidepressant effects of total iridoids of Valeriana jatamansi via the intestinal flora-blood-brain barrier pathway.

CONTEXT: Valeriana jatamansi Jones [syn. V. wallichii DC, (Valerianaceae)] (VJJ) is used to treat depression. OBJECTIVE: To explore the effects of total iridoids of VJJ extract (TIV) on chronic unpredictable mild stress (CUMS) in mice. MATERIALS AND METHODS: VJJ roots and rhizomes were extracted with 70% ethanol. CUMS rats were treated daily with fluoxetine (2.6 mg/kg, i.g.) or TIV (5.7, 11.4, and 22.8 mg/kg, i.g.) for 14 days. Male Kun Ming mice on normal chow and 0.5% CMC-Na solution were used as a control. Behavioural tests included the tail suspension (TST) and sucrose preference tests (SPT). Evans blue staining was used to evaluate blood-brain barrier (BBB) permeability. Western blotting was used to measure zonula occludens-1 (ZO-1) and occludin expression. 16S rRNA sequencing was used to analyse intestinal flora abundance. Tax4Fun was used to predict KEGG metabolic pathways. RESULTS: TIV treatment reduced TST time (117.35 ± 8.23 or 108.95 ± 6.76 vs. 144.45 ± 10.30 s), increased SPT (55.83 ± 7.24 or 53.12 ± 13.85 vs. 38.98 ± 5.43%), increased the abundance of phylum Firmicutes (86.99 ± 0.03 vs. 60.88 ± 0.19%) and genus Lactobacillus (75.20 ± 0.19 vs. 62.10 ± 0.13%), reduced the abundance of phylum Bacteroidetes (6.69 ± 0.06 or 11.50 ± 0.09 vs. 25.07 ± 0.20%). TIV increased carbohydrate metabolism (14.50 ± 3.00 × 10-3 or 14.60 ± 2.00 × 10-3 or 14.90 ± 2.00 × 10-3 vs.13.80 ± 4.00 × 10-3%), replication and repair functions (5.60 ± 1.00 × 10-3 or 5.60 ± 1.00 × 10-3 vs. 5.10 ± 4.00 × 10-3%), reduced the frequency of infectious disease (1.60 ± 2.00 × 10-4 or 1.90 ± 5.00 × 10-4 or 1.80 ± 3.00 × 10-4 vs. 2.20 ± 7.00 × 10-3%), BBB permeability (0.77 ± 0.30 vs. 1.81 ± 0.33 µg/g), and up-regulated the expression of ZO-1 (1.42-fold, 1.60-fold, 1.71-fold) and occludin (1.79-fold, 2.20-fold). CONCLUSIONS: TIV may modulate the intestinal flora, thereby inducing the expression of ZO-1 and occludin, protecting the BBB and exerting an antidepressant effect.

Six New neo-Clerodane Diterpenoids from Aerial Parts of Scutellaria barbata and Their Cytotoxic Activities.

Six new neo-clerodane diterpenoids (1: -6: ), scutebatas X - Z, A1-C1, along with twelve known ones (7: -18: ) were obtained via the phytochemical investigation of the aerial parts of Scutellaria barbata. Their structures were established by detailed spectroscopic analysis. The absolute configurations of 1: and 2: , as the representative members of this type, were identified based on a circular dichroic exciton chirality method. Moreover, in vitro cytotoxicity of compounds 1: -6: were evaluated against three human cancer cell lines (SGC-7901, MCF-7, and A-549) using the MTT method. Compound 6: showed cytotoxic activities against all the three cell lines with IC50 values of 17.9, 29.9, and 35.7 µM, respectively.

Taurine zinc solid dispersions attenuate doxorubicin-induced hepatotoxicity and cardiotoxicity in rats.

The clinical efficacy of anthracycline anti-neoplastic agents is limited by cardiac and hepatic toxicities. The aim of this study was to assess the hepatoprotective and cardioprotective effects of taurine zinc solid dispersions, which is a newly-synthesized taurine zinc compound, against doxorubicin-induced toxicity in Sprague-Dawley rats intraperitoneally injected with doxorubicin hydrochloride (3mg/kg) three times a week (seven injections) over 28 days. Hemodynamic parameters, levels of liver toxicity markers and oxidative stress were assessed. Taurine zinc significantly attenuated the reductions in blood pressure, left ventricular pressure and ± dp/dtmax, increases in serum alanine aminotransferase and aspartate aminotransferase activities, and reductions in serum Zn(2+) and albumin levels (P<0.05 or 0.01) induced by doxorubicin. In rats treated with doxorubicin, taurine zinc dose-dependently increased liver superoxide dismutase activity and glutathione concentration, and decreased malondialdehyde level (P<0.01). qBase(+) was used to evaluate the stability of eight candidate reference genes for real-time quantitative reverse-transcription PCR. Taurine zinc dose-dependently increased liver heme oxygenase-1 and UDP-glucuronyl transferase mRNA and protein expression (P<0.01). Western blotting demonstrated that taurine zinc inhibited c-Jun N-terminal kinase phosphorylation by upregulating dual-specificity phosphoprotein phosphatase-1. Additionally, taurine zinc inhibited cardiomyocyte apoptosis as there was decreased TUNEL/DAPI positivity and protein expression of caspase-3. These results indicate that taurine zinc solid dispersions prevent the side-effects of anthracycline-based anticancer therapy. The mechanisms might be associated with the enhancement of antioxidant defense system partly through activating transcription to synthesize endogenous phase II medicine enzymes and anti-apoptosis through inhibiting JNK phosphorylation.

Effect of Perineural or Intravenous Betamethasone on Femoral Nerve Block Outcomes in Knee Arthroplasty: A Randomized, Controlled Study.

OBJECTIVES: Despite the use of multimodal analgesia, patients undergoing knee arthroplasty still encounter residual moderate pain. The addition of betamethasone to local anesthetic has been shown to improve postoperative pain. However, it remains uncertain whether the positive effects of perineural or intravenous administration of betamethasone on analgesia outcomes lead to better early mobility and postoperative recovery. METHODS: Between June 2022 and February 2023, a total of 159 patients who were undergoing knee arthroplasty were included in this study. These patients were allocated randomly into three groups: (i) the NS group, received ropivacaine 0.375% and intravenous 3mL 0.9% normal saline; (ii) the PNB group, received ropivacaine 0.375% plus perineural betamethasone (12mg) 3mL and intravenous 3mL 0.9% normal saline; and (iii) the IVB group, received ropivacaine 0.375% and intravenous betamethasone (12mg) 3mL. RESULTS: Both perineural and intravenous administration of betamethasone led to improved median (IQR) numeric rating scale (NRS) scores on the 6-meter walk test, with a score of 1.0 (1.0-2.0) for both groups, compared with 2.0 (1.0-2.0) for the NS group (p = 0.003). Compared to the NS group, both the PNB and IVB groups showed significant reductions in NRS scores at 24 and 36 h after surgery, along with a significant increase in ROM at 24, 36, and 48 h post-operation. Additionally, it exhibited lower levels of cytokine IL-1ß and TNF-α in fluid samples, as well as lower level of HS-CRP in blood samples in the PNB and IVB groups compared to the NS group. CONCLUSION: The administration of perineural and intravenous betamethasone demonstrated an enhanced analgesic effect following knee arthroplasty. Furthermore, it was associated with reduced levels of IL-1ß, TNF-α, and HS-CRP, as well as enhanced knee ROM, which is conducive to early ambulation and postoperative rehabilitation after knee arthroplasty.

Effect of Bone Cement Thickness on the Risk of Scalded Skin in Joint Surgery.

OBJECTIVE: Bone cement releases a large amount of heat as it polymerizes. Skin burns caused by discarded bone cement are not well understood during arthroplasty. It is important to study the correlates and mechanisms of scalding and to accurately evaluate the severity of burns to guide treatment decisions. METHODS: Standardized burns were created in eight anesthetized rabbits using different thicknesses of bone cement. Bone cement was uniformly stirred to make thicknesses of 1 mm, 4 mm, 8 mm, 12 mm, 16 mm, and 20 mm and a 20 × 40 mm cuboid. Bone cement samples were then placed on the back of a rabbit, and the temperature changes were recorded with an industrial digital thermometer. One hour later, the appearance of scalded skin was observed, and the rabbits were euthanized. The scalded parts were cut to make pathological sections and stained with HE, and the differences in the depth of the scalded skin caused by different thicknesses of bone cement were observed under a light microscope. RESULTS: Damage caused by 1 mm-, 4 mm-, 8 mm-, 12 mm-, 16 mm-, and 20 mm-thick bone cement samples mainly involved the epidermis, the papillary dermis, the reticular dermis layer, and the full thickness of the skin and the subcutaneous tissue. The maximum temperature of 1 mm, 4 mm, 8 mm, and 12 mm bone cementation had a statistically significant difference (p < 0.001), while there was no significant difference between 12 mm, 16 mm, and 20 mm samples (p = 0.856). The time to severe scalding with bone cement at temperatures above 70°C was significantly different between different thicknesses (p < 0.001). CONCLUSION: The heat released by different thicknesses of bone cement leads to different maximum temperatures and the duration of severe burns, resulting in different degrees of skin burns. Attention should be paid to discarded bone cement to prevent this potential complication in knee arthroplasty.

PBX1 attenuates 6-OHDA-induced oxidative stress and apoptosis and affects PINK1/PARKIN expression in dopaminergic neurons via FOXA1.

PBX1 expression has been found to be significantly reduced in nigrostriatal neurons of PD patients, but the effect of PBX1 on ROS and apoptosis in nigrostriatal dopamine neurons is not yet known. This paper aimed to explore whether PBX1 could be involved in the development of PD. The construction of the in vitro PD model was followed by the determination of PBX1 expression. Then, PBX1 was overexpressed to observe the changes in the cell viability, TH expression, oxidative stress and apoptosis of the model. The mitochondrial membrane potential analysis and detection of PINK1/parkin expression were also conducted. To observe whether FOXA1 was involved in the mechanism, its expression was measured, and its association with PBX1 was determined. Subsequently, FOXA1 was silenced to observe whether PBX1 did effects on dopaminergic neuron via FOXA1. PBX1 attenuates 6-OHDA-induced dopaminergic neuronal cell injury and oxidative stress, and apoptosis. Its overexpression ameliorates mitochondrial dysfunction in dopaminergic neurons and upregulates the expression of PINK1/parkin. PBX1 could combine with FOXA1 and affects 6-OHDA-induced dopaminergic neuronal damage and regulates PINK1/PARKIN expression via FOXA1. To conclude, PBX1 attenuates 6-OHDA-induced oxidative stress and apoptosis in dopaminergic neurons, and affected PINK1/PARKIN expression via FOXA1, which indicates the great potential of the PBX1 in prevention against PD.

Influence of traditional Chinese medicines on the in vivo metabolism of lopinavir/ritonavir based on UHPLC-MS/MS analysis.

A fast, reliable, and cost-effective liquid chromatography-tandem mass spectrometry method was established to determine the effects of the traditional Chinese medicine employed to treat coronavirus disease 2019, namely, Lianhua Qingwen granules, Huoxiang Zhengqi capsules, Jinhua Qinggan granules, Shufeng Jiedu capsules, and Angong Niuhuang pills, on the pharmacokinetics of lopinavir/ritonavir in rats. Blood samples were prepared using the protein precipitation method and atazanavir was selected as the internal standard (IS). Separation was performed on an Agilent ZORBAX eclipse plus C18 (2.1 mm × 50 mm, 1.8 µm) column using acetonitrile and water containing 0.1% formic acid as the mobile phase for gradient elution. The flow rate was 0.4 mL/min and the injection volume was 2 µL. Agilent Jet Stream electrospray ionization was used for mass spectrometry detection under positive ion multiple reaction monitoring mode at a transition of m/z 629.3→447.3 for lopinavir, m/z 721.3→296.1 for ritonavir, and m/z 705.4→168.1 for the IS. The method showed good linearity in the concentration range of 25-2500 ng/mL (r=0.9981) for lopinavir and 5-500 ng/mL (r=0.9984) for ritonavir. The intra-day and inter-day precision and accuracy were both within ±15%. Items, such as dilution reliability and residual effect, were also within the acceptable limits. The method was used to determine the effects of five types of traditional Chinese medicines on the pharmacokinetics of lopinavir/ritonavir in rats. The pharmacokinetic results showed that the half-life of ritonavir in the groups administered Lianhua Qingwen granules and Huoxiang Zhengqi capsules combined with lopinavir/ritonavir was prolonged by approximately 1.5- to 2-fold relative to that in the control group. Similarly, the pharmacokinetic parameters of lopinavir were altered. Overall, the results of this study offer important theoretical parameters for the effective clinical use of five types of traditional Chinese medicines combined with lopinavir/ritonavir to reduce the occurrence of clinical adverse reactions.

Application and Development of Modern 3D Printing Technology in the Field of Orthopedics.

3D printing, also known as additive manufacturing, is a technology that uses a variety of adhesive materials such as powdered metal or plastic to construct objects based on digital models. Recently, 3D printing technology has been combined with digital medicine, materials science, cytology, and other multidisciplinary fields, especially in the field of orthopedic built-in objects. The development of advanced 3D printing materials continues to meet the needs of clinical precision medicine and customize the most suitable prosthesis for everyone to improve service life and satisfaction. This article introduces the development of 3D printing technology and different types of materials. We also discuss the shortcomings of 3D printing technology and the current challenges, including the poor bionics of 3D printing products, lack of ideal bioinks, product safety, and lack of market supervision. We also prospect the future development trends of 3D printing.

Sex differences in outcomes after mechanical thrombectomy for acute ischemic stroke in the 'real world': protocol for a systematic review and meta-analysis study.

INTRODUCTION: Mechanical thrombectomy (MT) had been regarded as the first-line therapy for acute ischaemic stroke patients. The sex differences in post-MT treatment outcomes were analysed by randomised controlled trial (RCT) studies with inconsistent conclusions. We suggest the results from the real-world data may differ from RCT containing studies. Therefore, the sex difference in non-clinical trial populations needs to be clarified. METHODS AND ANALYSIS: In order to obtain relative studies comprehensively, we will search the main document databases, consisting of Web of Science, Medline in Ovid, Embase in Ovid and Cochrane Library, and trials registers, including Clinical Trails register. The clinical outcomes of real-world studies published between January 2015 and March 2022 will be included. The assessment methods of bias risk will be performed according to study type. The inclusion of studies, evaluation of risk and publication bias, data extraction will be implemented by two reviewers, respectively. The primary outcomes include successful recanalisation and 90-day favourable outcome. Secondary outcomes include vascular complication, hospital-related complications, death during hospital stay and follow-up, and intracerebral haemorrhage. The risk bias of observational studies will be evaluated by Newcastle-Ottawa Scale. I2 statistic will be used to perform the assessment of study heterogeneity. ETHICS AND DISSEMINATION: With no need of ethics approval in this review, results in this review ground on public data. The results of the study will be eventually presented at international conferences or in a related journal. PROSPERO REGISTRATION NUMBER: CRD42021242597.

Can Increasing Scale Efficiency Curb Agricultural Nonpoint Source Pollution?

The Chinese government has made great efforts to improve the scale efficiency of land through various measures during recent years, hoping to realize the coordinated developing goal of promoting agricultural benefits and protecting the environment. Statistics show that China's land scale efficiency has steadily increased, but agricultural nonpoint source (NPS) pollution has also increased, which seems contrary to the expected outcome. Can increasing scale efficiency really curb agricultural NPS pollution? This study uses provincial-level data from China, together with a panel model and spatial econometric model, to investigate the relationship between scale efficiency and agricultural NPS pollution. It is found that the increase of scale efficiency aggravates the agricultural NPS pollution, and the conclusion still holds after considering spatial effect. The results of spatial analysis shows that the agricultural NPS pollution is spatially dependent. Further decomposition of the spatial effect shows that the scale efficiency not only intensifies the local agricultural NPS pollution, but also has a spillover effect (though not statistically significant) on agricultural NPS pollution in the surrounding areas. It is worth noting that financial policy, raising wage income and upgrading industrial structure can effectively curb agricultural NPS pollution in this region and adjacent areas, which also deserves our attention in the control of agricultural NPS pollution. In addition, it is necessary to make financial and fiscal support policies specifically for the governance of agricultural NPS pollution, adjust the distorted prices of input factors such as chemicals and pesticide, and accelerate the transformation of small-sized farmers to family farms, in order to maximize the inhibitory effect of scale efficiency on relieving agricultural NPS pollution.

Novel self-healing and multi-stimuli-responsive supramolecular gel based on d-sorbitol diacetal for multifunctional applications.

A simple-structured super gelator with self-healability and multi-stimuli responses was reported herein, which exhibited multiple visual molecular recognition abilities. Multifunctional applications such as effective lubricants, safe fuels, high-efficient propellants, dyes adsorbents, enhanced fluorescence emission and separation of aldehydes from aqueous solutions are integrated into a single organogelator, which was rarely reported.

Near-Infrared Light Irradiation Induced Mild Hyperthermia Enhances Glutathione Depletion and DNA Interstrand Cross-Link Formation for Efficient Chemotherapy.

DNA alkylating agents generally kill tumor cells by covalently binding with DNA to form interstrand or intrastrand cross-links. However, in the case of cisplatin, only a few DNA adducts (<1%) are highly toxic irreparable interstrand cross-links. Furthermore, cisplatin is rapidly detoxified by high levels of intracellular thiols such as glutathione (GSH). Since the discovery of its mechanism of action, people have been looking for ways to directly and efficiently remove intracellular GSH and increase interstrand cross-links to improve drug efficacy and overcome resistance, but there has been little breakthrough. Herein, we hypothesized that the anticancer efficiency of cisplatin can be enhanced through iodo-thiol click chemistry mediated GSH depletion and increased formation of DNA interstrand cross-links via mild hyperthermia triggered by near-infrared (NIR) light. This was achieved by preparing an amphiphilic polymer with platinum(IV) (Pt(IV)) prodrugs and pendant iodine atoms (iodides). The polymer was further used to encapsulate IR780 and assembled into Pt-I-IR780 nanoparticles. Induction of mild hyperthermia (43 °C) at the tumor site by NIR light irradiation had three effects: (1) it accelerated the GSH-mediated reduction of Pt(IV) in the polymer main chain to platinum(II) (Pt(II)); (2) it boosted the iodo-thiol substitution click reaction between GSH and iodide, thereby attenuating the GSH-mediated detoxification of cisplatin; (3) it increased the proportion of highly toxic and irreparable Pt-DNA interstrand cross-links. Therefore, we find that mild hyperthermia induced via NIR irradiation can enhance the killing of cancer cells and reduce the tumor burden, thus delivering efficient chemotherapy.

Established UPLC-MS/MS procedure for multicomponent quantitative analysis in rat plasma: A contrastive pharmacokinetics study of Qiangshen tablet in normal and kidney yang deficiency syndrome models.

Qiangshen tablet, an important prescription consisting of 14 kinds of Chinese herbal medicines, has been used for decades to treat kidney yang deficiency syndrome (KYDS) in China. Qiangshen tablet has been recorded in ChP (2015 edition) and possesses the effect of strengthening yang, invigorating qi and tonifying kidneys. In this research, a simple, reliable and specific method was established for simultaneous determination of stachydrine, psoralen, isopsoralen, morroniside, paeoniflorin and loganin in normal and KYDS rat plasma after intragastric administration of a Qiangshen tablet suspension by UPLC-MS/MS. Protein precipitation (PP) by acetonitrile and liquid-liquid extraction (LLE) by ethyl acetate - n-butanol (1: 1, v/v) were used for pretreatment of plasma samples. Chromatographic separation of two IS (Internal Standard) and six analytes was achieved using an ACQUITY UPLC® BEH C18 column (2.1 × 100 mm, 1.7 µm). The mobile phase consisted of 0.1% formic acid aqueous solution (solvent A) and acetonitrile (solvent B) with a gradient scheme. Multiple reaction monitoring (MRM) mode with positive and negative ion source switching was applied to perform the mass spectrometric analyses. This method has been validated with good linearity (r ≥ 0.9942) and acceptable precision and accuracy (RSD ≤ 11%, RE from -4.8% to 7.7%). The mean recovery values of the analytes and IS were all ≥68.28%, and the matrix effects ranged from 94.4% to 101.7%. The stability of the IS and analytes was measured throughout the experiment. The results showed significant differences between the pharmacokinetic traits of the analytes in the normal and KYDS groups, suggesting that pharmacokinetic procedures involving these analytes could be modified in cases of KYDS.

In vivo study of erysolin metabolic profile by ultra high performance liquid chromatography coupleded to Fourier transform ion cyclotron resonance mass spectrometry.

An ultra high performance liquid chromatography coupled to Fourier transform ion cyclotron resonance mass spectrometry (UHPLC-FT-ICR-MS) method was developed for the first time to study the in vivo metabolism of erysolin, a compound derived from cruciferous plants which has a definite effect of anti-tumor and anti-nerve injury. In this research, the chromatographic separation was performed on an ACQUITY UPLC® BEH C18 column (2.1 mm×100mm, 1.7µm, Waters, USA) and eluted by a gradient program, the identification work was achieved on a Bruker ultra-high resolution spectrometer in positive ion mode. Plasma, urine, feces and bile samples were collected from rats to screen metabolites after an intragastric administration of erysolin at the dose of 100mg/kg. As a result, the parent drug and a total of six phase II metabolites were detected and preliminarily identified by analyzing their MS and MS/MS spectrometry profiles. Our results indicated that erysolin mainly metabolized via the mercapturic acid metabolic pathway, erysolin first react with glutathione to form glutathione conjugate, followed by taking off the glutamic acid and glycine to form cysteine conjugate, then the N-acetylation reaction occurs, the product would be excreted out of the body at last. In conclusion, results obtained in our study may contribute to a better understanding of the metabolism process and characteristics of erysolin in vivo, and provide an important reference for future research.