PIM1 alleviated liver oxidative stress and NAFLD by regulating the NRF2/HO-1/NQO1 pathway.

AIMS: Non-alcoholic fatty liver disease (NAFLD) has risen as a significant global public health issue, for which vertical sleeve gastrectomy (VSG) has become an effective treatment method. The study sought to elucidate the processes through which PIM1 mitigates the advancement of NAFLD. The Pro-viral integration site for Moloney murine leukemia virus 1 (PIM1) functions as a serine/threonine kinase. Bioinformatics analysis revealed that reduced PIM1 expression in NAFLD. METHODS: To further prove the role of PIM1 in NAFLD, an in-depth in vivo experiment was performed, in which male C57BL/6 mice were randomly grouped to receive a normal or high-fat diet for 24 weeks. They were operated or delivered the loaded adeno-associated virus which the PIM1 was overexpressed (AAV-PIM1). In an in vitro experiment, AML12 cells were treated with palmitic acid to induce hepatic steatosis. KEY FINDINGS: The results revealed that the VSG surgery and virus delivery of mice alleviated oxidative stress, and apoptosis in vivo. For AML12 cells, the levels of oxidative stress, apoptosis, and lipid metabolism were reduced via PIM1 upregulation. Moreover, ML385 treatment resulted in the downregulation of the NRF2/HO-1/NQO1 signaling cascade, indicating that PIM1 mitigates NAFLD by targeting this pathway. SIGNIFICANCE: PIM1 alleviated mice liver oxidative stress and NAFLD induced by high-fat diet by regulating the NRF2/HO-1/NQO1 signaling Pathway.

[Determination of six halogenated solvent residues in olive oil by headspace gas chromatography].

The residual amount of halogenated solvents in olive oil is an important indicator of its quality. The National Olive Oil Quality Standard GB/T 23347-2021 states that the residual amount of individual halogenated solvents in olive oil should be ≤0.1 mg/kg and that the total residual amount of halogenated solvents should be ≤0.2 mg/kg. COI/T.20/Doc. No. 8-1990, which was published by the International Olive Council, describes the standard method used for the determination of halogenated solvents in olive oil. Unfortunately, this method is cumbersome, has poor repeatability and low automation, and is unsuitable for the detection and analysis of residual halogenated solvents in large quantities of olive oil. At present, no national standard method for determining residual halogenated solvents in olive oil is available in China. Thus, developing simple, efficient, accurate, and stable methods for the determination of residual halogenated solvents in olive oil is imperative. In this paper, a method based on automatic headspace gas chromatography was established for the determination of residual halogenated solvents, namely, chloroform, carbon tetrachloride, 1,1,1-trichloroethane, dibromochloromethane, tetrachloroethylene, and bromoform, in olive oil. The samples were processed as follows. After mixing, 2.00 g (accurate to 0.01 g) of the olive oil sample was added into a 20 mL headspace injection bottle and immediately sealed for headspace gas chromatography analysis. Blank virgin olive oil was used to prepare a standard working solution and the external standard method for quantification. The solvents used in the preparation of halogenated solvent standard intermediates were investigated and methanol was selected as a replacement for N,N-dimethylacetamide to prepare a halogenated solvent standard intermediate owing to its safety. The effects of different injection times (1, 2, 3, 4, 5, 6 s), equilibration temperatures (60, 70, 80, 90, 100, 110, 120 ℃), and equilibration times (4, 5, 8, 10, 20, 30, 40 min) of the headspace sampler on the detection of the residual amounts of the six halogenated solvents were investigated. The optimal injection time and equilibration temperature were 3 s and 90 ℃, respectively. The method demonstrated good analytical performance for the six halogenated solvents when the equilibration time was 30 min. A methodological study was conducted on the optimized method, and the results showed that the six halogenated solvents exhibited good linear relationships in the range of 0.002-0.200 mg/kg, with correlation coefficients of ≥0.9991. The limits of detection (LODs) and quantification (LOQs) of 1,1,1-trichloroethane and bromoform were 0.0006 and 0.002 mg/kg, respectively. The LODs and LOQs of chloroform, carbon tetrachloride, dibromochloromethane, and tetrachloroethylene were 0.0003 and 0.001 mg/kg, respectively. The average recoveries under different spiked levels were 85.53%-115.93%, and the relative standard deviations (n=6) were 1.11%-8.48%. The established method was used to analyze 13 olive oil samples available in the market. Although no halogenated solvents were detected in these samples, a limited number of samples does not represent all olive oils. Hence, monitoring residual halogenated solvents in olive oil remains necessary for its safe consumption. The LOQs of the method for the six halogenated solvents were significantly lower than that of the COI/T.20/Doc. No. 8-1990 standard method (0.02 mg/kg). In addition, the developed method can be conducted under short operation times with high precision and degree of automation as well as good accuracy. Thus, the proposed method is suitable for the determination and analysis of the residues of the six halogenated solvents in large batches of olive oil samples.

Copper-Catalyzed Enantioconvergent Radical N-Alkylation of Diverse (Hetero)aromatic Amines.

The 3d transition metal-catalyzed enantioconvergent radical cross-coupling provides a powerful tool for chiral molecule synthesis. In the classic mechanism, the bond formation relies on the interaction between nucleophile-sequestered metal complexes and radicals, limiting the nucleophile scope to sterically uncongested ones. The coupling of sterically congested nucleophiles poses a significant challenge due to difficulties in transmetalation, restricting the reaction generality. Here, we describe a probable outer-sphere nucleophilic attack mechanism that circumvents the challenging transmetalation associated with sterically congested nucleophiles. This strategy enables a general copper-catalyzed enantioconvergent radical N-alkylation of aromatic amines with secondary/tertiary alkyl halides and exhibits catalyst-controlled stereoselectivity. It accommodates diverse aromatic amines, especially bulky secondary and primary ones to deliver value-added chiral amines (>110 examples). It is expected to inspire the coupling of more nucleophiles, particularly challenging sterically congested ones, and accelerate reaction generality.

Neurogenic Effects of Inorganic Arsenic and Cdk5 Knockdown in Zebrafish Embryos: A Perspective on Modeling Autism.

The exact mechanisms of the development of autism, a multifactorial neurological disorder, are not clear. The pathophysiology of autism is complex, and investigations at the cellular and molecular levels are ongoing to provide clarity. Mutations in specific genes have been identified as risk factors for autism. The role of heavy metals in the pathogenesis of autism is subject to many studies and remains debatable. Although no exact neuronal phenotypes have been identified linked to autistic symptoms, overproduction and reduction of specific neurons have been implicated. A growing literature on generating genetic and non-genetic models of autism aims to help with understanding mechanistic studies that can explain the complexity of the disorder. Both genetic and non-genetic methods of zebrafish have been used to model autism. For several human autism risk genes, validated zebrafish mutant models have been generated. There is growing evidence indicating a potential link between autism and inorganic arsenic exposure. We have previously shown that inorganic arsenic induces supernumerary spinal motor neurons via Sonic hedgehog (Shh) signaling pathway, and Cdk5 knockdown causes an overproduction of cranial and spinal motor neurons in zebrafish. Here, in this review, we provide a perspective on what these findings of neurogenic phenotypes mean in terms of dysregulated pathways of motor neuron development and their applicability to understanding cellular and molecular underpinnings of autism.

Na2S2O3 Catalyzed Three-Component Synthesis and Anti-Bacterial Activity of 3-Methyl-4-(hetero)arylmethylene isoxazole-5(4H)-ones.

An efficient and green method for synthesizing 3-methyl-4-(hetero) arylmethylene isoxazole-5(4H)-ones was developed using a recyclable and environmental-friendly catalyst, Na2S2O3, and 16 target compounds were successfully synthesized under the obtained optimal reaction condition. Using rifampicin as a positive control, the antibacterial activity of all synthesized compounds was tested by micro dilution method, among them, 3-methyl-4-[(2,4-dimethoxyphenyl) methylene]-isoxazole-5-one (4 m) presented wonderful antimicrobial activity, which may contribute to the development of anti-tuberculosis drugs.

Silencing suppressor of cytokine signaling 3 induces apoptosis and activates the p-STAT3/NF-κ B pathway in hypoxic cultivated H9c2 cells

Suppressor of cytokine signaling 3 (SOCS3) plays a significant role in the process of myocardial adaptation to chronic hypoxia. SOCS3 finely regulates cell signaling cross-talk that occurs between NF-κB and STAT3 during the compensatory protective response. However, the role and mechanism of SOCS3 in hypoxic cardiomyocytes are not fully understood. In the study, we investigated the effect of SOCS3 on the p65 and STAT3 signaling pathways and further examined the potential molecular mechanism involved in regulating apoptosis. Our data showed that SOCS3 silencing could upregulate Ac-p65, p-p65, and p-STAT3 expression in nuclear extracts of H9c2 cells that received hypoxic treatment for 24, 48, and 72 h. SOCS3 silencing also remarkably increased the DNA-binding activity of the p65 motif in hypoxic cultivated H9c2 cells. We also found that SOCS3 knockdown increased cleaved-caspase-3, Bax, and PUMA expression and decreased cleaved PARP and Bcl-2 in expression in hypoxic H9c2 cells. Silencing of SOCS3 caused an increase in LDH leakage from injured cardiomyocytes and reduced cell viability under conditions of hypoxic stress. Furthermore, SOCS3 silencing enhanced the apoptosis of H9c2 cells at 72 h of hypoxia. These findings suggest that knockdown of SOCS3 leads to excessive activation of the NF-κB pathway, which, in turn, might promote apoptosis under conditions of chronic hypoxia. (AU)

Silencing suppressor of cytokine signaling 3 induces apoptosis and activates the p-STAT3/NF-κ B pathway in hypoxic cultivated H9c2 cells

Suppressor of cytokine signaling 3 (SOCS3) plays a significant role in the process of myocardial adaptation to chronic hypoxia. SOCS3 finely regulates cell signaling cross-talk that occurs between NF-κB and STAT3 during the compensatory protective response. However, the role and mechanism of SOCS3 in hypoxic cardiomyocytes are not fully understood. In the study, we investigated the effect of SOCS3 on the p65 and STAT3 signaling pathways and further examined the potential molecular mechanism involved in regulating apoptosis. Our data showed that SOCS3 silencing could upregulate Ac-p65, p-p65, and p-STAT3 expression in nuclear extracts of H9c2 cells that received hypoxic treatment for 24, 48, and 72 h. SOCS3 silencing also remarkably increased the DNA-binding activity of the p65 motif in hypoxic cultivated H9c2 cells. We also found that SOCS3 knockdown increased cleaved-caspase-3, Bax, and PUMA expression and decreased cleaved PARP and Bcl-2 in expression in hypoxic H9c2 cells. Silencing of SOCS3 caused an increase in LDH leakage from injured cardiomyocytes and reduced cell viability under conditions of hypoxic stress. Furthermore, SOCS3 silencing enhanced the apoptosis of H9c2 cells at 72 h of hypoxia. These findings suggest that knockdown of SOCS3 leads to excessive activation of the NF-κB pathway, which, in turn, might promote apoptosis under conditions of chronic hypoxia. (AU)

Copper-Catalyzed Enantioselective C(sp3 )-SCF3 Coupling of Carbon-Centered Benzyl Radicals with (Me4 N)SCF3.

In contrast with the well-established C(sp2 )-SCF3 cross-coupling to forge the Ar-SCF3 bond, the corresponding enantioselective coupling of readily available alkyl electrophiles to forge chiral C(sp3 )-SCF3 bond has remained largely unexplored. We herein disclose a copper-catalyzed enantioselective radical C(sp3 )-SCF3 coupling of a range of secondary/tertiary benzyl radicals with the easily available (Me4 N)SCF3 reagent. The key to the success lies in the utilization of chiral phosphino-oxazoline-derived anionic N,N,P-ligands through tuning electronic and steric effects for the simultaneous control of the reaction initiation and enantioselectivity. This strategy can successfully realize two types of asymmetric radical reactions, including enantioconvergent C(sp3 )-SCF3 cross-coupling of racemic benzyl halides and three-component 1,2-carbotrifluoromethylthiolation of arylated alkenes under mild reaction conditions. It therefore provides a highly flexible platform for the rapid assembly of an array of enantioenriched SCF3 -containing molecules of interest in organic synthesis and medicinal chemistry.

Cytochrome P450 26A1 Contributes to the Maintenance of Neuropathic Pain.

The cytochrome P450 proteins (CYP450s) have been implicated in catalyzing numerous important biological reactions and contribute to a variety of diseases. CYP26A1, a member of the CYP450 family, carries out the oxidative metabolism of retinoic acid (RA), the active metabolite of vitamin A. Here we report that CYP26A1 was dramatically upregulated in the spinal cord after spinal nerve ligation (SNL). CYP26A1 was mainly expressed in spinal neurons and astrocytes. HPLC analysis displayed that the content of all-trans-RA (at-RA), the substrate of CYP26A1, was reduced in the spinal cord on day 7 after SNL. Inhibition of CYP26A1 by siRNA or inhibition of CYP26A1-mediated at-RA catabolism by talarozole relieved the SNL-induced mechanical allodynia during the maintenance phase of neuropathic pain. Talarozole also reduced SNL-induced glial activation and proinflammatory cytokine production but increased anti-inflammatory cytokine (IL-10) production. The RA receptors RARα, RXRß, and RXRγ were expressed in spinal neurons and glial cells. The promoter of Il-10 has several binding sites for RA receptors, and at-RA directly increased Il-10 mRNA expression in vitro. Finally, intrathecal IL-10 attenuated SNL-induced neuropathic pain and reduced the activation of astrocytes and microglia. Collectively, the inhibition of CYP26A1-mediated at-RA catabolism alleviates SNL-induced neuropathic pain by promoting the expression of IL-10 and suppressing glial activation. CYP26A1 may be a potential therapeutic target for the treatment of neuropathic pain.

A general copper-catalysed enantioconvergent C(sp3)-S cross-coupling via biomimetic radical homolytic substitution.

Although α-chiral C(sp3)-S bonds are of enormous importance in organic synthesis and related areas, the transition-metal-catalysed enantioselective C(sp3)-S bond construction still represents an underdeveloped domain probably due to the difficult heterolytic metal-sulfur bond cleavage and notorious catalyst-poisoning capability of sulfur nucleophiles. Here we demonstrate the use of chiral tridentate anionic ligands in combination with Cu(I) catalysts to enable a biomimetic enantioconvergent radical C(sp3)-S cross-coupling reaction of both racemic secondary and tertiary alkyl halides with highly transformable sulfur nucleophiles. This protocol not only exhibits a broad substrate scope with high enantioselectivity but also provides universal access to a range of useful α-chiral alkyl organosulfur compounds with different sulfur oxidation states, thus providing a complementary approach to known asymmetric C(sp3)-S bond formation methods. Mechanistic results support a biomimetic radical homolytic substitution pathway for the critical C(sp3)-S bond formation step.

Silencing suppressor of cytokine signaling 3 induces apoptosis and activates the p-STAT3/NF-κB pathway in hypoxic cultivated H9c2 cells.

Suppressor of cytokine signaling 3 (SOCS3) plays a significant role in the process of myocardial adaptation to chronic hypoxia. SOCS3 finely regulates cell signaling cross-talk that occurs between NF-κB and STAT3 during the compensatory protective response. However, the role and mechanism of SOCS3 in hypoxic cardiomyocytes are not fully understood. In the study, we investigated the effect of SOCS3 on the p65 and STAT3 signaling pathways and further examined the potential molecular mechanism involved in regulating apoptosis. Our data showed that SOCS3 silencing could upregulate Ac-p65, p-p65, and p-STAT3 expression in nuclear extracts of H9c2 cells that received hypoxic treatment for 24, 48, and 72 h. SOCS3 silencing also remarkably increased the DNA-binding activity of the p65 motif in hypoxic cultivated H9c2 cells. We also found that SOCS3 knockdown increased cleaved-caspase-3, Bax, and PUMA expression and decreased cleaved PARP and Bcl-2 in expression in hypoxic H9c2 cells. Silencing of SOCS3 caused an increase in LDH leakage from injured cardiomyocytes and reduced cell viability under conditions of hypoxic stress. Furthermore, SOCS3 silencing enhanced the apoptosis of H9c2 cells at 72 h of hypoxia. These findings suggest that knockdown of SOCS3 leads to excessive activation of the NF-κB pathway, which, in turn, might promote apoptosis under conditions of chronic hypoxia.

Development and external validation of dual online tools for prognostic assessment in elderly patients with high-grade glioma: a comprehensive study using SEER and Chinese cohorts.

Background: Elderly individuals diagnosed with high-grade gliomas frequently experience unfavorable outcomes. We aimed to design two web-based instruments for prognosis to predict overall survival (OS) and cancer-specific survival (CSS), assisting clinical decision-making. Methods: We scrutinized data from the SEER database on 5,245 elderly patients diagnosed with high-grade glioma between 2000-2020, segmenting them into training (3,672) and validation (1,573) subsets. An additional external validation cohort was obtained from our institution. Prognostic determinants were pinpointed using Cox regression analyses, which facilitated the construction of the nomogram. The nomogram's predictive precision for OS and CSS was gauged using calibration and ROC curves, the C-index, and decision curve analysis (DCA). Based on risk scores, patients were stratified into high or low-risk categories, and survival disparities were explored. Results: Using multivariate Cox regression, we identified several prognostic factors for overall survival (OS) and cancer-specific survival (CSS) in elderly patients with high-grade gliomas, including age, tumor location, size, surgical technique, and therapies. Two digital nomograms were formulated anchored on these determinants. For OS, the C-index values in the training, internal, and external validation cohorts were 0.734, 0.729, and 0.701, respectively. We also derived AUC values for 3-, 6-, and 12-month periods. For CSS, the C-index values for the training and validation groups were 0.733 and 0.727, with analogous AUC metrics. The efficacy and clinical relevance of the nomograms were corroborated via ROC curves, calibration plots, and DCA for both cohorts. Conclusion: Our investigation pinpointed pivotal risk factors in elderly glioma patients, leading to the development of an instrumental prognostic nomogram for OS and CSS. This instrument offers invaluable insights to optimize treatment strategies.

CCL19: a novel prognostic chemokine modulates the tumor immune microenvironment and outcomes of cancers.

BACKGROUND: CCL19 is a chemokine involved in cancer research due to its important role in the tumor microenvironment (TME) and clinical relevance in cancers. This study aimed to analyze transcription expression, genomic alteration, association with tumor immune microenvironment of CCL19 expression and its prediction value for prognosis and responses to immunotherapy for patients with cancers. METHODS: RNA sequencing data and corresponding clinicopathological information of a total of large-scale cancer patients were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases. Multiplex immunofluorescence (mIF) was implemented to identify differential infiltration of Treg, CD8+ T cells, and tumor-associated macrophages, while CCL19 immunohistochemistry was conducted on 182 breast cancer samples from a real-world cohort. RESULTS: Based on large-scale multi-center survival analysis of cancer patients, we found the prognosis of patients with high CCL19 expression was prominently better than those with low CCL19 expression. For patients from multiple independent cohorts, suppressed CCL19 expression exerts significant progressive phenotype and apoptosis activity of cancers, especially in breast and ovarian cancer. Interestingly, anti-tumor immune cells, specifically the CD8+ T cells and macrophages, were clustered from TME by elevated CCL19 expression. Additionally, higher CCL19 levels reflected heightened immune activity and substantial heterogeneity. CONCLUSIONS: In conclusion, our findings support the notion that elevated CCL19 expression is linked to favorable outcomes and enhanced anti-tumor immunity, characterized by increased CD8+ T cells within the TME. This suggests the potential of CCL19 as a prognostic marker, predictive biomarker for immunotherapy, therapeutic target of cancers.

Long-term fencing can't benefit plant and microbial network stability of alpine meadow and alpine steppe in Three-River-Source National Park.

A great number of fencing facilities has been established in Three-River-Source National Park. However, with the transformation of wild animals into the main consumers of grassland ecosystem and the increasing years of fence (>15 years), whether the fence still has a positive effect on grassland ecosystem has become controversial. Therefore, taking the alpine steppe and alpine meadow in Three-River-Source National Park as the case study, this study focused on the effects of long-term enclosure on different ecological components by investigating plant communities, soil physical and chemical characteristics and soil microbial characteristics (16S, ITS). Furthermore, we evaluated the ecological benefits of long-term fencing based on the stability of plant communities and microbial networks. We found that fencing did not significantly promote the stability of plant community in different grassland types. The analysis of bacteria-fungal symbiotic network indicated that fencing significantly reduced the stability of soil microbial network in alpine meadows. The results of structural equation showed that the microbial community was indirectly affected by the changes of soil moisture content (SMC) and soil total nutrient content in the alpine steppe, and the stability of microbial network was significantly correlated with the diversity of fungal community. In alpine meadows, fencing indirectly affected soil microbial community by changing SMC and pH. High SMC was not conducive to microbial network stability, while high plant community stability was beneficial to microbial network stability. Network stability was remarkably related to bacterial community composition and diversity, as well as fungal community diversity. Therefore, in Three-River-Source National Park, the positive effects of long-term fencing on various components in different grassland types are weak, especially the negative effects on the stability of soil microbial community in alpine meadows may also weaken the stability of the ecosystem, which is not conducive to the ecological protection of grassland ecosystem.

Gene expression analyses reveal potential mechanism of inorganic arsenic-induced apoptosis in zebrafish.

Our previous study showed that sodium arsenite (200 mg/L) affected the nervous system and induced motor neuron development via the Sonic hedgehog pathway in zebrafish larvae. To gain more insight into the effects of arsenite on other signaling pathways, including apoptosis, we have performed quantitative polymerase chain reaction array-based gene expression analyses. The 96-well array plates contained primers for 84 genes representing 10 signaling pathways that regulate several biological functions, including apoptosis. We exposed eggs at 5 h postfertilization until the 72 h postfertilization larval stage to 200 mg/L sodium arsenite. In the Janus kinase/signal transducers and activators of transcription, nuclear factor κ-light-chain-enhancer of activated B cells, and Wingless/Int-1 signaling pathways, the expression of only one gene in each pathway was significantly altered. The expression of multiple genes was altered in the p53 and oxidative stress pathways. Sodium arsenite induced excessive apoptosis in the larvae. This compelled us to analyze specific genes in the p53 pathway, including cdkn1a, gadd45aa, and gadd45ba. Our data suggest that the p53 pathway is likely responsible for sodium arsenite-induced apoptosis. In addition, sodium arsenite significantly reduced global DNA methylation in the zebrafish larvae, which may indicate that epigenetic factors could be dysregulated after arsenic exposure. Together, these data elucidate potential mechanisms of arsenic toxicity that could improve understanding of arsenic's effects on human health.

Copper-Catalyzed Enantioconvergent Radical C(sp3)-N Cross-Coupling of Activated Racemic Alkyl Halides with (Hetero)aromatic Amines under Ambient Conditions.

The enantioconvergent C(sp3)-N cross-coupling of racemic alkyl halides with (hetero)aromatic amines represents an ideal means to afford enantioenriched N-alkyl (hetero)aromatic amines yet has remained unexplored due to the catalyst poisoning specifically for strong-coordinating heteroaromatic amines. Here, we demonstrate a copper-catalyzed enantioconvergent radical C(sp3)-N cross-coupling of activated racemic alkyl halides with (hetero)aromatic amines under ambient conditions. The key to success is the judicious selection of appropriate multidentate anionic ligands through readily fine-tuning both electronic and steric properties for the formation of a stable and rigid chelating Cu complex. Thus, this kind of ligand could not only enhance the reducing capability of a copper catalyst to provide an enantioconvergent radical pathway but also avoid the coordination with other coordinating heteroatoms, thereby overcoming catalyst poisoning and/or chiral ligand displacement. This protocol covers a wide range of coupling partners (89 examples for activated racemic secondary/tertiary alkyl bromides/chlorides and (hetero)aromatic amines) with high functional group compatibility. When allied with follow-up transformations, it provides a highly flexible platform to access synthetically useful enantioenriched amine building blocks.

Evaluating the Activity of Neuraminidase in Bacterial Vaginosis Microflora and Imaging Sialic Acid on the Cell Membrane by Boron and Nitrogen Codoped Fluorescent Carbon Dots.

Sialic acids (SAs) are commonly located on the cell surface as terminal ends of glycoproteins and glycolipids. Neuraminidase (NEU) is a class of glycoside hydrolase enzymes that can cleave SAs from receptors. Both SA and NEU play important roles in human physiological and pathological processes of cell-cell interaction, communication, and signaling. Additionally, bacterial vaginosis (BV), a form of gynecological inflammation caused by dysbiosis of the vaginal microbiome, results in the abnormal activity of NEU in vaginal fluid. Here, we developed a novel probe for rapidly and selectively sensing SA and NEU based on a one-step prepared boron and nitrogen codoped fluorescent carbon dots (BN-CDs). The selective recognition reaction between SA and the phenylboronic acid groups on the surface of BN-CDs inhibits fluorescence emission from BN-CDs, while the NEU-catalyzed hydrolysis of SA bound on BN-CDs leads to fluorescence recovery. The probe was applied in diagnosing BV and showed consistent results to Amsel criteria. Moreover, the low cytotoxicity of BN-CDs facilitates its application in fluorescence imaging of SA on the membrane of red blood cells (RBCs) and leukemia cell lines (U937, KAS-1). The excellent sensitivity, accuracy, and applicability of the developed probe support its broad potential applications in future clinical diagnosis and treatment.

Association between the systemic immune-inflammation index and the efficacy of neoadjuvant chemotherapy, prognosis in HER2 positive breast cancer-a retrospective cohort study.

Background: The prognosis of patients who can achieve a complete response after neoadjuvant chemotherapy could be significantly improved. Thus, accurately predicting the efficacy of neoadjuvant chemotherapy is of great clinical significance. Currently, previous indicators such as neutrophil to lymphocyte ratio was poor in predicting the efficacy and prognosis of neoadjuvant chemotherapy in human epidermal growth factor receptor 2 (HER2) positive breast cancer patients. Methods: The data of 172 HER2 positive breast cancer patients admitted to the Nuclear 215 Hospital of Shaanxi Province from January 2015 to January 2017 were retrospectively collected. After neoadjuvant chemotherapy, the patients were divided into the complete response group (n=70) and the non-complete response group (n=102). The clinical characteristics and systemic immune-inflammation index (SII) levels of the two groups were compared. The patients were followed-up for 5 years post-surgery to observe whether recurrence or metastasis occurred after the operation by clinic visit combined with telephone calls. Results: The SII of the complete response group was significantly lower than that of the non-complete response group (587.43±175.97 vs. 821.82±231.58; P=0.000). The SII was valuable in predicting which HER2 positive breast cancer patients would fail to achieve a pathological complete response, and the area under the curve (AUC) was 0.773 [95% confidence interval (CI): 0.705-0.804; P=0.000]. A SII >755.10 was an adverse factor for HER2 positive breast cancer patients achieving a pathological complete response after neoadjuvant chemotherapy [P=0.000; relative risk (RR): 0.172 (95% CI: 0.082-0.358)]. The SII level was valuable in predicting recurrence within 5 years of surgery, and had an AUC of 0.828 (95% CI: 0.757-0.900; P=0.000). A SII >755.10 was a risk factor for recurrence within 5 years of surgery [P=0.001; RR: 4.945 (95% CI: 1.949-12.544)]. The SII level was valuable in predicting metastasis within 5 years of surgery, and had an AUC of 0.837 (95% CI: 0.756-0.917; P=0.000). A SII >755.10 was a risk factor for metastasis within 5 years of surgery [P=0.014, RR: 4.553 (95% CI: 1.362-15.220)]. Conclusions: The SII was associated with the prognosis and efficacy of neoadjuvant chemotherapy in HER2 positive breast cancer patients.

Bioinformatic analyzes and validation of cystathionine gamma-lyase as a prognostic biomarker and related to immune infiltrates in hepatocellular carcinoma.

Background: The role of cystathionine γ-lyase (CTH) in the prognosis and immune invasion of hepatocellular carcinoma (HCC) remains poorly understood. Methods: In this study, the clinical data of patients with HCC were analyzed, and the expression level of CTH was compared between HCC and normal tissues using the R package and various databases. Results: We found that CTH expression was significantly decreased in HCC compared with normal tissues, and its expression was associated with various clinicopathological factors, including tumor stage, gender, tumor status, residual tumor, histologic stage, race, alpha-fetoprotein (AFP), albumin, drinking, and smoking. Our results suggest that CTH might be a protective factor for the survival of patients with HCC. Further functional analysis revealed that high CTH expression was enriched in the Reactome signaling by interleukins and the Reactome neutrophil degranulation. Moreover, CTH expression was closely correlated with a variety of immune cells, including a negative correlation with the CD56 (bright) NK cells and follicular helper T cell (TFH), while a positive correlation with Th17 cells and central memory T cell (Tcm). High expression of CTH in immune cells predicted a better prognosis of HCC. Our findings further indicated Pyridoxal phosphate, l-cysteine, Carboxymethylthio-3-(3-chlorophenyl)-1,2,4-oxadiazol, 2-[(3-Hydroxy-2-Methyl-5-Phosphonooxymethyl-Pyridin-4-Ylmethyl)-Imino]-5-phosphono-pent-3-enoic acid and L-2-amino-3-butynoic acid as potential target candidate medications for HCC treatment based on CTH. Conclusion: Our study suggests that CTH can serve as a biomarker to predict the prognosis and immune infiltration of HCC.

Copper-Catalyzed Enantioconvergent Radical C(sp3 )-N Cross-Coupling: Access to α,α-Disubstituted Amino Acids.

Transition-metal catalyzed enantioconvergent cross-coupling of tertiary alkyl halides with ammonia offers a rapid avenue to chiral unnatural α,α-disubstituted amino acids. However, the construction of chiral C-N bonds between tertiary-carbon electrophiles and nitrogen nucleophiles presented a great challenge owing to steric congestion. We report a copper-catalyzed enantioconvergent radical C-N cross-coupling of alkyl halides with sulfoximines (as ammonia surrogates) under mild conditions by employing a chiral anionic N,N,N-ligand with a long spreading side arm. An array of α,α-disubstituted amino acid derivatives were obtained with good efficiency and enantioselectivity. The synthetic utility of the strategy has been showcased by the elaboration of the coupling products into different chiral α-fully substituted amine building blocks.