Inhibition of GSDMD-dependent pyroptosis decreased methamphetamine self-administration in rats.

It is widely believed that the activation of the central dopamine (DA) system is crucial to the rewarding effects of methamphetamine (METH) and to the behavioral outcomes of METH use disorder. It was reported that METH exposure induced gasdermin D (GSDMD)-dependent pyroptosis in rats. The membrane pore formation caused by METH-induced pyroptosis may also contribute to the overflow of DA into the extracellular space and subsequently increase the DA levels in the brain. The present study firstly investigated whether the membrane pore information induced by GSDMD-dependent pyroptosis was associated with the increased DA levels in the ventral tegmental area (VAT) and nucleus accumbens (NAc) of rats self-administering METH and SY-SH5Y cells treated by METH. Subsequently, the effect of pore formation blockade or genetic inhibition of GSDMD on the reinforcing and motivational effect of METH was determined in rats, using the animal model of METH self-administration (SA). METH exposure significantly increased the activity of NLRP1/Cas-1/GSDMD pathway and the presence of pyroptosis, accompanied by the significantly increased DA levels in VTA and NAc. Moreover, intraperitoneal injections of disulfiram (DSF) or microinjection of rAAV-shGSDMD into VTA/NAc significantly reduced the reinforcing and motivational effect of METH, accompanied by the decreased level of DA in VTA and NAc. The results provided novel evidence that METH-induced pyroptosis could increase DA release in VTA and NAc via the NLRP1/Cas-1/GSDMD pathway. Additionally, membrane pores or GSDMD blockade could significantly reduce the reinforcing and motivational effect of METH. In conclusion, blocking GSDMD and membrane pore formation could be a promising potential target for the development of agents to treat METH use disorder.

Photo-metallo-immunotherapy: Fabricating Chromium-Based Nanocomposites to Enhance CAR-T Cell Infiltration and Cytotoxicity against Solid Tumors.

The infiltration and cytotoxicity of chimeric antigen receptor (CAR)-T cells are crucial for effective elimination of solid tumors. While metallo-immunotherapy is a promising strategy that can activate the antitumor immunity, its role in promoting CAR-T cell therapy remains elusive. We have previously reported the first single-element nanomaterial based on chromium nanoparticles for cancer photo-metallo-immunotherapy. We report herein an extended study using biodegradable polydopamine as a versatile carrier for these nanoparticles, enabling synergistic CAR-T cell therapy. The results showed that these nanocomposites with or without further encapsulation of the anticancer drug alpelisib could promote the CAR-T cell migration and antitumor effect. Upon irradiation with near-infrared light, they caused mild hyperthermia that could "warm" the "cold" tumor microenvironment. The administration of B7-H3 CAR-T cells to NOD severe combined immunodeficiency gamma mice bearing a human hepatoma or PIK3CA-mutated breast tumor could significantly inhibit the tumor growth after the induction of tumor hyperthermia by the nanocomposites and promote the secretion of serum cytokines, including IL-2, IFN-γ, and TNF-α. The trivalent Cr3+ ions, which are the major degradation product of these nanocomposites, could increase the CXCL13 and CCL3 chemokine expressions to generate tertiary lymphoid structures in the tumor tissues, facilitating the CAR-T cell infiltration. This article is protected by copyright. All rights reserved.

Assembly of the Tn7 targeting complex by a regulated stepwise process.

The Tn7 family of transposons is notable for its highly regulated integration mechanisms, including programmable RNA-guided transposition. The targeting pathways rely on dedicated target selection proteins from the TniQ family and the AAA+ adaptor TnsC to recruit and activate the transposase at specific target sites. Here, we report the cryoelectron microscopy (cryo-EM) structures of TnsC bound to the TniQ domain of TnsD from prototypical Tn7 and unveil key regulatory steps stemming from unique behaviors of ATP- versus ADP-bound TnsC. We show that TnsD recruits ADP-bound dimers of TnsC and acts as an exchange factor to release one protomer with exchange to ATP. This loading process explains how TnsC assembles a heptameric ring unidirectionally from the target site. This unique loading process results in functionally distinct TnsC protomers within the ring, providing a checkpoint for target immunity and explaining how insertions at programmed sites precisely occur in a specific orientation across Tn7 elements.

Interaction behavior, mechanisms and hazardous changes of microplastics on single and binary component pesticide in the environment and food: Diethofencarb and pyrimethanil.

In order to investigate the adsorption behavior and mechanism of microplastics (MPs) on multiple coexisting pesticides in practical systems, as well as their hazardous changes upon binding, diethofencarb and pyrimethanil were selected to be studied with four MPs. The adsorption rate of both pesticides would be faster in the binary-component case, conforming to pseudo-second-order kinetics, with adsorption sites and chemical adsorption dominating. And the more hydrophobic the pesticide, the faster the adsorption rate and the higher the adsorption capacity. Diethofencarb belonged to monolayer adsorption, whereas pyrimethanil belonged to monomolecular combined with multilayer adsorption, depending on the size of pesticides. And the adsorption process was both competitive and synergistic when pesticides coexist. In addition, the adsorption process was a spontaneous heat absorption process. Electrostatic forces have little effect on adsorption, while the adsorption capacity can be altered by the adsorption sites and hydrophobicity of MPs. The salting-out effect also facilitated the adsorption process. As for changes in hazard, the bioluminescence of A. fischeri wasn't significantly inhibited, lacking of acute environmental toxicity. However, in vitro digestion experiments demonstrated a significant increase in bioavailability of diethofencarb and pyrimethanil in combination with MPs. These findings suggest the stronger adsorption behaviors and higher loading capacities between pesticides and MPs could lead more serious hazards to the human body, which deserves further attention.

Loss of CELF2 promotes skin tumorigenesis and increases drug resistance.

BACKGROUND: CELF2 belongs to the CELF RNA-binding protein family and exhibits antitumor activity in various tumor models. Analysis of the pan-cancer TCGA database reveals that CELF2 expression strongly correlates with favorable prognosis among cancer patients. The function of CELF2 in nonmelanoma skin cancer has not been studied. METHODS: We used shRNA-mediated knockdown (KD) of CELF2 expression in human squamous cell carcinoma (SCC) cells to investigate how CELF2 impacted SCC cell proliferation, survival, and xenograft tumor growth. We determined CELF2 expression in human SCC tissues and adjacent normal skin using immunofluorescence staining. Additionally, we investigated the changes in CELF2 and its target gene expression during UV-induced and chemical-induced skin tumorigenesis by western blotting. RESULTS: CELF2 KD significantly increased SCC cell proliferation, colony growth, and SCC xenograft tumor growth in immunodeficient mice. CELF2 KD in SCC cells led to activation of KRT80 and GDF15, which can potentially promote cell proliferation and tumor growth. While control SCC cells were sensitive to anticancer drugs such as doxorubicin, SCC cells with CELF2 KD became resistant to drug-induced tumor growth retardation. Finally, we found CELF2 expression diminished during both UV- and chemical-induced skin tumorigenesis in mice, consistent with reduced CELF2 expression in human SCC tumors compared to adjacent normal skin. CONCLUSION: This study shows for the first time that CELF2 loss occurs during skin tumorigenesis and increases drug resistance in SCC cells, highlighting the possibility of targeting CELF2-regulated pathways in skin cancer prevention and therapies.

Active DNA Demethylase, TET1, Increases Oxidative Phosphorylation and Sensitizes Ovarian Cancer Stem Cells to Mitochondrial Complex I Inhibitor.

Ten-eleven translocation 1 (TET1) is a methylcytosine dioxygenase involved in active DNA demethylation. In our previous study, we demonstrated that TET1 reprogrammed the ovarian cancer epigenome, increased stem properties, and activated various regulatory networks, including metabolic networks. However, the role of TET1 in cancer metabolism remains poorly understood. Herein, we uncovered a demethylated metabolic gene network, especially oxidative phosphorylation (OXPHOS). Contrary to the concept of the Warburg effect in cancer cells, TET1 increased energy production mainly using OXPHOS rather than using glycolysis. Notably, TET1 increased the mitochondrial mass and DNA copy number. TET1 also activated mitochondrial biogenesis genes and adenosine triphosphate production. However, the reactive oxygen species levels were surprisingly decreased. In addition, TET1 increased the basal and maximal respiratory capacities. In an analysis of tricarboxylic acid cycle metabolites, TET1 increased the levels of α-ketoglutarate, which is a coenzyme of TET1 dioxygenase and may provide a positive feedback loop to modify the epigenomic landscape. TET1 also increased the mitochondrial complex I activity. Moreover, the mitochondrial complex I inhibitor, which had synergistic effects with the casein kinase 2 inhibitor, affected ovarian cancer growth. Altogether, TET1-reprogrammed ovarian cancer stem cells shifted the energy source to OXPHOS, which suggested that metabolic intervention might be a novel strategy for ovarian cancer treatment.

Atg7 autophagy-independent role on governing neural stem cell fate could be potentially applied for regenerative medicine.

A literature review showed that Atg7 biological role was associated with the development and pathogenesis of nervous system, but very few reports focused on Atg7 role on neurogenesis at the region of spinal cord, so that we are committed to explore the subject. Atg7 expression in neural tube is incrementally increased during neurogenesis. Atg7 neural-specific knockout mice demonstrated the impaired motor function and imbalance of neuronal and glial cell differentiation during neurogenesis, which was similarly confirmed in primary neurosphere culture and reversely verified by Atg7 overexpression in unilateral neural tubes of gastrula chicken embryos. Furthermore, activating autophagy in neural stem cells (NSCs) of neurospheres did not rescue Atg7 deficiency-suppressed neuronal differentiation, but Atg7 overexpression on the basis of autophagy inhibition could reverse Atg7 deficiency-suppressed neuronal differentiation, which provides evidence for the existence of Atg7 role of autophagy-independent function. The underlying mechanism is that Atg7 deficiency directly caused the alteration of cell cycle length of NSCs, which is controlled by Atg7 through specifically binding Mdm2, thereby affecting neuronal differentiation during neurogenesis. Eventually, the effect of overexpressing Atg7-promoting neuronal differentiation was proved in spinal cord injury model as well. Taken together, this study revealed that Atg7 was involved in regulating neurogenesis by a non-autophagic signaling process, and this finding also shed light on the potential application in regenerative medicine.

Photosensitive and dual-targeted chromium nanoparticle delivering small interfering RNA YTHDF1 for molecular-targeted immunotherapy in liver cancer.

Tumor-associated macrophages (TAMs) are a promising target for cancer immunotherapy, but delivering therapeutic agents to TAMs within the tumor microenvironment (TME) is challenging. In this study, a photosensitive, dual-targeting nanoparticle system (M.RGD@Cr-CTS-siYTHDF1 NPs) was developed. The structure includes a shell of DSPE-modified RGD peptides targeting integrin receptors on tumor cells and carboxymethyl mannose targeting CD206 receptors on macrophages, with a core of chitosan adsorbing m6A reading protein YTHDF1 siRNA and chromium nanoparticles (Cr NPs). The approach is specifically designed to target TAM and cancer cells, utilizing the photothermal effect of Cr NPs to disrupt the TME and deliver siYTHDF1 to TAM. In experiments with tumor-bearing mice, M.RGD@Cr-CTS-siYTHDF1 NPs, when exposed to laser irradiation, effectively killed tumor cells, disrupted the TME, delivered siYTHDF1 to TAMs, silenced the YTHDF1 gene, and shifted the STAT3-STAT1 equilibrium by reducing STAT3 and enhancing STAT1 expression. This reprogramming of TAMs towards an anti-tumor phenotype led to a pro-immunogenic TME state. The strategy also suppressed immunosuppressive IL-10 production, increased expression of immunostimulatory factors (IL-12 and IFN-γ), boosted CD8 + T cell infiltration and M1-type TAMs, and reduced Tregs and M2-type TAMs within the TME. In conclusion, the dual-targeting M.RGD@Cr-CTS-siYTHDF1 NPs, integrating dual-targeting capabilities with photothermal therapy (PTT) and RNA interference, offer a promising approach for molecular targeted cancer immunotherapy with potential for clinical application.

A General Strategy for Food Traceability and Authentication Based on Assembly-Tunable Fluorescence Sensor Arrays.

Food traceability and authentication systems play an important role in ensuring food quality and safety. Current techniques mainly rely on direct measurement by instrumental analysis, which is usually designed for one or a group of specific foods, not available for various food categories. To develop a general strategy for food identification and discrimination, a novel method based on fluorescence sensor arrays is proposed, composed of supramolecular assemblies regulated by non-covalent interactions as an information conversion system. The stimuli-responsiveness and tunability of supramolecular assemblies provided an excellent platform for interacting with various molecules in different foods. In this work, five sensor arrays constructed by supramolecular assemblies composed of pyrene derivatives and perylene derivatives are designed and prepared. Assembly behavior and sensing mechanisms are investigated systematically by spectroscopy techniques. The traceability and authentication effects on several kinds of food from different origins or grades are evaluated and verified by linear discriminant analysis (LDA). It is confirmed that the cross-reactive signals from different sensor units encompassing all molecular interactions can generate a unique fingerprint pattern for each food and can be used for traceability and authentication toward universal food categories with 100% accuracy.

Plasmodium yoelii surface-related antigen (PySRA) modulates the host pro-inflammatory responses via binding to CD68 on macrophage membrane.

Malaria, one of the major infectious diseases in the world, is caused by the Plasmodium parasite. Plasmodium antigens could modulate the inflammatory response by binding to macrophage membrane receptors. As an export protein on the infected erythrocyte membrane, Plasmodium surface-related antigen (SRA) participates in the erythrocyte invasion and regulates the immune response of the host. This study found that the F2 segment of P. yoelii SRA activated downstream MAPK and NF-κB signaling pathways by binding to CD68 on the surface of the macrophage membrane and regulating the inflammatory response. The anti-PySRA-F2 antibody can protect mice against P. yoelii, and the pro-inflammatory responses such as IL-1ß, TNF-α, and IL-6 after infection with P. yoelii are attenuated. These findings will be helpful for understanding the involvement of the pathogenic mechanism of malaria with the exported protein SRA.

A review of immunotargeted therapy for Philadelphia chromosome positive acute lymphoblastic leukaemia: making progress in chemotherapy-free regimens.

Philadelphia chromosome-positive acute lymphoblastic leukemia (PH + ALL) is the most common cytogenetic abnormality of B-ALL in adults and is associated with poor prognosis. Previously, the only curative treatment option in PH + ALL was allogeneic hematopoietic stem cell transplantation (Allo-HSCT). Since 2000, targeted therapy combined with chemotherapy, represented by the tyrosine kinase inhibitor Imatinib, has become the first-line treatment for PH + ALL. Currently, the remission rate and survival rate of Imatinib are superior to those of simple chemotherapy, and it can also improve the efficacy of transplantation. More recently, some innovative immune-targeted therapy greatly improved the prognosis of PH + ALL, such as Blinatumomab and Inotuzumab Ozogamicin. For patients with ABL1 mutations and those who have relapsed or are refractory to other treatments, targeted oral small molecule drugs, monoclonal antibodies, Bispecific T cell Engagers (BiTE), and chimeric antigen receptor (CAR) T cells immunotherapy are emerging as potential treatment options. These new therapeutic interventions are changing the treatment landscape for PH + ALL. In summary, this review discusses the current advancements in targeted therapeutic agents shift in the treatment strategy of PH + ALL towards using more tolerable chemotherapy-free induction and consolidation regimens confers better disease outcomes and might obviate the need for HSCT.

Effects of motor imagery training on gait performance in individuals after stroke: a systematic review and meta-analysis.

PURPOSE: This review systematically explores and summarise the effects of motor imagery training (MIT) compared to conventional therapy on gait performance in individuals after stroke. MATERIALS AND METHODS: Randomised controlled trials (RCTs) were systematically searched in five electronic databases (PubMed, EMBASE, PsycINFO, OVID Nursing and CINAHL) from inception to 30 December 2022. Studies investigating MITs, targeted at individuals after stroke were eligible. Data were extracted related to study and intervention characteristics. RESULTS: Sixteen studies were included. Compared with 'routine methods of treatment or training', the meta-analyses showed that MIT was more effective in improving cadence immediately post intervention (SMD: 1.22, 95% CI: 0.59, 1.85, p = 0.0001, I2 = 25%) and at 1- or 2-months post intervention (SMD: 0.78, 95% CI: 0.35, 1.20, p = 0.0004, I2 = 46%). The results also showed that MIT improves the step length of the affected side and the unaffected side at 1- or 2-months post intervention. Separate meta-analyses were also conducted on different tests of walking endurance (assessed by the 6-Minute Walk Test) and functional mobility (assessed by the Timed-Up-and-Go test). CONCLUSIONS: MIT effectively improved gait performance. The findings in individuals after stroke remain inconclusive due to significant heterogeneity in included studies.

Restoring gait performance and daily functional abilities is an important goal of post-stroke rehabilitation.Motor imagery training (MIT) may be a promising method to improve gait restoration and is expected to provide another option for the effective rehabilitation of stroke patients.This review highlights the limited research on MIT and thus the limited evidence to guide clinical rehabilitation.In the stroke rehabilitation, clinical specialists may consider incorporating MIT into the treatment programme to improve patients' gait performance and ensure effective early lower limb rehabilitation.

Plasmonic Alloys Enhanced Metabolic Fingerprints for the Diagnosis of COPD and Exacerbations.

Accurate diagnosis of chronic obstructive pulmonary disease (COPD) and exacerbations by metabolic biomarkers enables individualized treatment. Advanced metabolic detection platforms rely on designed materials. Here, we design mesoporous PdPt alloys to characterize metabolic fingerprints for diagnosing COPD and exacerbations. As a result, the optimized PdPt alloys enable the acquisition of metabolic fingerprints within seconds, requiring only 0.5 µL of native plasma by laser desorption/ionization mass spectrometry owing to the enhanced electric field, photothermal conversion, and photocurrent response. Machine learning decodes metabolic profiles acquired from 431 individuals, achieving a precise diagnosis of COPD with an area under the curve (AUC) of 0.904 and an accurate distinction between stable COPD and acute exacerbations of COPD (AECOPD) with an AUC of 0.951. Notably, eight metabolic biomarkers identified accurately discriminate AECOPD from stable COPD while providing valuable information on disease progress. Our platform will offer an advanced nanoplatform for the management of COPD, complementing standard clinical techniques.

Internet of things-based management versus standard management of home noninvasive ventilation in COPD patients with hypercapnic chronic respiratory failure: a multicentre randomized controlled non-inferiority trial.

Background: Effective monitoring and management are crucial during long-term home noninvasive positive pressure ventilation (NPPV) in patients with hypercapnic chronic obstructive pulmonary disease (COPD). This study investigated the benefit of Internet of Things (IOT)-based management of home NPPV. Methods: This multicenter, prospective, parallel-group, randomized controlled non-inferiority trial enrolled patients requiring long-term home NPPV for hypercapnic COPD. Patients were randomly assigned (1:1), via a computer-generated randomization sequence, to standard home management or IOT management based on telemonitoring of clinical and ventilator parameters over 12 months. The intervention was unblinded, but outcome assessment was blinded to management assignment. The primary outcome was the between-group comparison of the change in health-related quality of life, based on severe respiratory insufficiency questionnaire scores with a non-inferiority margin of -5. This study is registered with Chinese Clinical Trials Registry (No. ChiCTR1800019536). Findings: Overall, 148 patients (age: 72.7 ± 6.8 years; male: 85.8%; forced expiratory volume in 1 s: 0.7 ± 0.3 L; PaCO2: 66.4 ± 12.0 mmHg), recruited from 11 Chinese hospitals between January 24, 2019, and June 28, 2021, were randomly allocated to the intervention group (n = 73) or the control group (n = 75). At 12 months, the mean severe respiratory insufficiency questionnaire score was 56.5 in the intervention group and 50.0 in the control group (adjusted between-group difference: 6.26 [95% CI, 3.71-8.80]; P < 0.001), satisfying the hypothesis of non-inferiority. The 12-month risk of readmission was 34.3% in intervention group compared with 56.0% in the control group, adjusted hazard ratio of 0.56 (95% CI, 0.34-0.92; P = 0.023). No severe adverse events were reported. Interpretation: Among stable patients with hypercapnic COPD, using IOT-based management for home NPPV improved health-related quality of life and prolonged the time to readmission. Funding: Air Liquide Healthcare (Beijing) Co., Ltd.

Glutamine prevents high-fat diet-induced hepatic lipid accumulation in mice by modulating lipolysis and oxidative stress.

Metabolic-associated fatty liver disease (MAFLD) is related to metabolic dysfunction and is characterized by excess fat storage in the liver. Several studies have indicated that glutamine could be closely associated with lipid metabolism disturbances because of its important role in intermediary metabolism. However, the effect of glutamine supplementation on MAFLD progression remains unclear. Here, we used a high-fat diet (HFD)-induced MAFLD C57BL/6 mouse model, and glutamine was supplied in the drinking water at different time points for MAFLD prevention and reversal studies. A MAFLD prevention study was performed by feeding mice an HFD concomitant with 4% glutamine treatment for 24 weeks, whereas the MAFLD reversal study was performed based on 4% glutamine treatment for 13 weeks after feeding mice an HFD for 10 weeks. In the prevention study, glutamine treatment ameliorated serum lipid storage, hepatic lipid injury, and oxidative stress in HFD-induced obese mice, although glutamine supplementation did not affect body weight, glucose homeostasis, energy expenditure, and mitochondrial function. In the MAFLD reversal study, there were no noticeable changes in the basic physiological phenotype and hepatic lipid metabolism. In summary, glutamine might prevent, but not reverse, HFD-induced MAFLD in mice, suggesting that a cautious attitude is required regarding its use for MAFLD treatment.

Exceptional Magnetocaloric Responses in a Gadolinium Silicate with Strongly Correlated Spin Disorder for Sub-Kelvin Magnetic Cooling.

The development of magnetocaloric materials with a significantly enhanced volumetric cooling capability is highly desirable for the application of adiabatic demagnetization refrigerators in confined spatial environments. Here, the thermodynamic characteristics of a magnetically frustrated spin-7/2 Gd9.33[SiO4]6O2 is presented, which exhibits strongly correlated spin disorder below ≈1.5 K. A quantitative model is proposed to describe the magnetization results by incorporating nearest-neighbor Heisenberg antiferromagnetic and dipolar interactions. Remarkably, the recorded magnetocaloric responses are unprecedentedly large and applicable below 1.0 K. It is proposed that the S = 7/2 spin liquids serve as versatile platforms for investigating high-performance magnetocaloric materials in the sub-kelvin regime, particularly those exhibiting a superior cooling power per unit volume.

Aerobic granular sludge for complex heavy metal-containing wastewater treatment: characterization, performance, and mechanisms analysis.

Complex heavy metal (HM)-containing wastewater discharges pose substantial risks to global water ecosystems and human health. Aerobic granular sludge (AGS) has attracted increased attention as an efficient and low-cost adsorbent in HM-containing wastewater treatment. Therefore, this study systematically evaluates the effect of Cu(II), Ni(II), and Cr(III) addition on the characteristics, performance and mechanism of AGS in complex HM-containing wastewater treatment process by means of fourier transform infrared spectroscopy, inductively coupled plasma spectrocopcy, confocal laser scanning microscopy, extracellular polymeric substances (EPS) fractions detection and scanning electron microscope-energy dispersive X-ray. The results showed that AGS efficiently eliminated Cu(II), Ni(II), and Cr(III) by the orchestrated mechanisms of ion exchange, three-layer EPS adsorption [soluble microbial products EPS (SMP-EPS), loosely bound EPS (LB-EPS), tightly bound EPS (TB-EPS)], and inner-sphere adsorption; notably, almost 100% of Ni(II) was removed. Three-layer EPS adsorption was the dominant mechanism through which the HM were removed, followed by ion exchange and inner-sphere adsorption. SMP-EPS and TB-EPS were identified as the key EPS fractions for adsorbing Cr(III) and Cu(II), respectively, while Ni(II) was adsorbed evenly on SMP-EPS, TB-EPS, and LB-EPS. Moreover, the rates at which the complex HM penetrated into the granule interior and their affinity for EPS followed the order Cu(II) > Ni(II) > Cr(III). Ultimately, addition of complex HM stimulated microorganisms to excrete massive phosphodiesterases (PDEs), leading to a pronounced decrease in cyclic diguanylate (c-di-GMP) levels, which subsequently suppressed EPS secretion due to the direct linkage between c-di-GMP and EPS. This study unveils the adaptability and removal mechanism of AGS in the treatment of complex HM-containing wastewater, which is expected to provide novel insights for addressing the challenges posed by intricate real wastewater scenarios.

Cu-Catalyzed Direct Asymmetric Mannich Reaction of 2-Alkylazaarenes and Isatin-Derived Ketimines.

The first direct catalytic asymmetric Mannich reaction of 2-alkylazaarenes and ketimines was realized with a chiral Cu-bis(oxazoline) complex as the catalyst. The asymmetric addition of 2-alkylpyridines to isatin-derived ketimines proceeded smoothly to afford α,ß-functionalized 2-substituted pyridines bearing 3-amino-3,3-disubstituted oxindole motifs with excellent results (≤99% yield, 99:1 dr, and 98% ee). The catalytic system was also extended to 2-alkylbenzothiazoles as nucleophiles for the asymmetric Mannich reaction of ketimines.

The cuproptosis-related gene glutaminase promotes alveolar macrophage copper ion accumulation in chronic obstructive pulmonary disease.

Cuproptosis, a novel mode of cell death, is strongly associated with a variety of diseases. However, the contribution of cuproptosis to the onset or progression of chronic obstructive pulmonary disease (COPD), the third most common chronic cause of mortality, is not yet clear. To investigate the potential role of cuproptosis in COPD, raw datasets from multiple public clinical COPD databases (including RNA-seq, phenotype, and lung function data) were used. For further validation, mice exposed to cigarette smoke for three months were used as in vivo models, and iBMDMs (immortalized bone marrow-derived macrophages) and RAW264.7 cells stimulated with cigarette smoke extract were used as in vitro models. For the first time, the expression of the cuproptosis-related gene glutaminase (GLS) was found to be decreased in COPD, and the low expression of GLS was significantly associated with the grade of pulmonary function. In vivo experiments confirmed the decreased expression of GLS in COPD, particularly in alveolar macrophages. Furthermore, in vitro studies revealed that copper ions accumulated in alveolar macrophages, leading to a substantially decreased amount of cell activity of macrophages when stimulated with cigarette extract. In summary, we demonstrate the high potential of GLS as an avenue for diagnosis and therapy in COPD.