The mitochondrial stress signaling tunes immunity from a view of systemic tumor microenvironment and ecosystem.

Mitochondria play important roles in cell fate, calcium signaling, mitophagy, and the signaling through reactive oxygen species (ROS). Recently, mitochondria are considered as a signaling organelle in the cell and communicate with other organelles to constitute the mitochondrial information processing system (MIPS) that transduce input-to-output biological information. The success in immunotherapy, a concept of systemic therapy, has been proved to be dependent on paracrine interactions within the tumor microenvironment (TME) and distant organs including microbiota and immune components. We will adopt a broader view from the concept of TME to tumor micro- and macroenvironment (TM 2 E) or tumor-organ ecosystem (TOE). In this review, we will discuss the role of mitochondrial signaling by mitochondrial ROS, calcium flux, metabolites, mtDNA, vesicle transportation, and mitochondria-derived peptide in the TME and TOE, in particular immune regulation and effective cancer immunotherapy.

Effects of Life-Long Exercise on Age-Related Inflammation, Apoptosis, Oxidative Stress, Ferroptosis Markers, and NRF2/KAEP 1/Klotho Pathway in Rat Kidneys.

Xi-Kun Yuan Pin-Shi Ni Zhen-Hao Yan Zhi Yu Zhuang-Zhi Wang Chen-Kai Zhang Fang-Hui Li Xiao-Ming Yu 1Sports Department, Nanjing University of Science and Technology ZiJin College, Nanjing, China, 2School of Sport Sciences, Nanjing Normal University, Nanjing, China, 3Shanghai Seventh People's Hospital, Shanghai, China To investigate the effects of life-long exercise (LLE) on age-related inflammatory cytokines, apoptosis, oxidative stress, ferroptosis markers, and the NRF2/KAEP 1/Klotho pathway in rats. Eight-month-old female Sprague-Dawley rats were divided into four groups: 1) LLE: 18-month LLE training starting at 8 months of age, 2) Old moderate-intensity continuous training (OMICT): 8 months of moderate-intensity continuous training starting at 18 months of age, 3) Adult sedentary (ASED): 8 month-old adult sedentary control group, and 4) Old sedentary (OSED): a 26-month-old sedentary control group. Hematoxylin eosin staining was performed to observe the pathological changes of kidney tissue injury in rats; Masson's staining to observe the deposition of collagen fibers in rat kidney tissues; and western blotting to detect the expression levels of IL-6, IL 1beta, p53, p21, TNF-alpha, GPX4, KAEP 1, NRF2, SLC7A11, and other proteins in kidney tissues. Results: Compared with the ASED group, the OSED group showed significant morphological changes in renal tubules and glomeruli, which were swollen and deformed, with a small number of inflammatory cells infiltrated in the tubules. Compared with the OSED group, the expression levels of inflammation-related proteins such as IL-1beta, IL-6, TNF alpha, and MMP3 were significantly lower in the LLE group. Quantitative immunofluorescence analysis and western blotting revealed that compared with the ASED group, KAEP 1 protein fluorescence intensity and protein expression levels were significantly enhanced, while Klotho and NRF2 protein fluorescence intensity and protein expression levels were reduced in the OSED group. Compared with the OSED group, KAEP 1 protein fluorescence intensity and protein expression levels were reduced in the LLE and OMICT groups. Klotho and KAEP 1 protein expression levels and immunofluorescence intensity were higher in the LLE group than in the OSED group. The expression levels of GPX4 and SLC7A11, two negative marker proteins associated with ferroptosis, were significantly higher in the LLE group than in the OSED group, while the expression of p53 a cellular senescence-associated protein that negatively regulates SLC7A11, and the downstream protein p21 were significantly decreased. LLE may ameliorated aging-induced oxidative stress, inflammatory response, apoptosis, and ferroptosis by regulating Klotho and synergistically activating the NRF2/KAEP 1 pathway. Keywords: Life-long exercise, Moderate intensity continuous training, Aging, Kidney tissue, Ferroptosis.

Neurophysiological Basis of Electroacupuncture Stimulation in the Treatment of Cardiovascular-Related Diseases: Vagal Interoceptive Loops.

PURPOSE: The vagal sensory nerve (VSN) is an essential interoceptive pathway that is connected to every level of the body. Its intricate genetic coding provides sustenance for physiological processes, including controlling blood pressure and respiration. Electroacupuncture (EA) is a proven surface stimulation therapy that can regulate vagal nerve activity, which can effectively prevent cardiovascular diseases. A growing number of studies have concentrated on the mapping of VSN codes, but little is known, and the physiological background of how EA influences interoceptive has not been fully explored. METHOD: Here, we incorporate the hypothesized interaction among EA targets, VSNs, and the heart. This offers suggestions for using a versatile and focused EA strategy to modify vagal interoceptive awareness to enhance cardiovascular conditions. We first clarified the major role of vagal nerve in the control of cardiac activity. Additionally, we clarified the multidimensional coding pattern in the VSNs, revealing that the targeted control of multimodal interoceptive is the functional basis of the synchronization of cardiovascular system. FINDING: We propose a strategy in which EA of the VSNs is employed to activate the interoceptive loop and reduce the risk of cardiovascular disease.

Excessive hydrogen sulfide-induced activation of NMDA receptors in the colon participates in anxiety- and compulsive-like behaviors in a rodent model of hemorrhagic shock and resuscitation.

OBJECTIVE: Hemorrhagic shock and resuscitation (HSR) cause inflammatory responses in the gastrointestinal tract and is associated with substantial morbidity and mortality rates. Hydrogen sulfide (H2S), a gasotransmitter with pleiotropic activity, exhibits anti-inflammatory benefits at physiological levels. However, deleterious effects are observed when its concentration increases. In this investigation, we employed a mouse model of HSR to examine the effects of an H2S scavenger on the gastrointestinal tract and brain, with emphasis on N-Methyl-d-Aspartate (NMDA) receptor function. METHODS: Mice were immediately administered dl-propargylglycine (PAG) intragastrically as an H2S scavenger after HSR exposure. The O-maze and buried beads tests were used to assess compulsive- and anxiety-like behaviors. Pathological changes in the intestine were evaluated at 24 and 30 days after HSR. Subsequently, at 30 days after HSR, we examined electrophysiological and pathological changes in the amygdala. RESULTS: Within 24 h of HSR exposure, animals treated with PAG showed significantly lower colonic injury. Additionally, compared to the HSR-treated mice 30 days after HSR, the PAG-treated mice displayed reduced buried beads, increased open-arm time, lower blood levels of Diamine Oxidase (DAO) and considerably improved ZO-1 intensity, a stronger association between the delta rhythm phase and beta activity amplitude, and lower neuroinflammatory response in the amygdala. MK-801, an NMDA receptor inhibitor, significantly reversed H2S-induced intestinal and cerebral injury. CONCLUSION: This experimental data suggests that H2S-induced excessive activation of NMDA receptors contributes to anxiety- and compulsive-like behaviors caused by HSR.

Polymeric Microneedle Drug Delivery Systems: Mechanisms of Treatment, Material Properties, and Clinical Applications-A Comprehensive Review.

Our comprehensive review plunges into the cutting-edge advancements of polymeric microneedle drug delivery systems, underscoring their transformative potential in the realm of transdermal drug administration. Our scrutiny centers on the substrate materials pivotal for microneedle construction and the core properties that dictate their efficacy. We delve into the distinctive interplay between microneedles and dermal layers, underscoring the mechanisms by which this synergy enhances drug absorption and precision targeting. Moreover, we examine the acupoint-target organ-ganglion nexus, an innovative strategy that steers drug concentration to specific targets, offering a paradigm for precision medicine. A thorough analysis of the clinical applications of polymeric microneedle systems is presented, highlighting their adaptability and impact across a spectrum of therapeutic domains. This review also accentuates the systems' promise to bolster patient compliance, attributed to their minimally invasive and painless mode of drug delivery. We present forward-looking strategies aimed at optimizing stimulation sites to amplify therapeutic benefits. The anticipation is set for the introduction of superior biocompatible materials with advanced mechanical properties, customizing microneedles to cater to specialized clinical demands. In parallel, we deliberate on safety strategies aimed at boosting drug loading capacities and solidifying the efficacy of microneedle-based therapeutics. In summation, this review accentuates the pivotal role of polymeric microneedle technology in contemporary healthcare, charting a course for future investigative endeavors and developmental strides within this burgeoning field.

Molecular Insight into the Electric Field Regulation of N2 and CH4 Adsorption in the Trapdoor ZSM-25 Zeolites.

Controlling gas admission by regulating pore accessibility in porous materials has been a topic of extensive research. Recently, the electric field (E-field) has emerged as an external stimulus to alter the adsorption behavior of some microporous adsorbents. However, the mechanism behind this phenomenon is not yet fully understood. Here, we demonstrate the crucial role of the trapdoor cations of zeolite molecular sieves in E-field-regulated gas adsorption. The E-field activation caused framework expansion and cation deviation, significantly reducing the energy barrier for gas molecules passing through the pore aperture gated by the trapdoor cation. This led to an increase in the N2 adsorption capacity of ZSM-25 and a 60% improvement in N2/CH4 selectivity in the quest for nitrogen rejection for natural gas processing. By combining experimental and computational approaches, we elucidated the influence of E-field activation as a concurrent effect of the reduced heat of adsorption caused by framework expansion and the decrease in the energy barrier resulting from promoted cation oscillation. These findings pave the way for the material design of E-field-regulated adsorption and its application in molecular separation.

Causal association between peripheral immune cells and IgA nephropathy: a Mendelian randomization study.

Background: The relationship between peripheral immune cells and immunoglobulin A nephropathy (IgAN) is widely known; however, causal evidence of this link is lacking. Here, we aimed to determine the causal effect of peripheral immune cells, specifically total white blood cells, lymphocytes, monocytes, basophils, eosinophils, and neutrophils, as well as lymphocyte subset traits, on the IgAN risk using a Mendelian randomization (MR) analysis. Methods: The inverse-variance weighted (IVW) method was used for the primary analysis. We applied three complementary methods, including the weighted median, MR-Egger regression, and MR-PRESSO, to detect and correct for the effect of horizontal pleiotropy. Additionally, we performed a multivariable MR (MVMR) analysis, adjusting for the effects of C-reactive protein (CRP) levels. The roles of specific lymphocyte subtypes and their significance have garnered interest. Bidirectional two-sample MR analysis was performed to test the potential causal relationships between immune traits, including median fluorescence intensities (MFIs) and the relative cell count (AC), and IgAN. Results: The IVW-MR analysis suggested a potential causal relationship between lymphocyte counts and IgAN in Europe (OR per 1-SD increase: 1.43, 95% CI: 1.08-1.88, P = 0.0123). The risk effect of lymphocytes remained even after adjusting for CRP levels using the MVMR method (OR per 1-SD increase: 1.44, 95% CI: 1.05-1.96, P = 0.0210). The other sensitivity analyses showed a consistent trend. The largest GWAS published to date was used for peripheral blood immunophenotyping to explore the potential causal relationship between peripheral immune cell subsets and IgAN. Six AC-IgAN and 14 MFI-IgAN pairs that reached statistical significance (P < 0.05) were detected. Notably, CD3, expressed in eight subsets of T cells, consistently showed a positive correlation with IgAN. The bidirectional MR analysis did not reveal any evidence of reverse causality. According to the sensitivity analysis, horizontal pleiotropy was unlikely to distort the causal estimates. Conclusions: Genetically determined high lymphocyte counts were associated with IgAN, supporting that high lymphocyte counts is causal risk factor for IgAN.

Enhanced lipid metabolism reprogramming in CHF rats through IL-6-mediated cardiac glial cell modulation by digilanid C and electroacupuncture stimulation combination.

Background: Cardiac lipid metabolism reprogramming is recognized as a critical pathological factor in the progression of chronic heart failure (CHF). The therapeutic potential of digilanid C and electroacupuncture stimulation (ES) in enhancing lipid metabolism and cardiac function has been established. However, the optimal synergistic regulatory strategies of these interventions on cardiac lipid metabolism have yet to be elucidated. Methods: This study aimed to comprehensively evaluate the impact of a digilanid C-ES combination on cardiac steatosis remodeling in CHF. Assessments were conducted across various dimensions, including myocardial oxygen consumption, mitochondrial function, and lipid metabolism. Additionally, we sought to uncover the underlying neuromolecular mechanisms. Results: Our findings, at both molecular and morphological levels, indicated that the synergistic application of digilanid C and ES significantly inhibited myocardial fibrosis and steatosis. This combination therapy facilitated the repair of cardiac neuro-vascular uncoupling and induced a reprogramming of lipid metabolism. Notably, the digilanid C-ES combination ameliorated cardiomyocyte apoptosis and enhanced mitochondrial biogenesis in CHF, leading to a restructured energy supply pattern. Cardiac immunofluorescence analyses revealed the aggregation of cardiac glial cells (CGCs) at sites of abnormal neurovascular coupling, a response to cardiac lipid degeneration. This was accompanied by a marked reduction in the abnormally elevated expression of interleukin 6 (IL-6) and glutamatergic signaling, which correlated with the severity of cardiac steatosis and the aberrant activation of CGCs. The combined therapy was found to activate the Janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3) pathway, effectively attenuated lipid accumulation and over-recruitment of CGCs and deprivation of glutamatergic nerves. Conclusion: These findings underscore the potential of digilanid C and ES combination therapy as a novel approach to modulate the complex interplay between neurovascular dynamics and metabolic dysregulation in CHF.

Invasive Mucinous Adenocarcinoma in a Newborn With Antenatally Diagnosed Congenital Pulmonary Airway Malformation: A Case Report.

Congenital pulmonary airway malformations (CPAMs) are rare multicystic lung lesions typically diagnosed antenatally. We present a case of a term female neonate with antenatally diagnosed CPAM who required pleuro-amniotic shunting at 22 weeks of gestation. The patient was born with a right-sided pneumothorax and severe cardiorespiratory distress, necessitating extracorporeal membrane oxygenation (ECMO). Chest CT confirmed CPAM, revealing multiple cystic lesions in the right middle lobe and a significant contralateral mediastinal shift. On the second day of life, while on ECMO, the patient underwent a right middle lobectomy and an upper lobe anterior segmentectomy via a posterolateral thoracotomy. Post-surgery cardiac CT showed narrowing of the left pulmonary artery, although a perfusion study indicated normal left lung perfusion. Histopathological examination identified CPAM type 1 with invasive mucinous adenocarcinoma (IMA; stage 1: pT1b), featuring low-to-intermediate cellularity and KRAS G12D mutations. The invasive mucinous component measured at least 15 mm but did not invade the visceral pleura. After a gradual weaning process, the patient was successfully extubated and discharged home after 70 days. To our knowledge, this is the first reported case of CPAM type 1 with IMA that underwent pleuro-amniotic shunting in the second trimester.

Real Topological Phonons in 3D Carbon Allotropes.

There has been a significant focus on real topological systems that enjoy space-time inversion symmetry and lack spin-orbit coupling. While the theoretical classification of the real topology has been established, more progress has yet to be made in the materials realization of real topological phononic states in 3D. To address this crucial issue, high-throughput computing is performed to inspect the real topology in the phonon spectrums of the 3D carbon allotropes. Among 1661 carbon allotropes listed in the Samara Carbon Allotrope Database (SACADA), 79 candidates host a phononic real Chern insulating (PRCI) state, 2 candidates host a phononic real nodal line (PRNL) state, 12 candidates host a phononic real Dirac point (PRDP) state, and 10 candidates host a phononic real triple-point pair (PRTPP) state. The PRCI, PRNL, PRTPP, and PRDP states of 27-SG. 166-pcu-h, 1081-SG. 194-42T13-CA, 52-SG. 141-gis, and 132-SG. 191-3,4T157 are exhibited as illustrative examples, and the second-order phononic hinge modes are explored. This study broadens the understanding of 3D topological phonons and expands the material candidates with phononic hinge modes and phononic real topology.

I2-Induced Umpolung: Synthesis of a 1,6-Dihydrofuro[3,2-b]pyrazolo[3,4-e][1,4]thiazine Skeleton via an Unconventional 1,4-Dithiane-2,5-diol Reaction Mode.

In this paper, novel sulfur-containing 1,6-dihydrofuro[3,2-b]pyrazolo[3,4-e][1,4]thiazine skeletons were constructed from the simple and readily available materials enaminone, 5-aminopyrazole, and 1,4-dithiane-2,5-diol. Furthermore, a novel 1,4-dithiane-2,5-diol reaction mode has been developed through a double-dipole-reversal process induced by iodine that results in the formation of six new bonds and two new rings in a one-pot reaction. This method shows good substrate compatibility, and the products can be further modified with a variety of pharmaceuticals. Additionally, this novel skeleton exhibits good fluorescence properties in solution, enabling bright and stable green fluorescence imaging in HeLa cells.

Persteroid, a new steroid from the marine-derived fungus Penicillium sp. ZYX-Z-143.

A new steroid named persteroid (1) and seven known compounds (2-8) were isolated from the marine-derived fungus Penicillium sp. ZYX-Z-143. The structure of 1 was determined by HRESIMS, NMR, and ECD calculations. Compound 1 showed inhibitory activity against protein tyrosine phosphatase 1B (PTP1B) with IC50 value of 46.31 ± 0.52 µM. Moreover, compound 1 potently suppressed nitric oxide (NO) production on lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. The cytotoxicity and antibacterial activity of all isolates were tested.

Construction simulation and scheme optimisation of complex underground cavities.

Underground cavities have complex spatial structures and geological settings, their arrangement is dense and crisscrossed. The construction system involves multiple work surfaces, levels, and processes. The close integration of construction simulation with actual production conditions is crucial for enhancing the guidance that simulation results provide for practical engineering. Therefore, from the perspective of optimizing construction organization and management, this article comprehensively considers various factors in the construction process, innovatively introduces the principle of production line balance and the concept of rule cycle, and combines technology and management, an underground cavities construction simulation system (UCCSS) is developed. In UCCSS, a hierarchical model is built and calculation are performed on models with different construction methods by modifying the parameters as per the actual engineering characteristics. The simulation results are comprehensively analysed to determine the optimal construction programme. An application case is proposed based on the construction organisation design of the long and parallel diversion tunnels at the CB Hydropower Station. The results show that the system has good practicality and credibility and can provide guidance for the construction organisation design of underground cavities with various features.

Diagnostic significance of EyeMAX in diagnosing patients with tumor in the terminal end of the common bile duct.

A biliary stricture is an abnormal narrowing in the ductal drainage system of the liver. There are many etiologies of biliary stricture, the most common and ominous of which is malignancy, either primary or metastatic.It is difficult to obtain pathological tissue of the terminal end of the common bile duct. A 72-year-old woman, complained of abdominal pain for 2 months, underwent cholecystectomy for acute cholecystitis 11 years ago. Abdominal CT and MRI examination revealed soft tissue occupation (12*8 mm) in the duodenal papillary area, and endoscopic ultrasonography revealed a hypoechoic lesion (11.1*10.7 mm) in the ampulla. We performed ERCP, and intraoperative biliary cell brushing on the patient, but no positive pathological results were obtained. We further performed novel 9F digital single operator cholangioscopy system (DSOC) (eyeMAX, Micro-Tech, Nanjing, China) and observed intraoperative hyperemia and edema of the mucosa in the terminal end of the common bile duct, presenting fish-like changes with mucous attachment and clear lesion boundaries. The pathological results suggested cholangiocarcinoma.

Five-Axis Curved-Surface Multi-Material Printing on Conformal Surface to Construct Aqueous Zinc-Ion Battery Modules.

Compact batteries and electronic devices offer a plethora of advantages, including space optimization, portability, integration capability, responsiveness, and reliability. These attributes are crucial technical enablers for the design and implementation of various electronic devices and systems within scientific exploration. Thus, the group harnesses additive manufacturing technology, specifically utilizing five-axis curved-surface multi-material printing equipment, to fabricate aqueous zinc-ion batteries with tungsten-doped manganese dioxide cathode for enhanced adaptability and customization. The five-axis linkage motion system facilitates shorter ion transportation paths for compact batteries and ensures precise and efficient molding of non-developable curved surfaces. Afterward, the compact cell is integrated with a printed nano-silver serpentine resistor temperature sensor, and an integrated functional circuit is created using intense-pulse sintering. Incorporating an emitting Light Emitting Diode (LED) allows temperature measurement through variations in LED brightness. The energy storage module with a high degree of conformity on the carrier surface has the advantages of small size and improved space utilization. The capability to produce Zinc-ion batteries (ZIBs) on curved surfaces presents new avenues for innovation in energy storage technologies, paving the way for the realization of flexible and conformal power sources.

C-H functionalization of 2-alkyl tryptamines: direct assembly of azepino[4,5-b]indoles and total synthesis of ngouniensines.

The Pictet-Spengler type condensation of tryptamine derivatives and aldehydes or ketones is a classic reaction, and has been previously applied to assemble indole-annulated 5-, 6- and 8-membered heterocyclic rings. In this work, we further expand the synthetic scope of this reaction to the 7-membered azepino[4,5-b]indole skeleton through the direct C-H functionalization of 2-alkyl tryptamines, in which the non-activated methylene group participates in a 7-membered ring formation with aldehydes. By combining this unprecedented ring-forming process with a second C-H olefination at the same carbon, the concise total synthesis of natural products ngouniensines is achieved, demonstrating the synthetic potential of the developed chemistry in simplifying retrosynthetic disconnections.

Robust Edge States of Quasi-1D Material Ta2NiSe7 and Applications in Saturable Absorbers.

The helical edge states (ESs) protected by underlying Z2 topology in two-dimensional topological insulators (TIs) arouse upsurges in saturable absorptions thanks to the strong photon-electron coupling in ESs. However, limited TIs demonstrate clear signatures of topological ESs at liquid nitrogen temperatures, hindering the applications of such exotic quantum states. Here, we demonstrate the existence of one-dimensional (1D) ESs at the step edge of the quasi-1D material Ta2NiSe7 at 78 K by scanning tunneling microscopy. Such ESs are rather robust against the irregularity of the edges, suggesting a possible topological origin. The exfoliated Ta2NiSe7 flakes were used as saturable absorbers (SAs) in an Er-doped fiber laser, hosting a mode-locked pulse with a modulation depth of up to 52.6% and a short pulse duration of 225 fs, far outstripping existing TI-based SAs. This work demonstrates the existence of robust 1D ESs and the superior SA performance of Ta2NiSe7.

Deep learning-derived splenic radiomics, genomics, and coronary artery disease.

Background: Despite advances in managing traditional risk factors, coronary artery disease (CAD) remains the leading cause of mortality. Circulating hematopoietic cells influence risk for CAD, but the role of a key regulating organ, spleen, is unknown. The understudied spleen is a 3-dimensional structure of the hematopoietic system optimally suited for unbiased radiologic investigations toward novel mechanistic insights. Methods: Deep learning-based image segmentation and radiomics techniques were utilized to extract splenic radiomic features from abdominal MRIs of 42,059 UK Biobank participants. Regression analysis was used to identify splenic radiomics features associated with CAD. Genome-wide association analyses were applied to identify loci associated with these radiomics features. Overlap between loci associated with CAD and the splenic radiomics features was explored to understand the underlying genetic mechanisms of the role of the spleen in CAD. Results: We extracted 107 splenic radiomics features from abdominal MRIs, and of these, 10 features were associated with CAD. Genome-wide association analysis of CAD-associated features identified 219 loci, including 35 previously reported CAD loci, 7 of which were not associated with conventional CAD risk factors. Notably, variants at 9p21 were associated with splenic features such as run length non-uniformity. Conclusions: Our study, combining deep learning with genomics, presents a new framework to uncover the splenic axis of CAD. Notably, our study provides evidence for the underlying genetic connection between the spleen as a candidate causal tissue-type and CAD with insight into the mechanisms of 9p21, whose mechanism is still elusive despite its initial discovery in 2007. More broadly, our study provides a unique application of deep learning radiomics to non-invasively find associations between imaging, genetics, and clinical outcomes.

Hsp60 deletion in cholinergic neurons: Impact on neuroinflammation and memory.

Cholinergic circuit defects have been linked to various neurological abnormalities, yet the precise mechanisms underlying the impact of cholinergic signaling on cognitive functions, particularly in the context of neuroinflammation-associated, remain poorly understood. Similarly, while the dopamine receptor (D2R) has been implicated in the pausing of cholinergic interneurons (CIN), its relationship with behavior remains inadequately elucidated. In this study, we aimed to investigate whether D2R plays a role in the regulation of fear and memory in the Hsp60 knockout condition, given the non-canonical involvement of Hsp60 in inflammation. Using a CRE-floxed system, we selectively generated cholinergic neurons specific to Hsp60 knockout mice and subjected them to memory tests. Our results revealed a significant increase in freezing levels during recall and contextual tests in Hsp60-deprived mice. We also observed dysregulation of neurotransmitters and D2R in the hippocampus of Hsp60 knockout mice, along with enhanced impairments in cytokine levels and synaptic protein dysregulations. These changes were accompanied by alterations in PI3K/eIF4E/Jak/ERK/CREB signaling pathways. Notably, D2R agonism via Quinpirole led to a decrease in freezing levels during recall and contextual tests, alongside an increase in IBA-1 expression and improvements in inflammatory response-linked signaling pathways, including JAK/STAT/P38/JNK impairments. Given that these pathways are well-known downstream signaling cascades of D2R, our findings suggest that D2R signaling may contribute to the neuroinflammation induced by Hsp60 deprivation, potentially exacerbating memory impairments.

Divergent synthesis of pyrrolidone fused pyrimido[1,2-b]indazole through selective trapping of an enone intermediate by 1H-indazol-3-amine.

An oxidant-controlled divergent synthesis of a pyrrolidone fused pyrimido[1,2-b]indazole skeleton was developed through selective cyclization of an in situ generated enone intermediate and 1H-indazol-3-amine. The one-pot, metal-free process formed three C-N bonds, one C-C bond, and a tetrasubstituted carbon stereocenter containing a hydroxyl group. This method not only allowed for the synthesis of over 60 new pyrrolidone fused pyrimido[1,2-b]indazole derivatives, but was also compatible with the transformation of complex active molecules and the derivation of target products. Significantly, product 4q exhibited aggregation-induced emission (AIE) characteristics without any further modification.