Cu(II)-Organic Framework for Carboxylative Cyclization of Propargylic Amines with CO2.

Effective CO2 transformations hold essential significance for carbon neutrality and sustainable energy development. Carboxylative cyclization of propargylic amines with CO2 serves as an atom-economic reaction to afford oxazolidinones, showing broad applications in organic synthesis and pharmaceutical fields. However, most catalysts involved noble metals, exhibited low efficiency, or required large amounts of base. Hence, it is imperative to explore alternative noble-metal-free catalysts in order to achieve efficient conversion while minimizing the use of additives. Herein, a novel nanopore-based Cu(II)-organic framework (1) based on a new imidazole carboxylic ligand was successfully constructed and exhibited excellent stability. Catalytic investigations revealed that the combination of 1 with 1,4-diaza[2.2.2]bicyclooctane (DABCO) efficiently catalyzed the carboxylative cyclization of propargylic amines with CO2, achieving turnover numbers of 142 based on the catalyst and 7.1 based on DABCO. 1 as a heterogeneous catalyst maintained high catalytic performance even after being reused at least 5 cycles, with its structure remaining stable. The strong activation of Cu(II) cluster nodes of catalyst 1 toward -NH- groups within organic substrates, as demonstrated by mechanism experiments, along with excellent CO2 adsorption performance and the presence of regular 1D channels, synergistically facilitates the reaction rate. This research presents the first instance of a Cu(II)-organic framework achieving this cyclization reaction, offering wide prospects for novel catalyst design and CO2 utilization.

Obeticholic acid ameliorates sepsis-induced renal mitochondrial damage by inhibiting the NF-κb signaling pathway.

Acute kidney injury (AKI), a common complication of sepsis, might be caused by overactivated inflammation, mitochondrial damage, and oxidative stress. However, the mechanisms underlying sepsis-induced AKI (SAKI) have not been fully elucidated, and there is a lack of effective therapies for AKI. To this end, this study aimed to investigate whether obeticholic acid (OCA) has a renoprotective effect on SAKI and to explore its mechanism of action. Through bioinformatics analysis, our study confirmed that the mitochondria might be a critical target for the treatment of SAKI. Thus, a septic rat model was established by cecal ligation puncture (CLP) surgery. Our results showed an evoked inflammatory response via the NF-κB signaling pathway and NLRP3 inflammasome activation in septic rats, which led to mitochondrial damage and oxidative stress. OCA, an Farnesoid X Receptor (FXR) agonist, has shown anti-inflammatory effects in numerous studies. However, the effects of OCA on SAKI remain unclear. In this study, we revealed that pretreatment with OCA can inhibit the inflammatory response by reducing the synthesis of proinflammatory factors (such as IL-1ß and NLRP3) via blocking NF-κB and alleviating mitochondrial damage and oxidative stress in the septic rat model. Overall, this study provides insight into the excessive inflammation-induced SAKI caused by mitochondrial damage and evidence for the potential use of OCA in SAKI treatment.

Exploring the therapeutic potential of Nelumbo nucifera leaf extract against amyloid-beta-induced toxicity in the Caenorhabditis elegans model of Alzheimer's disease.

Introduction: Alzheimer's disease (AD) represents a critical global health challenge with limited therapeutic options, prompting the exploration of alternative strategies. A key pathology in AD involves amyloid beta (Aß) aggregation, and targeting both Aß aggregation and oxidative stress is crucial for effective intervention. Natural compounds from medicinal and food sources have emerged as potential preventive and therapeutic agents, with Nelumbo nucifera leaf extract (NLE) showing promising properties. Methods: In this study, we utilized transgenic Caenorhabditis elegans (C. elegans) models to investigate the potential of NLE in countering AD and to elucidate the underlying mechanisms. Various assays were employed to assess paralysis rates, food-searching capabilities, Aß aggregate accumulation, oxidative stress, lifespan under stress conditions, and the expression of stress-resistance-related proteins. Additionally, autophagy induction was evaluated by measuring P62 levels and the formation of LGG-1+ structures, with RNAi-mediated inhibition of autophagy-related genes to confirm the mechanisms involved. Results: The results demonstrated that NLE significantly reduced paralysis rates in CL4176 and CL2006 worms while enhancing food-searching capabilities in CL2355 worms. NLE also attenuated Aß aggregate accumulation and mitigated Aß-induced oxidative stress in C. elegans. Furthermore, NLE extended the lifespan of worms under oxidative and thermal stress conditions, while concurrently increasing the expression of stress-resistance-related proteins, including SOD-3, GST-4, HSP-4, and HSP-6. Moreover, NLE induced autophagy in C. elegans, as evidenced by reduced P62 levels in BC12921 worms and the formation of LGG-1+ structures in DA2123 worms. The RNAi-mediated inhibition of autophagy-related genes, such as bec-1 and vps-34, negated the protective effects of NLE against Aß-induced paralysis and aggregate accumulation. Discussion: These findings suggest that NLE ameliorates Aß-induced toxicity by activating autophagy in C. elegans. The study underscores the potential of NLE as a promising candidate for further investigation in AD management, offering multifaceted approaches to mitigate AD-related pathology and stress-related challenges.

Metal Hydrogen-Bonded Organic Frameworks as Open Lewis Acid Catalysts for Two Types of CO2 Transformations.

Efficient and multiple CO2 utilization into high-value-added chemicals holds significant importance in carbon neutrality and industry production. However, most catalysis systems generally exhibit only one type of CO2 transformation with the efficiency to be improved. The restricted abundance of active catalytic sites or an inefficient utilization rate of these sites results in the constraint. Consequently, we designed and constructed two metal hydrogen-bonded organic frameworks (M-HOFs) {[M3(L3-)2(H2O)10]·2H2O}n (M = Co (1), Ni (2); L = 1-(4-carboxyphenyl)-1H-pyrazole-3,5-dicarboxylic acid) in this research. 1 and 2 are well-characterized, and both show excellent stability. The networks connected by multiple hydrogen bonds enhance the structural flexibility and create accessible Lewis acidic sites, promoting interactions between the substrates and catalytic centers. This enhancement facilitates efficient catalysis for two types of CO2 transformations, encompassing both cycloaddition reactions with epoxides and aziridines to afford cyclic carbonates and oxazolidinones. The catalytic activities (TON/TOF) are superior compared with those of most other catalysts. These heterogeneous catalysts still exhibited high performance after being reused several times. Mechanistic studies indicated intense interactions between the metal sites and substrates, demonstrating the reason for efficient catalysis. This marks the first instance on M-HOFs efficiently catalyzing two types of CO2 conversions, finding important significance for catalyst design and CO2 utilization.

Identification of NINJ1 as a novel prognostic predictor for retroperitoneal liposarcoma.

BACKGROUND: Retroperitoneal liposarcoma (RPLS) is known for its propensity for local recurrence and short survival time. We aimed to identify a credible and specific prognostic biomarker for RPLS. METHODS: Cases from The Cancer Genome Atlas (TCGA) sarcoma dataset were included as the training group. Co-expression modules were constructed using weighted gene co-expression network analysis (WGCNA) to explore associations between modules and survival. Survival analysis of hub genes was performed using the Kaplan-Meier method. In addition, independent external validation was performed on a cohort of 135 Chinese RPLS patients from the REtroperitoneal SArcoma Registry (RESAR) study (NCT03838718). RESULTS: A total of 19 co-expression modules were constructed based on the expression levels of 26,497 RNAs in the TCGA cohort. Among these modules, the green module exhibited a positive correlation with overall survival (OS, p = 0.10) and disease-free survival (DFS, p = 0.06). Gene set enrichment analysis showed that the green module was associated with endocytosis and soft-tissue sarcomas. Survival analysis demonstrated that NINJ1, a hub gene within the green module, was positively associated with OS (p = 0.019) in the TCGA cohort. Moreover, in the validation cohort, patients with higher NINJ1 expression levels displayed a higher probability of survival for both OS (p = 0.023) and DFS (p = 0.012). Multivariable Cox analysis further confirmed the independent prognostic significance of NINJ1. CONCLUSIONS: We here provide a foundation for the establishment of a consensus prognostic biomarker for RPLS, which should not only facilitate medical treatment but also guide the development of novel targeted drugs.

Penthorum chinense Pursh inhibits ferroptosis in cellular and Caenorhabditis elegans models of Alzheimer's disease.

BACKGROUND: Ferroptosis, a unique type of cell death triggered by iron-dependent lipid peroxidation, plays a critical role in the pathogenesis of Alzheimer's disease (AD), a debilitating condition marked by memory loss and cognitive impairment due to the accumulation of beta-amyloid (Aß) and hyperphosphorylated Tau protein. Increasing evidence suggests that inhibitors of ferroptosis could be groundbreaking in the treatment of AD. METHOD: In this study, we established in vitro ferroptosis using erastin-, RSL-3-, hemin-, and iFSP1-induced PC-12 cells. Using MTT along with Hoechst/PI staining, we assessed cell viability and death. To determine various aspects of ferroptosis, we employed fluorescence probes, including DCFDA, JC-1, C11 BODIPY, Mito-Tracker, and PGSK, to measure ROS production, mitochondrial membrane potential, lipid peroxidation, mitochondrial morphology, and intracellular iron levels. Additionally, Western blotting, biolayer interferometry technology, and shRNA were utilized to investigate the underlying molecular mechanisms. Furthermore, p-CAX APP Swe/Ind- and pRK5-EGFP-Tau P301L overexpressing PC-12 cells, along with Caenorhabditis elegans (C. elegans) strains CL4176, CL2331, and BR5270, were employed to examine ferroptosis in AD models. RESULTS: Here, we conducted a screening of our natural medicine libraries and identified the ethanol extract of Penthorum chinense Pursh (PEE), particularly its ethyl acetate fraction (PEF), displayed inhibitory effects on ferroptosis in cells. Specifically, PEF inhibited the generation of ROS, lipid peroxidation, and intracellular iron levels. Furthermore, PEF demonstrated protective effects against H2O2-induced cell death, ROS production, and mitochondrial damage. Mechanistic investigations unveiled PEF's modulation of intracellular iron accumulation, GPX4 expression and activity, and FSP1 expression. In p-CAX APP Swe/Ind and pRK5-EGFP-Tau P301L overexpressing PC-12 cells, PEF significantly reduced cell death, as well as ROS and lipid peroxidase production. Moreover, PEF ameliorated paralysis and slowing rate in Aß and Tau transgenic C. elegans models, while inhibiting ferroptosis, as evidenced by decreased DHE intensity, lipid peroxidation levels, iron accumulation, and expression of SOD-3 and gst-4. CONCLUSION: Our findings highlight the suppressive effects of PEF on ferroptosis in AD cellular and C. elegans models. This study helps us better understand how ferroptosis affects AD and emphasizes the potential of PCP as a candidate for AD intervention.

Novel 18-norspirostane steroidal saponins: Extending lifespan and mitigating neurodegeneration through promotion of mitophagy and mitochondrial biogenesis in Caenorhabditis elegans.

Pharmacological strategies to delay aging and combat age-related diseases are increasingly promising. This study explores the anti-aging and therapeutic effects of two novel 18-norspirostane steroidal saponins from Trillium tschonoskii Maxim, namely deoxytrillenoside CA (DTCA) and epitrillenoside CA (ETCA), using Caenorhabditis elegans (C. elegans). Both DTCA and ETCA significantly extended the lifespan of wild-type N2 worms and improved various age-related phenotypes, including muscle health, motility, pumping rate, and lipofuscin accumulation. Furthermore, these compounds exhibited notable alleviation of pathology associated with Parkinson's disease (PD) and Huntington's disease (HD), such as the reduction of α-synuclein and poly40 aggregates, improvement in motor deficits, and mitigation of neuronal damage. Meanwhile, DTCA and ETCA improved the lifespan and healthspan of PD- and HD-like C. elegans models. Additionally, DTCA and ETCA enhanced the resilience of C. elegans against heat and oxidative stress challenges. Mechanistic studies elucidated that DTCA and ETCA induced mitophagy and promoted mitochondrial biogenesis in C. elegans, while genetic mutations or RNAi knockdown affecting mitophagy and mitochondrial biogenesis effectively eliminated their capacity to extend lifespan and reduce pathological protein aggregates. Together, these compelling findings highlight the potential of DTCA and ETCA as promising therapeutic interventions for delaying aging and preventing age-related diseases.

Dynamic feature analysis of handwritten electronic signatures based on Fourier transform.

The utilization of handwritten electronic signatures has expanded in various application scenarios, leading to an increased demand for identification. Unlike handwriting signatures, handwritten electronic signatures offer the advantage of extracting dynamic feature data, including writing pressure, velocity, and acceleration. In this study, the Fourier transform was employed to extract 18 characteristics from the time domain and frequency domain of writing pressure, velocity, and acceleration. The experimental findings revealed distinguishable differences between genuine signatures and random forgeries in writing pressure. However, no statistically significant differences were observed in writing velocity and writing acceleration. Moreover, significant differences were detected in most characteristics when comparing genuine signatures with freehand imitation forgeries and tracing imitation forgeries. The canonical discriminant analysis was performed between the genuine and Non-genuine signatures; the cross-validation estimated the discriminating power of these characteristics with a satisfactory result. The study proposed a new approach to analyzing handwritten electronic signatures using time-domain and frequency-domain characteristics and demonstrated its effectiveness in the examination.

Carpesii fructus extract exhibits neuroprotective effects in cellular and Caenorhabditis elegans models of Parkinson's disease.

OBJECTIVE: Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra. Despite extensive research, no definitive cure or effective disease-modifying treatment for PD exists to date. Therefore, the identification of novel therapeutic agents with neuroprotective properties is of utmost importance. Here, we aimed to investigate the potential neuroprotective effects of Carpesii fructus extract (CFE) in both cellular and Caenorhabditis elegans (C. elegans) models of PD. METHODS: The neuroprotective effect of CFE in H2O2- or 6-OHDA-induced PC-12 cells and α-synuclein-overexpressing PC-12 cells were investigated by determining the cell viability, mitochondrial damage, reactive oxygen species (ROS) production, apoptosis, and α-synuclein expression. In NL5901, BZ555, and N2 worms, the expression of α-synuclein, motive ability, the viability of dopaminergic neurons, lifespan, and aging-related phenotypes were investigated. The signaling pathway was detected by Western blotting and validated by employing small inhibitors and RNAi bacteria. RESULTS: In cellular models of PD, CFE significantly attenuated H2O2- or 6-OHDA-induced toxicity, as evidenced by increased cell viability and reduced apoptosis rate. In addition, CFE treatment suppressed ROS generation and restored mitochondrial membrane potential, highlighting its potential as a mitochondrial protective agent. Furthermore, CFE reduced the expression of α-synuclein in wide type (WT)-, A53T-, A30P-, or E46K-α-synuclein-overexpressing PC-12 cells. Our further findings reveal that CFE administration reduced α-synuclein expression and improved its induced locomotor deficits in NL5901 worms, protected dopaminergic neurons against 6-OHDA-induced degeneration in BZ555 worms, extended lifespan, delayed aging-related phenotypes, and enhanced the ability of stress resistance in N2 worms. Mechanistic studies suggest that the neuroprotective effects of CFE may involve the modulation of the MAPK signaling pathway, including ERK, JNK, and p38, whereas the interference of these pathways attenuated the neuroprotective effect of CFE in vitro and in vivo. CONCLUSION: Overall, our study highlights the potential therapeutic value of CFE as a neuroprotective agent in the context of PD. Furthermore, elucidation of the active compounds of CFE will provide valuable insights for the development of novel therapeutic strategies for PD.

The Protective Effects of Reineckia carnea Ether Fraction against Alzheimer's Disease Pathology: An Exploration in Caenorhabditis elegans Models.

Alzheimer's disease (AD) presents a significant challenge to global healthcare systems, with current treatments offering only modest relief and often bringing unwanted side effects, necessitating the exploration of more effective and safer drugs. In this study, we employed the Caenorhabditis elegans (C. elegans) model, specifically the AD-like CL4176 strain expressing the human Aß(1-42) protein, to investigate the potential of Reineckia carnea extract and its fractions. Our results showed that the Reineckia carnea ether fraction (REF) notably diminished the paralysis rates of CL4176 worms. Additionally, REF also attenuated the neurotoxicity effects prompted by Tau proteins in the BR5270 worms. Moreover, REF was observed to counteract the accumulation of Aß and pTau proteins and their induced oxidative stress in C. elegans AD-like models. Mechanistic studies revealed that REF's benefits were associated with the induction of autophagy in worms; however, these protective effects were nullified when autophagy-related genes were suppressed using RNAi bacteria. Together, these findings highlight Reineckia carnea ether fraction as a promising candidate for AD treatment, warranting further investigation into its autophagy-inducing components and their molecular mechanisms.

Secretory IgA-ETEC F5 Immune Complexes Promote Dendritic Cell Differentiation and Prime T Cell Proliferation in the Mouse Intestine.

Although secretory IgA (SIgA) is the dominant antibody in mucosal secretions, the capacity of the SIgA-antigen complex to prime the activation of dendritic cells (DCs) and T cells in the intestinal epithelium is not well understood. To this end, the SIgA-ETEC F5 immune complexes (ICs) were prepared via Ni-NTA pull-down. After injecting the ICs into the intestines of SPF BALB/c mice, most ICs were observed in the Peyer's patch (PP). We established a microfold (M) cell culture model in vitro for transport experiments and the inhibition test. To evaluate the priming effect of mucosal immunity, we employed the DC2.4 stimulation test, T lymphocyte proliferation assays, and cytokine detection assays. We found that the ICs were taken up via clathrin-dependent endocytosis through M cells. The high expression of costimulatory molecules CD86, CD80, and CD40 indicated that the ICs promoted the differentiation and maturation of DC2.4 cells. The stimulation index (SI) in the complex group was significantly higher than in the control group, suggesting that the ICs stimulated the proliferation of primed T cells. The secretion of some cytokines, namely TNF-α, IFN-γ, IL-2, IL-4, IL-5, and IL-6, in spleen cells from the immunized mice was upregulated. These results indicate that ETEC F5 delivery mediated by SIgA in PPs initiates mucosal immune responses.

Lychee seed polyphenol ameliorates DR via inhibiting inflammasome/apoptosis and angiogenesis in hRECs and db/db mice.

Blood retinal barrier (BRB) damage is an important pathogenesis of diabetic retinopathy, and alleviating BRB damage has become a key target for DR treatment. We previously found that Lycopene seed polyphenols (LSP) maintained BRB integrity by inhibiting NLRP3 inflammasome-mediated inflammation. However, it is still unknown whether LSP inhibits retinal neovascularization with abnormal capillaries and its mechanism of action. Here, we employed db/db mice and hRECs to find that LSP increases the level of glycolipid metabolism, maintains the morphology of retinal endothelial cells and inhibits acellular capillary neogenesis. Mechanistic studies revealed that LSP inhibits the NLRP3 inflammasome, reduces cell apoptosis in retinal tissue, increases tight junction protein (TJ) expression, and reduces vascular endothelial growth factor (VEGF) and Ve-Cadherin in vivo and in vitro. Collectively, this study finds that LSP inhibits inflammation and angiogenesis to improve BRB function to ameliorate DR.

Poly (ADP-ribose) polymerase 1 and neurodegenerative diseases: Past, present, and future.

Poly (ADP-ribose) polymerase 1 (PARP1) is a first responder that recognizes DNA damage and facilitates its repair. Neurodegenerative diseases, characterized by progressive neuron loss driven by various risk factors, including DNA damage, have increasingly shed light on the pivotal involvement of PARP1. During the early phases of neurodegenerative diseases, PARP1 experiences controlled activation to swiftly address mild DNA damage, thereby contributing to maintain brain homeostasis. However, in late stages, exacerbated PARP1 activation precipitated by severe DNA damage exacerbates the disease condition. Consequently, inhibition of PARP1 overactivation emerges as a promising therapeutic approach for neurodegenerative diseases. In this review, we comprehensively synthesize and explore the multifaceted role of PARP1 in neurodegenerative diseases, with a particular emphasis on its over-activation in the aggregation of misfolded proteins, dysfunction of the autophagy-lysosome pathway, mitochondrial dysfunction, neuroinflammation, and blood-brain barrier (BBB) injury. Additionally, we encapsulate the therapeutic applications and limitations intrinsic of PARP1 inhibitors, mainly including limited specificity, intricate pathway dynamics, constrained clinical translation, and the heterogeneity of patient cohorts. We also explore and discuss the potential synergistic implementation of these inhibitors alongside other agents targeting DNA damage cascades within neurodegenerative diseases. Simultaneously, we propose several recommendations for the utilization of PARP1 inhibitors within the realm of neurodegenerative disorders, encompassing factors like the disease-specific roles of PARP1, combinatorial therapeutic strategies, and personalized medical interventions. Lastly, the encompassing review presents a forward-looking perspective along with strategic recommendations that could guide future research endeavors in this field.

Protective effects of Radix Stellariae extract against Alzheimer's disease via autophagy activation in Caenorhabditis elegans and cellular models.

Enhancing the clearance of proteins associated with Alzheimer's disease (AD) emerges as a promising approach for AD therapeutics. This study explores the potential of Radix Stellariae, a traditional Chinese medicine, in treating AD. Utilizing transgenic C. elegans models of AD, we demonstrated that a 75% ethanol extract of Radix Stellariae (RSE) (at 50 µg/mL) effectively diminishes Aß and Tau protein expression, and alleviates their induced impairments including paralysis, behavioral dysfunction, neurotoxicity, and ROS accumulation. Additionally, RSE enhances the stress resistance of C. elegans. Further investigations revealed that RSE promotes autophagy, a critical cellular process for protein degradation, in these models. We found that inhibiting autophagy-related genes negated the neuroprotective effects of RSE, suggesting a central role for autophagy in the actions of RSE. In PC-12 cells, we observed that RSE not only inhibited Aß fibril formation but also promoted the degradation of AD-related proteins and reduced their cytotoxicity. Mechanistically, RSE was found to induce autophagy via modulating PI3K/AKT/mTOR and AMPK/mTOR signaling pathways. Importantly, inhibiting autophagy counteracted the beneficial effects of RSE on the clearance of AD-associated proteins. Moreover, we identified Dichotomine B, a ß-carboline alkaloid, as a key active constituent of RSE in mitigating AD pathology in C. elegans at concentrations ranging from 50 to 1000 µM. Collectively, our study presents novel discoveries that RSE alleviates AD pathology and toxicity primarily by inducing autophagy, both in vivo and in vitro. These findings open up new avenues for exploring the therapeutic potential of RSE and its active component, Dichotomine B, in treating neurodegenerative diseases like AD.

Lysine butyrylation of HSP90 regulated by KAT8 and HDAC11 confers chemoresistance.

Posttranslational modification dramatically enhances protein complexity, but the function and precise mechanism of novel lysine acylation modifications remain unknown. Chemoresistance remains a daunting challenge to successful treatment. We found that lysine butyrylation (Kbu) is specifically upregulated in chemoresistant tumor cells and tissues. By integrating butyrylome profiling and gain/loss-of-function experiments, lysine 754 in HSP90 (HSP90 K754) was identified as a substrate for Kbu. Kbu modification leads to overexpression of HSP90 in esophageal squamous cell carcinoma (ESCC) and its further increase in relapse samples. Upregulation of HSP90 contributes to 5-FU resistance and can predict poor prognosis in cancer patients. Mechanistically, HSP90 K754 is regulated by the cooperation of KAT8 and HDAC11 as the writer and eraser, respectively; SDCBP increases the Kbu level and stability of HSP90 by binding competitively to HDAC11. Furthermore, SDCBP blockade with the lead compound V020-9974 can target HSP90 K754 to overcome 5-FU resistance, constituting a potential therapeutic strategy.

Ameliorative effect of Luffa cylindrica fruits on Caenorhabditis elegans and cellular models of Alzheimer's disease-related pathology via autophagy induction.

BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder without an effective cure. Natural products, while showing promise as potential therapeutics for AD, remain underexplored. AIMS: This study was conducted with the goal of identifying potential anti-AD candidates from natural sources using Caenorhabditis elegans (C. elegans) AD-like models and exploring their mechanisms of action. MATERIALS & METHODS: Our laboratory's in-house herbal extract library was utilized to screen for potential anti-AD candidates using the C. elegans AD-like model CL4176. The neuroprotective effects of the candidates were evaluated in multiple C. elegans AD-like models, specifically targeting Aß- and Tau-induced pathology. In vitro validation was conducted using PC-12 cells. To investigate the role of autophagy in mediating the anti-AD effects of the candidates, RNAi bacteria and autophagy inhibitors were employed. RESULTS: The ethanol extract of air-dried fruits of Luffa cylindrica (LCE), a medicine-food homology species, was found to inhibit Aß- and Tau-induced pathology (paralysis, ROS production, neurotoxicity, and Aß and pTau deposition) in C. elegans AD-like models. LCE was non-toxic and enhanced C. elegans' health. It was shown that LCE activates autophagy and its anti-AD efficacy is weakened with the RNAi knockdown of autophagy-related genes. Additionally, LCE induced mTOR-mediated autophagy, reduced the expression of AD-associated proteins, and decreased cell death in PC-12 cells, which was reversed by autophagy inhibitors (bafilomycin A1 and 3-methyladenine). DISCUSSION: LCE, identified from our natural product library, emerged as a valuable autophagy enhancer that effectively protects against neurodegeneration in multiple AD-like models. RNAi knockdown of autophagy-related genes and cotreatment with autophagy inhibitors weakened its anti-AD efficacy, implying a critical role of autophagy in mediating the neuroprotective effects of LCE. CONCLUSION: Our findings highlight the potential of LCE as a functional food or drug for targeting AD pathology and promoting human health.

Growth history of hepatitis C virus among HIV/HCV co-infected patients in Guizhou Province.

Background: The evolutionary and epidemiological history and the regional differences of various hepatitis C virus (HCV) genotypes are complex. Our aim was to better understand the molecular epidemiology and evolutionary dynamics of HCV among HIV/HCV co-infected individuals in Guizhou Province. This information could contribute to improve HCV prevention and control strategies in Guizhou and surrounding provinces. Methods: The HCV RNA was extracted from the serum of HIV/HCV co-infected patients, and reverse transcription/nested PCR was performed to amplify nucleotide sequences of the C-E1 region. Then, the successfully amplified sequences were selected for phylogenetic analysis. The available C-E1 region reference sequences from the surrounding provinces of Guizhou (Guangxi, Yunnan, Hunan, and Sichuan) were retrieved in GenBank, and the evolutionary analysis by Bayesian Markov chain Monte Carlo (MCMC) algorithm was performed using BEAST software to reconstruct a phylogeographic tree in order to explore their migration patterns. Finally, the epidemiological history of HCV in the Guizhou region was retraced by reconstructing Bayesian skyline plots (BSPs) after excluding sequences from surrounding provinces. Results: Among 186 HIV/HCV co-infected patients, the C-E1 region sequence was successfully amplified in 177 cases. Phylogenetic analysis classified these sequences into six subtypes: 1a, 1b, 3a, 3b, 6a, and 6n. Among them, subtype 6a was the most dominant strain (n = 70), followed by 3b (n = 55), 1b (n = 31), 3a (n = 11), 1a (n = 8), and 6n (n = 2). By reconstructing the phylogeographic tree, we estimated that the 6a strain in Guizhou mainly originated from Yunnan and Guangxi, while the 3b strain emerged due to transmission from the IDU network in Yunnan. Subtypes 1b, 3a, 3b, and 6a, as the major subtypes of HCV in HIV/HCV co-infected individuals in Guizhou, emerged and later grew more rapidly than the national average. Notably, BSPs of the currently prevalent HCV predominant strain subtype 6a in Guizhou have shown a rapid population growth since 2004. Although the growth rate slowed down around 2010, this growth has continued to date. Conclusion: Overall, despite the improvement and implementation of a series of HCV prevention and control policies and measures, a delayed growth pattern may indicate a unique history of the spread of 6a in Guizhou. Its trend as the dominant strain in Guizhou in recent years may continue to increase slowly over subsequent years.

Targeting autophagy to discover the Piper wallichii petroleum ether fraction exhibiting antiaging and anti-Alzheimer's disease effects in Caenorhabditis elegans.

BACKGROUND: With population aging, the incidence of aging-related Alzheimer's disease (AD) is increasing, accompanied by decreased autophagy activity. At present, Caenorhabditis elegans (C. elegans) is widely employed to evaluate autophagy and in research on aging and aging-related diseases in vivo. To discover autophagy activators from natural medicines and investigate their therapeutic potential in antiaging and anti-AD effects, multiple C. elegans models related to autophagy, aging, and AD were used. METHOD: In this study, we employed the DA2123 and BC12921 strains to discover potential autophagy inducers using a self-established natural medicine library. The antiaging effect was evaluated by determining the lifespan, motor ability, pumping rate, lipofuscin accumulation of worms, and resistance ability of worms under various stresses. In addition, the anti-AD effect was examined by detecting the paralysis rate, food-sensing behavior, and amyloid-ß and Tau pathology in C. elegans. Moreover, RNAi technology was used to knock down the genes related to autophagy induction. RESULTS: We discovered that Piper wallichii extract (PE) and the petroleum ether fraction (PPF) activated autophagy in C. elegans, as evidenced by increased GFP-tagged LGG-1 foci and decreased GFP-p62 expression. In addition, PPF extended the lifespan and enhanced the healthspan of worms by increasing body bends and pumping rates, decreasing lipofuscin accumulation, and increasing resistance to oxidative, heat, and pathogenic stress. Moreover, PPF exhibited an anti-AD effect by decreasing the paralysis rate, improving the pumping rate and slowing rate, and alleviating Aß and Tau pathology in AD worms. However, the feeding of RNAi bacteria targeting unc-51, bec-1, lgg-1, and vps-34 abolished the antiaging and anti-AD effects of PPF. CONCLUSION: Piper wallichii may be a promising drug for antiaging and anti-AD. More future studies are also needed to identify autophagy inducers in Piper wallichii and clarify their molecular mechanisms.

Analysis of pulmonary artery variation based on 3D reconstruction of CT angiography.

Objective: The aim of this study is to acquire pulmonary CT (Computed tomography) angiographic data for the purpose of creating a three-dimensional reconstruction. Additionally, we aim to analyze the features and deviations of the branches in both pulmonary lobes. This information is intended to serve as a more comprehensive and detailed reference for medical professionals when conducting preoperative evaluations and devising surgical plans. Method: Between August 2019 and December 2021, 420 patients were selected from the thoracic surgery department at the First Hospital of Jilin University, and underwent pulmonary 64 channel contrast enhanced CT examinations (Philips ICT 256). The images were acquired at a 1.5 mm slice thickness, and the DCM files that complied with DICOM (Digital Imaging and Communications in Medicine) standards were analysed for 3D (three dimensional) reconstruction using Mimics 22.0 software. The reconstructed pulmonary artery models were assessed by attending chest surgeons and radiologists with over 10 years of clinical experience. The two-dimensional image planes, as well as the coronary and sagittal planes, were utilized to evaluate the arteries. The study analyzed the characteristics and variations of the branches and courses of pulmonary arteries in each lobe of the lungs, with the exception of the subsegmental arterial system. Two chest surgeons and two radiologists with professional titles-all of whom had over a decade of clinical experience-jointly evaluated the 3D models of the pulmonary artery and similarly assessed the characteristics and variations of the branches and courses in each lobe of the lungs. Results: Significant variations were observed in the left superior pulmonary artery across the 420 subjects studied. In the left upper lobe, the blood supply of 4 arteries accounted for 50.5% (n = 212), while the blood supply of 2 arteries in the left lower lobe was the most common, accounting for 79.5% (n = 334). The greatest variation in the right pulmonary artery was observed in the branch supply of the right upper lobe mediastinal artery. In the majority of cases (77.9%), there were two arteries present, which was the most common configuration observed accounting for 64% (n = 269). In the right inferior lobe of the lung, there were typically 2-4 arteries, with 2 arteries being the most common configuration (observed in 79% of cases, n = 332). Conclusion: The three-dimensional reconstruction of pulmonary artery CT angiography enables clear observation of the branches and distribution of the pulmonary artery while also highlighting any variations. This technique holds significant clinical value for preoperative assessments regarding lesions and blood vessels.