PROTAC as a novel anti-cancer strategy by targeting aging-related signaling.

Aging and cancer share common cellular hallmarks, including cellular senescence, genomic instability, and abnormal cell death and proliferation, highlighting potential areas for therapeutic interventions. Recent advancements in targeted protein degradation technologies, notably Proteolysis-Targeting Chimeras (PROTACs), offer a promising approach to address these shared pathways. PROTACs leverage the ubiquitin-proteasome system to specifically degrade pathogenic proteins involved in cancer and aging, thus offering potential solutions to key oncogenic drivers and aging-related cellular dysfunction. This abstract summarizes the recent progress of PROTACs in targeting critical proteins implicated in both cancer progression and aging, and explores future perspectives in integrating these technologies for more effective cancer treatments.

Targeted protein posttranslational modifications by chemically induced proximity for cancer therapy.

Post-translational modifications (PTMs) regulate all aspects of protein function. Therefore, upstream regulators of PTMs, such as kinases, acetyltransferases, or methyltransferases, are potential therapeutic targets for human diseases, including cancer. To date, multiple inhibitors and/or agonists of these PTM upstream regulators are in clinical use, while others are still in development. However, these upstream regulators control not only the PTMs of disease-related target proteins but also other disease-irrelevant substrate proteins. Thus, nontargeted perturbing activities may introduce unwanted off-target toxicity issues that limit the use of these drugs in successful clinical applications. Therefore, alternative drugs that solely regulate a specific PTM of the disease-relevant protein target may provide a more precise effect in treating disease with relatively low side effects. To this end, chemically induced proximity has recently emerged as a powerful research tool, and several chemical inducers of proximity (CIPs) have been used to target and regulate protein ubiquitination, phosphorylation, acetylation, and glycosylation. These CIPs have a high potential to be translated into clinical drugs and several examples such as PROTACs and MGDs are now in clinical trials. Hence, more CIPs need to be developed to cover all types of PTMs, such as methylation and palmitoylation, thus providing a full spectrum of tools to regulate protein PTM in basic research and also in clinical application for effective cancer treatment.

A Liquid Biopsy Signature for the Early Detection of Gastric Cancer in Patients.

BACKGROUND & AIMS: Diagnosing gastric cancer (GC) while the disease remains eligible for surgical resection is challenging. In view of this clinical challenge, novel and robust biomarkers for early detection thus improving prognosis of GC are necessary. The present study is to develop a blood-based long noncoding RNA (LR) signature for the early-detection of GC. METHODS: The present 3-step study incorporated data from 2141 patients, including 888 with GC, 158 with chronic atrophic gastritis, 193 with intestinal metaplasia, 501 healthy donors, and 401 with other gastrointestinal cancers. The LR profile of stage I GC tissue samples were analyzed using transcriptomic profiling in discovery phase. The extracellular vesicle (EV)-derived LR signature was identified with a training cohort (n = 554) and validated with 2 external cohorts (n = 429 and n = 504) and a supplemental cohort (n = 69). RESULTS: In discovery phase, one LR (GClnc1) was found to be up-regulated in both tissue and circulating EV samples with an area under the curve (AUC) of 0.9369 (95% confidence interval [CI], 0.9073-0.9664) for early-stage GC (stage I/II). The diagnostic performance of this biomarker was further confirmed in 2 external validation cohorts (Xi'an cohort, AUC: 0.8839; 95% CI: 0.8336-0.9342; Beijing cohort, AUC: 0.9018; 95% CI: 0.8597-0.9439). Moreover, EV-derived GClnc1 robustly distinguished early-stage GC from precancerous lesions (chronic atrophic gastritis and intestinal metaplasia) and GC with negative traditional gastrointestinal biomarkers (CEA, CA72-4, and CA19-9). The low levels of this biomarker in postsurgery and other gastrointestinal tumor plasma samples indicated its GC specificity. CONCLUSIONS: EV-derived GClnc1 serves as a circulating biomarker for the early detection of GC, thus providing opportunities for curative surgery and improved survival outcomes.

Targeting micro-environmental pathways by PROTACs as a therapeutic strategy.

Tumor microenvironment (TME) composes of multiple cell types and non-cellular components, which supports the proliferation, metastasis and immune surveillance evasion of tumor cells, as well as accounts for the resistance to therapies. Therefore, therapeutic strategies using small molecule inhibitors (SMIs) and antibodies to block potential targets in TME are practical for cancer treatment. Targeted protein degradation using PROteolysis-TArgeting Chimera (PROTAC) technic has several advantages over traditional SMIs and antibodies, including overcoming drug resistance. Thus many PROTACs are currently under development for cancer treatment. In this review, we summarize the recent progress of PROTAC development that target TME pathways and propose the potential direction of future PROTAC technique to advance as novel cancer treatment options.

Quercetin and its derivatives for wound healing in rats/mice: Evidence from animal studies and insight into molecular mechanisms.

Aimed to clarify the effect of quercetin and its derivatives on wound healing in animal experiments. PubMed, Embase, Science Direct, Web of Science, SinoMed, Vip Journal Integration Platform, China National Knowledge Infrastructure and WanFang databases were searched for animal experiments investigating the effect of quercetin and its derivatives on wound healing to April 2023. The Review Manager 5.4 software was used to conduct meta-analysis. Eighteen studies were enrolled in this article. According to the SYRCLE's RoB tool assessment, these studies exposed relatively low methodological quality. It was shown that animals with cutaneous wound receiving quercetin had faster wound healing in wound closure (%) than the control group. Moreover, the difference in efficacy gradually emerged after third day (WMD = 7.13 [5.52, 8.74]), with a peak reached on the tenth day after wounding (WMD = 19.78 [17.82, 21.74]). Subgroup analysis revealed that quercetin for wound closure (%) was independent of the types of rats and mice, wound area and with or without diabetes. Clear conclusion was also shown regarding the external application of quercetin for wound healing (WMD = 17.77 [11.11, 24.43]). A significant reduction in the distribution of inflammatory cells occurred in the quercetin group. Quercetin could increase blood vessel density (WMD = 1.85 [0.68, -3.02]), fibroblast distribution and collagen fraction. Biochemical indicators, including IL-1ß, IL-10, TNF-α, TGF-ß, vascular endothelial growth factor (VEGF), hydroxyproline and alpha-smooth muscle actin (α-SMA), had the consistent results. Quercetin and its derivatives could promote the recovery of cutaneous wound in animals, through inhibiting inflammatory response and accelerating angiogenesis, proliferation of fibroblast and collagen deposition.

Network pharmacology and molecular docking reveal the mechanism of Qinghua Xiaoyong Formula in Crohn's disease.

Crohn's disease (CD) is a chronic inflammatory illness of the digestive system with unknown etiology, and its incidence is increasing worldwide. However, there are currently no effective treatments or medications available for individuals with CD. Therefore, novel therapeutic strategies are urgently needed. The bioactive compounds and targets associated with compounds of Qinghua Xiaoyong Formula (QHXYF) were examined using The Traditional Chinese Medicine Systems Pharmacology database, and 5 disease target databases were also used to identify CD-related disease targets. A total of 166 overlapping targets were identified from QHXYF-related and CD-related disease targets and they were found to be enriched in oxidative stress-related pathways and the PI3K/AKT signaling pathway. Molecular docking was then used to predict how the bioactive compounds would bind to the hub targets. It was found that quercetin could be the core bioactive compound and had good binding affinity to the top 5 hub targets. Finally, animal experiments were performed to further validate the findings, and the results revealed that QHXYF or quercetin inhibited 2,4,6-trinitrobenzenesulfonic acid-induced inflammation and oxidative stress processes by inhibiting the PI3K/AKT pathway, thereby improving CD symptoms. These findings suggest that QHXYF and quercetin may be potential novel treatments for CD.

Daphnetin ameliorates Aß pathogenesis via STAT3/GFAP signaling in an APP/PS1 double-transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) has become a major public health problem that affects the elderly population. Therapeutic compounds with curative effects are not available due to the complex pathogenesis of AD. Daphnetin, a natural coumarin derivative and inhibitor of various kinases, has anti-inflammatory and antioxidant activities. In this study, we found that daphnetin improved spatial learning and memory in an amyloid precursor protein (APP)/presenilin 1 (PS1) double-transgenic mouse model of AD. Daphnetin markedly decreased the levels of amyloid-ß peptide 1-40 (Aß40) and 1-42 (Aß42) in the cerebral cortex, downregulated the expressions of enzymes involved in APP processing, e.g., beta-site APP-cleaving enzyme (BACE), nicastrin and presenilin enhancer protein 2 (PEN2). We further found the reduced serum levels of inflammatory factors, including interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and chemokine (C-C motif) ligand 3 (CCL3), while daphnetin increased total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) levels in the serum. Interestingly, daphnetin markedly decreased the expression of glial fibrillary acidic protein (GFAP) and the upstream regulatory molecule- phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in APP/PS1 mice, and mainly inhibited the phosphorylation of STAT3 at Ser727 to decrease GFAP expression evidenced in a LPS-activated glial cell model. These results suggest that daphnetin ameliorates cognitive deficits and that Aß deposition in APP/PS1 mice is mainly correlated with astrocyte activation and APP processing.

Level of phosphate diets effect on fibroblast growth factor-23 levels in chronic kidney disease subjects: A meta-analysis.

BACKGROUND: High fibroblast growth factor-23 levels increase cardiovascular disease risk in chronic kidney disease subjects. The effects of dietary phosphate levels on fibroblast growth factor-23 in chronic kidney disease subjects have conflicting results. This meta-analysis was performed to evaluate this relationship. METHODS: A systematic-literature search up to July 2020 was performed and 7 studies were detected with 548 chronic kidney disease subjects at the baseline of the studies; a total of 170 of them were with lower dietary phosphate levels and 175 were higher dietary phosphate levels. They reported relationships between dietary phosphate levels and fibroblast growth factor-23 level in chronic kidney disease subjects. Mean differences (MD) with 95% confidence intervals (CIs) were calculated comparing the lower versus higher phosphate levels effect on urinary phosphate levels and fibroblast growth factor-23 level in chronic kidney disease subjects using the contentious methods with a random or fixed-effect model. RESULTS: Lower dietary phosphate levels had significantly lower 24-hour urinary phosphate excretion (MD, -41.23; 95% CI, -59.95 to 22.52, P < .001), and lower intact fibroblast growth factor-23 level (MD, -25.68; 95% CI, -39.85 to -11.51, P < .001) compared with higher dietary phosphate levels in chronic kidney disease subjects. However, no significant difference was found between low and high dietary phosphate levels in C-terminal fibroblast growth factor-23 level in chronic kidney disease subjects (MD, -7.10; 95% CI, -14.29 to 0.10, P = .05). CONCLUSIONS: Lower dietary phosphate levels had significantly lower 24-hour urinary phosphate excretion, intact fibroblast growth factor-23 level compared with higher dietary phosphate levels in chronic kidney disease subjects. This relationship forces us to recommend low dietary phosphate levels in chronic kidney disease subjects to decrease fibroblast growth factor-23 level to avoid any possible cardiovascular disease risk in such a subject.

Aberrant expression for microRNA is potential crucial factors of haemorrhoid.

BACKGROUND: Haemorrhoids occur commonly and frequently in the human digestive system. There are diverse causes of haemorrhoids and their in-depth pathogenesis is still currently unclear. METHODS: In this study, we explored haemorrhoids from an epigenetics perspective by employing RNA-Seq for comprehensive and in-depth analysis of the differences in microRNA (miRNA) transcripts between haemorrhoidal tissue and normal tissue in 48 patients with Grade II and above haemorrhoids. RESULTS: The results showed that 9 miRNAs were significantly upregulated (ratio > 3.5 and P-value < 0.01) and 16 miRNAs were significantly downregulated (ratio > 0.6 and P-value < 0.01) in haemorrhoid tissue. Subsequently, target gene prediction results showed that there were 184 potential target genes of significantly upregulated miRNAs (common to both TargetScan7.1 and MirdbV5 databases) and there were 372 potential target genes of significantly downregulated miRNAs. Gene ontology analysis results showed that the target genes of differentially expressed miRNAs in haemorrhoids are involved in regulating "cell composition" and "protein binding". Lastly, KEGG search found that the differentially expressed miRNAs that are associated with the occurrence of haemorrhoids mainly regulate the activity of endocytosis and the synaptic vesicle cycle. CONCLUSIONS: In summary, the results of high-throughput RNA-Seq screening suggested that the occurrence of haemorrhoids may be intimately associated with aberrant miRNA transcription, resulting in aberrant target gene expression and an imbalance in certain signal transduction pathways.

Targeting SCF E3 Ligases for Cancer Therapies.

SKP1-cullin-1-F-box-protein (SCF) E3 ubiquitin ligase complex is responsible for the degradation of proteins in a strictly regulated manner, through which it exerts pivotal roles in regulating various key cellular processes including cell cycle and division, apoptosis, and differentiation. The substrate specificity of the SCF complex largely depends on the distinct F-box proteins, which function in either tumor promotion or suppression or in a context-dependent manner. Among the 69 F-box proteins identified in human genome, FBW7, SKP2, and ß-TRCP have been extensively investigated among various types of cancer in respective of their roles in cancer development, progression, and metastasis. Moreover, several specific inhibitors have been developed to target those E3 ligases, and their efficiency in tumors has been determined. In this review, we provide a summary of the roles of SCF E3 ligases in cancer development, as well as the potential application of miRNA or specific inhibitors for cancer therapy.

Endogenously generated amyloid-ß increases stiffness in human neuroblastoma cells.

Amyloid-ß (Aß) is widely recognized as toxic to neuronal cells. Its deposition on plasma and intracellular membranes and aggregation into amyloid plaques can disturb the composition and physiological function of neurons. Whether a physical property of cells, such as stiffness, is altered by endogenously overexpressed Aß has not yet been investigated. In this study, we used human neuroblastoma cells stably overexpressing amyloid precursor protein (APP) and its Swedish mutant form (APPswe) to measure the changes in cell stiffness. Our results showed that the stiffness of cells overexpressing APP or APPswe was higher than that of control SH-SY5Y cells. Either reducing levels of Aß with the γ secretase inhibitor DAPT or blocking the membrane calcium channel formed by Aß with tromethamine decreased cell stiffness to a level close to the control SH-SY5Y cells. Our results suggested that Aß, not APP, contributed to increased cell stiffness and that closure of calcium channels formed by Aß can alleviate the effects of Aß on membrane stiffness.

Is oral contraceptive use associated with an increased risk of cervical cancer? An evidence-based meta-analysis.

AIM: The purpose of this meta-analysis is to synthesize evidence-based case-control studies to evaluate the association between oral contraceptive (OC) use and the risk of cervical cancer. METHODS: Two reviewers independently selected potentially relevant studies through PubMed, Embase, Chinese National Knowledge Infrastructure, Wanfang Data, and the Chongqing VIP databases using the core terms cervical intraepithelial neoplasia/ cervix dysplasia/ cervi* AND oral contraceptive in the article titles, abstracts, and keywords. All data were analyzed using stata 12.0. The heterogeneity was assessed by Q-test and I2 statistic. Forest plot was used to display results graphically. Publication bias was assessed by Begg's test. RESULTS: In total, 16 case-control studies, including 15 619 participants (7433 cases and 8186 controls), met the eligibility criteria. Individuals with OC use were not found to have a risk of cervical cancer (odds ratio [OR], 1.12; 95% confidence interval [CI], 0.90-1.38). In subgroup analyses, no significant associations were found for different durations of OC use (<5 years: OR, 0.84; 95%CI, 0.68-1.04; 5-10 years: OR, 1.06; 95%CI, 0.66-1.71; >10 years: OR, 1.25; 95%CI, 0.76-2.06). Additionally, using OC was not shown to increase the risk of cervical cancer among women with human papillomavirus infections (OR, 1.09; 95%CI, 0.80-1.49). However, an increased risk of cervical cancer was found in Asian populations with OC use. CONCLUSION: The meta-analysis of case-control studies did not show an association between OC use and risk of cervical cancer. However, other necessary prospective cohort studies should be conducted to assess the impact of OC use on cervical cancer risk in the future.

Early inflammation-associated factors blunt sterol regulatory element-binding proteins-1-mediated lipogenesis in high-fat diet-fed APPSWE /PSEN1dE9 mouse model of Alzheimer's disease.

Alzheimer's disease (AD) patients have an increased incidence of Type 2 diabetes (T2D); however, the underlying mechanisms are not well understood. Since AD is considered a multifactorial disease that affects both the central nerves system and periphery and the dysregulation of hepatic lipid and glucose metabolism play critical roles in T2D, we, therefore, aim to explore the influence of AD genotype on the liver during the progress of high-fat diet (HFD)-induced T2D. Fourteen-week-old female APPSWE /PSEN1dE9 (AD) mice and age-, gender-matched wild-type controls C57BL/6J (WT) mice were fed a HFD (45% kcal fat content) or a standard chow diet (chow, 12% kcal fat content) for 22 weeks. The effects of diet and genotype were analyzed. Mouse primary hepatocytes were used to decipher the underlying mechanisms. HFD induced significantly higher body weight gain, more severe hyperglycemia, glucose intolerance and hepatic insulin resistance in AD mice than in WT mice. However, AD mice showed reduced HFD-induced hepatic steatosis, and SREBP-1-mediated lipogenic signaling was activated by HFD in WT mice but not in AD mice. In addition, 14-week-old AD mice exhibited higher expression of NF-κB p65, p-JNK and p-p38MAPK, as well as higher hepatic and serum contents of IL-6 and TNFα. In mouse primary hepatocyte cultures, IL-6 and TNFα inhibited high-glucose plus insulin-induced activation of SREBP-1-mediated lipogenic signaling and biosynthesis of non-esterified fatty acid and triglyceride. Early inflammation-associated factors most likely diminish HFD-induced hepatic lipid deposition by inhibiting SREBP-1-mediated de novo lipogenesis, thus driving substrate flux to glucose production for hyperglycemia and hepatic insulin resistance in T2D development. Alzheimer's disease (AD) is a multifactorial disease affecting both central nerves system and periphery organs. Therefore, we explored the hepatic susceptibility to high-fat diet (HFD) in AD mice. We found that AD mice were resistant to HFD-induced hepatic fat accumulation in spite of more severe obesity, hyperglycemia, glucose intolerance and hepatic insulin resistance. Mechanistically, AD mice exhibited hepatic inflammation at an early stage, which inhibited sterol regulatory element-binding proteins-1 (SREBP-1)-mediated de novo lipogenesis, and most likely drive substrate flux to glucose production for hyperglycemia and hepatic insulin resistance. Cover Image for this issue: doi: 10.1111/jnc.13306.

Mitochondrial dysfunction precedes depression of AMPK/AKT signaling in insulin resistance induced by high glucose in primary cortical neurons.

Recent studies have demonstrated brain insulin signaling impairment and mitochondrial dysfunction in diabetes. Hyperinsulinemia and hyperlipidemia arising from diabetes have been linked to neuronal insulin resistance, and hyperglycemia induces peripheral sensory neuronal impairment and mitochondrial dysfunction. However, how brain glucose at diabetic conditions elicits cortical neuronal insulin signaling impairment and mitochondrial dysfunction remains unknown. In the present study, we cultured primary cortical neurons with high glucose levels and investigated the neuronal mitochondrial function and insulin response. We found that mitochondrial function was declined in presence of 10 mmol/L glucose, prior to the depression of AKT signaling in primary cortical neurons. We further demonstrated that the cerebral cortex of db/db mice exhibited both insulin resistance and loss of mitochondrial complex components. Moreover, we found that adenosine monophosphate-activated protein kinase (AMPK) inactivation is involved in high glucose-induced mitochondrial dysfunction and insulin resistance in primary cortical neurons and neuroblastoma cells, as well as in cerebral cortex of db/db mice, and all these impairments can be rescued by mitochondrial activator, resveratrol. Taken together, our results extend the finding that high glucose (≥10 mmol/L) comparable to diabetic brain extracellular glucose level leads to neuronal mitochondrial dysfunction and resultant insulin resistance, and targeting mitochondria-AMPK signaling might be a promising strategy to protect against diabetes-related neuronal impairment in central nerves system. We found that high glucose (≥10 mmol/L), comparable to diabetic brain extracellular glucose level, leads to neuronal mitochondrial dysfunction and resultant insulin resistance in an AMPK-dependent manner, and targeting mitochondria-AMPK signaling might be a promising strategy to protect against diabetes-related neuronal impairment in central nerves system.

Mitochondrial Dysfunction Launches Dexamethasone-Induced Skeletal Muscle Atrophy via AMPK/FOXO3 Signaling.

Muscle atrophy occurs in several pathologic conditions such as diabetes and chronic obstructive pulmonary disease (COPD), as well as after long-term clinical administration of synthesized glucocorticoid, where increased circulating glucocorticoid accounts for the pathogenesis of muscle atrophy. Others and we previously reported mitochondrial dysfunction in muscle atrophy-related conditions and that mitochondria-targeting nutrients efficiently prevent kinds of muscle atrophy. However, whether and how mitochondrial dysfunction involves glucocorticoid-induced muscle atrophy remains unclear. Therefore, in the present study, we measured mitochondrial function in dexamethasone-induced muscle atrophy in vivo and in vitro, and we found that mitochondrial respiration was compromised on the 3rd day following after dexamethasone administration, earlier than the increases of MuRF1 and Fbx32, and dexamethasone-induced loss of mitochondrial components and key mitochondrial dynamics proteins. Furthermore, dexamethasone treatment caused intracellular ATP deprivation and robust AMPK activation, which further activated the FOXO3/Atrogenes pathway. By directly impairing mitochondrial respiration, FCCP leads to similar readouts in C2C12 myotubes as dexamethasone does. On the contrary, resveratrol, a mitochondrial nutrient, efficiently reversed dexamethasone-induced mitochondrial dysfunction and muscle atrophy in both C2C12 myotubes and mice, by improving mitochondrial function and blocking AMPK/FOXO3 signaling. These results indicate that mitochondrial dysfunction acts as a central role in dexamethasone-induced skeletal muscle atrophy and that nutrients or drugs targeting mitochondria might be beneficial in preventing or curing muscle atrophy.

Neo-adjuvant chemotherapy plus surgery versus surgery alone for cervical cancer: Meta-analysis of randomized controlled trials.

The aim of this study was to evaluate the efficacy and safety of neo-adjuvant chemotherapy (NACT) versus radical surgery (RS) for patients with cervical cancer. A meta-analysis of randomized controlled trials (RCT) of NACT + RS versus RS alone for patients with cervical cancer was performed according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. The following electronic databases were searched from their inception to April 2015: PUBMED, EMBASE and Cochrane Library. Statistical analysis was done using REVIEW MANAGER 5.3. Five RCT involving 739 patients were studied. There were significant differences between the NACT + RS and the RS-alone groups for positive lymph nodes (OR, 0.45; 95%CI: 0.29-0.70) and parametrial infiltration (OR, 0.48; 95% CI: 0.25-0.92), while treatment efficacy did not differ significantly for 5-year overall survival rate (OR, 1.17; 95% CI: 0.85-1.61), 5-year disease-free survival rate (OR, 1.09; 95% CI: 0.77-1.56) or recurrence rate (OR, 1.17; 95% CI: 0.85-1.61). The results also indicated that chemotherapy-related toxicity was well tolerated. For patients with cervical cancer, NACT could significantly reduce the number of positive lymph nodes and the level of parametrial infiltration compared with RS alone, and be well tolerated.

Hydroxytyrosol improves mitochondrial function and reduces oxidative stress in the brain of db/db mice: role of AMP-activated protein kinase activation.

Hydroxytyrosol (HT) is a major polyphenolic compound found in olive oil with reported anti-cancer and anti-inflammatory activities. However, the neuroprotective effect of HT on type 2 diabetes remains unknown. In the present study, db/db mice and SH-SY-5Y neuroblastoma cells were used to evaluate the neuroprotective effects of HT. After 8 weeks of HT administration at doses of 10 and 50 mg/kg, expression levels of the mitochondrial respiratory chain complexes I/II/IV and the activity of complex I were significantly elevated in the brain of db/db mice. Likewise, targets of the antioxidative transcription factor nuclear factor erythroid 2 related factor 2 including p62 (sequestosome-1), haeme oxygenase 1 (HO-1), and superoxide dismutases 1 and 2 increased, and protein oxidation significantly decreased. HT treatment was also found to activate AMP-activated protein kinase (AMPK), sirtuin 1 and PPARγ coactivator-1α, which constitute an energy-sensing protein network known to regulate mitochondrial function and oxidative stress responses. Meanwhile, neuronal survival indicated by neuron marker expression levels including activity-regulated cytoskeleton-associated protein, N-methyl-d-aspartate receptor and nerve growth factor was significantly improved by HT administration. Additionally, in a high glucose-induced neuronal cell damage model, HT effectively increased mitochondrial complex IV and HO-1 expression through activating AMPK pathway, followed by the prevention of high glucose-induced production of reactive oxygen species and declines of cell viability and VO2 capacity. Our observations suggest that HT improves mitochondrial function and reduces oxidative stress potentially through activation of the AMPK pathway in the brain of db/db mice.

Correlation of serum Klotho, fetuin-A, and MGP levels with coronary artery calcification in maintenance hemodialysis patients.

OBJECTIVE: This study was to investigate the role of serum Klotho, fetuin-A, and Matrix Gla Protein (MGP) in Coronary Artery Calcification (CAC) in patients with Maintenance Hemodialysis (MHD) and their predictive value for CAC. METHODS: 100 patients receiving MHD were selected. Serum Klotho, fetuin-A, and MGP levels were detected by ELISA. CAC scores were assessed by coronary CT scan. Multifactor analysis was used to evaluate the risk factors affecting CAC. The ability of serum Klotho, fetuin-A, and MGP levels to diagnose CAC was evaluated by receiver operating characteristic curves. RESULTS: Serum Klotho, fetuin-A, and MGP were independent risk factors for CAC. Serum Klotho, fetuin-A, and MGP were valuable in the diagnosis of CAC in MHD patients. CONCLUSION: There is a close relationship between Klotho, fetuin-A, and MGP levels in MHD patients and CAC.

Mining Alzheimer's disease clinical data: reducing effects of natural aging for predicting progression and identifying subtypes.

Introduction: Because Alzheimer's disease (AD) has significant heterogeneity in encephalatrophy and clinical manifestations, AD research faces two critical challenges: eliminating the impact of natural aging and extracting valuable clinical data for patients with AD. Methods: This study attempted to address these challenges by developing a novel machine-learning model called tensorized contrastive principal component analysis (T-cPCA). The objectives of this study were to predict AD progression and identify clinical subtypes while minimizing the influence of natural aging. Results: We leveraged a clinical variable space of 872 features, including almost all AD clinical examinations, which is the most comprehensive AD feature description in current research. T-cPCA yielded the highest accuracy in predicting AD progression by effectively minimizing the confounding effects of natural aging. Discussion: The representative features and pathogenic circuits of the four primary AD clinical subtypes were discovered. Confirmed by clinical doctors in Tangdu Hospital, the plaques (18F-AV45) distribution of typical patients in the four clinical subtypes are consistent with representative brain regions found in four AD subtypes, which further offers novel insights into the underlying mechanisms of AD pathogenesis.

Sleep Deprivation Triggers Mitochondrial DNA Release in Microglia to Induce Neural Inflammation: Preventative Effect of Hydroxytyrosol Butyrate.

Sleep deprivation (SD) triggers mitochondrial dysfunction and neural inflammation, leading to cognitive impairment and mental issues. However, the mechanism involving mitochondrial dysfunction and neural inflammation still remains unclear. Here, we report that SD rats exhibited multiple behavioral disorders, brain oxidative stress, and robust brain mitochondrial DNA (mtDNA) oxidation. In particular, SD activated microglia and microglial mtDNA efflux to the cytosol and provoked brain pro-inflammatory cytokines. We observed that the mtDNA efflux and pro-inflammatory cytokines significantly reduced with the suppression of the mtDNA oxidation. With the treatment of a novel mitochondrial nutrient, hydroxytyrosol butyrate (HTHB), the SD-induced behavioral disorders were significantly ameliorated while mtDNA oxidation, mtDNA release, and NF-κB activation were remarkably alleviated in both the rat brain and the N9 microglial cell line. Together, these results indicate that microglial mtDNA oxidation and the resultant release induced by SD mediate neural inflammation and HTHB prevents mtDNA oxidation and efflux, providing a potential treatment for SD-induced mental issues.