All-aqueous droplets-templated tailorable core-shell alginate microspheres for constructing vascularized intestinal mucosain vitromodels.

Recently,in vitromodels of intestinal mucosa have become important tools for drug screening and studying the physiology and pathology of the intestine. These models enable the examination of cellular behavior in diseased states or in reaction to alterations in the microenvironment, potentially serving as alternatives to animal models. One of the major challenges in constructing physiologically relevantin vitromodels of intestinal mucosa is the creation of three-dimensional microstructures that accurately mimic the integration of intestinal epithelium and vascularized stroma. Here, core-shell alginate (Alg) microspheres were generated to create the compartmentalized extracellular matrix microenvironment needed to simulate the epithelial and vascularized stromal compartments of the intestinal mucosa. We demonstrated that NIH-3T3 and human umbilical vein endothelial cells embedded in the core of the microspheres can proliferate and develop a vascular network, while human colorectal adenocarcinoma cells (Caco-2) can form an epithelial monolayer in the shell. Compared to Caco-2 monolayer encapsulated within the shell, the presence of the vascularized stroma enhances their proliferation and functionality. As such, our core-shell Alg microspheres provide a valuable method for generatingin vitromodels of vascularized intestinal mucosa with epithelial and vascularized stroma arranged in a spatially relevant manner and demonstrating near-physiological functionality.

Case Report: A 42-year-old male with IABP developing multiple organ embolism and intestinal necrosis.

We report a 42-year-old male patient who was diagnosed with acute myocardial infarction (AMI), and subsequently underwent percutaneous coronary intervention (PCI) for revascularization. The patient was transferred to the cardiac intensive care unit for intra-aortic balloon pump (IABP) due to frequent malignant arrhythmia after PCI. Then the patient experienced the most severe complications of IABP, including multiple organ embolism and intestinal necrosis. This report highlights the rare serious complications of IABP and the challenges encountered in handling this complex case.

Optimized rat models better mimic patients with irinotecan-induced severe diarrhea.

Irinotecan-induced severe diarrhea (IISD) not only limits irinotecan's application but also significantly affects patients' quality of life. However, existing animal models often inadequately represent the dynamics of IISD development, progression, and resolution across multiple chemotherapy cycles, yielding non-reproducible and highly variable response with limited clinical translation. Our studies aim to establish a reproducible and validated IISD model that better mimics the pathophysiology progression observed in patients, enhancing translational potential. We investigated the impact of dosing regimens (including different dose, infusion time, and two cycles of irinotecan administration), sex, age, tumor-bearing conditions, and irinotecan formulation on the IISD incidence and severity in mice and rats. Lastly, we investigated above factors' impact on pharmacokinetics of irinotecan, intestinal injury, and carboxylesterase activities. In summary, we successfully established a standard model establishment procedure for an optimized IISD model with highly reproducible severe diarrhea incidence rate (100%) and a low mortality rate (11%) in F344 rats. Additionally, the rats tolerated at least two cycles of irinotecan chemotherapy treatment. In contrast, the mouse model exhibited suboptimal IISD incidence rates (60%) and an extremely high mortality rate (100%). Notably, dosing regimen, age and tumor-bearing conditions of animals emerged as critical factors in IISD model establishment. In conclusion, our rat IISD model proves superior in mimicking pathophysiology progression and characteristics of IISD in patients, which stands as an effective tool for mechanism and efficacy studies in future chemotherapy-induced gut toxicity research.

Nrf2 protects against cartilage endplate degeneration through inhibiting NCOA4­mediated ferritinophagy.

Iron overload and ferroptosis are associated with intervertebral disc degeneration (IDD); however, the mechanism underlying the regulation of iron homeostasis remains to be elucidated. Nuclear factor erythroid 2­related factor 2 (Nrf2) has been reported to regulate cellular iron homeostasis; however, its impact on IDD pathology and the underlying mechanism of action requires further investigation. In the present study, immunohistochemistry analysis of Nrf2 expression in the cartilage endplate (CEP) was conducted and it was demonstrated that Nrf2 expression was increased in the CEP at the early stages of the development of IDD, whereas it was decreased at the late stages of the development of IDD. The results of western blot analysis indicated that the inadequate activation of Nrf2 may aggravate mitochondrial dysfunction and oxidative stress, thus promoting CEP chondrocyte degeneration and calcification. It was also revealed that Nrf2 was involved in TNF­α­induced CEP chondrocyte iron metabolism dysfunction and ferroptosis. Inhibition of Nrf2 expression using Nrf2 small interfering RNA could enhance the process of nuclear receptor coactivator 4 (NCOA4)­mediated ferritinophagy and increase ferrous ion content, which may promote CEP chondrocyte ferroptotic cell death and extracellular matrix degradation. Furthermore, a decrease in cellular iron concentration may inhibit CEP chondrocyte ferroptosis, and CEP degeneration and calcification. The present study highlights the role of the Nrf2/NCOA4 axis in chondrocyte ferroptosis and IDD pathogenesis, thus suggesting that activation of Nrf2 may be a promising strategy for IDD treatment.

Exercise is inversely associated with functional dyspepsia among a sample of Chinese male armed police recruits.

BACKGROUND: There is no study evaluating the association between exercise and functional dyspepsia (FD) based on the Rome IV criteria. We aimed to investigate the prevalence of FD and evaluate the association between exercise and FD based on Rome IV criteria among a sample of Chinese armed police recruits. METHODS: An on-site questionnaire survey on FD among a sample of Chinese armed police recruits was conducted based on the Rome IV criteria in 2021. Potential confounders included age, body mass index (BMI), race, marriage, education, smoking, and drinking variables were adjusted. RESULTS: A total of 2594 recruits were enrolled, including 46 FD participants and 2548 non-FD participants. In the model adjusted for all demographic variables among participants excluding irritable bowel syndrome (IBS) and functional constipation (FC), compared with no exercise participants, 1 h < each exercise time ≤ 2 h (OR = 0.15, 95% CI: 0.03-0.77, P = 0.0230) was inversely associated with FD and compared with no exercise participants, mild exercise (OR = 0.09, 95% CI: 0.01-0.71, P = 0.0220) was significantly inversely associated with FD. CONCLUSIONS: The incidence rate of FD in this sample Chinese armed police recruits was 1.77%, and 1 h < each exercise time ≤ 2 h and mild intensity exercise were independently inversely associated with FD. However, the causal relationship needs to be verified by further randomized controlled trials.

Differential regulation of hair cell actin cytoskeleton mediated by SRF and MRTFB.

The MRTF-SRF pathway has been extensively studied for its crucial role in driving the expression of a large number of genes involved in actin cytoskeleton of various cell types. However, the specific contribution of MRTF-SRF in hair cells remains unknown. In this study, we showed that hair cell-specific deletion of Srf or Mrtfb, but not Mrtfa, leads to similar defects in the development of stereocilia dimensions and the maintenance of cuticular plate integrity. We used fluorescence-activated cell sorting-based hair cell RNA-Seq analysis to investigate the mechanistic underpinnings of the changes observed in Srf and Mrtfb mutants, respectively. Interestingly, the transcriptome analysis revealed distinct profiles of genes regulated by Srf and Mrtfb, suggesting different transcriptional regulation mechanisms of actin cytoskeleton activities mediated by Srf and Mrtfb. Exogenous delivery of calponin 2 using Adeno-associated virus transduction in Srf mutants partially rescued the impairments of stereocilia dimensions and the F-actin intensity of cuticular plate, suggesting the involvement of Cnn2, as an Srf downstream target, in regulating the hair bundle morphology and cuticular plate actin cytoskeleton organization. Our study uncovers, for the first time, the unexpected differential transcriptional regulation of actin cytoskeleton mediated by Srf and Mrtfb in hair cells, and also demonstrates the critical role of SRF-CNN2 in modulating actin dynamics of the stereocilia and cuticular plate, providing new insights into the molecular mechanism underlying hair cell development and maintenance.

Activation of LXRα attenuates 2-Ethylhexyl diphenyl phosphate (EHDPP) induced placental dysfunction.

2-Ethylhexyl diphenyl phosphate (EHDPP) is one of the typical organophosphate flame retardants (OPFRs) and has been widely detected in environmental media. Exposure to EHDPP during pregnancy affects placental development and fetal growth. Liver X receptor α (LXRα) is essential to placental development. However, finite information is available regarding the function of LXRα in placenta damages caused by EHDPP. In present study we investigated to figure out whether LXRα is playing roles in EHDPP-induced placenta toxicity. While EHDPP restrained cell viability, migration, and angiogenesis dose-dependently in HTR-8/SVneo and JEG-3 cells, overexpression or activation by agonist T0901317 of LXRα alleviated the above phenomenon, knockdown or inhibition by antagonist GSK2033 had the opposite effects in vitro. Further study indicated EHDPP decreased LXRα expression and transcriptional activity leading to mRNA, protein expression levels downregulation of viability, migration, angiogenesis-related genes Forkhead box M1 (Foxm1), endothelial nitric oxide synthase (eNos), matrix metalloproteinase-2 (Mmp-2), matrix metalloproteinase-9 (Mmp-9), vascular endothelial growth factor-A (Vegf-a) and upregulation of inflammatory genes interleukin-6 (Il-6), interleukin-1ß (Il-1ß) and tumor necrosis factor-α (Tnf-α) in vitro and in vivo. Moreover, EHDPP caused decreased placental volume and fetal weight in mice, treatment with LXRα agonist T0901317 restored these adverse effects. Taken together, our study unveiled EHDPP-induced placenta toxicity and the protective role of LXRα in combating EHDPP-induced placental dysfunction. Activating LXRα could serve as a therapeutic strategy to reverse EHDPP-induced placental toxicity.

Dual-Mechanism Tuned Engineered Polyphenols with Cascade Photocatalytic Self-Fenton Reaction for Sustainable Biocidal Coatings.

Traditional disposable personal protective equipment (PPE) only blocks pathogenic bacteria by mechanical filtration, with the risk of recontamination and transmission remaining. Herein, inspired by phenolic-enabled nanotechnology (PEN), we proposed engineered polyphenol coatings by plant-derived aromatic aldehydes and metal involvement, denoted as FQM, to obtain the desired photocatalysis-self-Fenton antibacterial performance. Experiments and theoretical analysis proved the dual mechanism of Fe-induced enhancement: (1) tuning of molecular structure realized improved optical properties; (2) Fe(III)/Fe(II) triggered photocatalytic cascade self-Fenton reaction. Mechanism study reveals FQM killing bacteria by direct-contact ROS attack and gene regulation. Further, the FQM was developed as the ideal antibacterial coating on different fabrics (cloth cotton, polyester, and N95 mask), killing more than 93% of bacteria after 5 cycles of use. Such photocatalysis-self-Fenton coatings based on engineered polyphenols endowed with desirable safety, sustainability, and efficient antibacterial features are promising solutions to meet the challenges of the currently available PPE.

A High-Fat, High-Cholesterol Diet Promotes Intestinal Inflammation by Exacerbating Gut Microbiome Dysbiosis and Bile Acid Disorders in Cholecystectomy.

Patients with post-cholecystectomy (PC) often experience adverse gastrointestinal conditions, such as PC syndrome, colorectal cancer (CRC), and non-alcoholic fatty liver disease (NAFLD), that accumulate over time. An epidemiological survey further revealed that the risk of cholecystectomy is associated with high-fat and high-cholesterol (HFHC) dietary intake. Mounting evidence suggests that cholecystectomy is associated with disrupted gut microbial homeostasis and dysregulated bile acids (BAs) metabolism. However, the effect of an HFHC diet on gastrointestinal complications after cholecystectomy has not been elucidated. Here, we aimed to investigate the effect of an HFHC diet after cholecystectomy on the gut microbiota-BA metabolic axis and elucidate the association between this alteration and the development of intestinal inflammation. In this study, a mice cholecystectomy model was established, and the levels of IL-Iß, TNF-α, and IL-6 in the colon were increased in mice fed an HFHC diet for 6 weeks. Analysis of fecal BA metabolism showed that an HFHC diet after cholecystectomy altered the rhythm of the BA metabolism by upregulating liver CPY7A1, CYP8B1, and BSEP and ileal ASBT mRNA expression levels, resulting in increased fecal BA levels. In addition, feeding an HFHC diet after cholecystectomy caused a significant dysbiosis of the gut microbiota, which was characterized by the enrichment of the metabolic microbiota involved in BAs; the abundance of pro-inflammatory gut microbiota and related pro-inflammatory metabolite levels was also significantly higher. In contrast, the abundance of major short-chain fatty acid (SCFA)-producing bacteria significantly decreased. Overall, our study suggests that an HFHC diet after cholecystectomy promotes intestinal inflammation by exacerbating the gut microbiome and BA metabolism dysbiosis in cholecystectomy. Our study also provides useful insights into the maintenance of intestinal health after cholecystectomy through dietary or probiotic intervention strategies.

A promising nucleic acid therapy drug: DNAzymes and its delivery system.

Based on the development of nucleic acid therapeutic drugs, DNAzymes obtained through in vitro selection technology in 1994 are gradually being sought. DNAzymes are single-stranded DNA molecules with catalytic function, which specifically cleave RNA under the action of metal ions. Various in vivo and in vitro models have recently demonstrated that DNAzymes can target related genes in cancer, cardiovascular disease, bacterial and viral infection, and central nervous system disease. Compared with other nucleic acid therapy drugs, DNAzymes have gained more attention due to their excellent cutting efficiency, high stability, and low cost. Here, We first briefly reviewed the development and characteristics of DNAzymes, then discussed disease-targeting inhibition model of DNAzymes, hoping to provide new insights and ways for disease treatment. Finally, DNAzymes were still subject to some restrictions in practical applications, including low cell uptake efficiency, nuclease degradation and interference from other biological matrices. We discussed the latest delivery strategy of DNAzymes, among which lipid nanoparticles have recently received widespread attention due to the successful delivery of the COVID-19 mRNA vaccine, which provides the possibility for the subsequent clinical application of DNAzymes. In addition, the future development of DNAzymes was prospected.

The synergistic effect of EMT regulators and m6A modification on prognosis-related immunological signatures for ovarian cancer.

Recently, there has been growing interest among researchers in exploring the effects of epithelial-mesenchymal transformation (EMT) or N6-Methyladenosine (m6A) modification regulators on tumor development. However, the synergistic efficiency of these regulators in relation to ovarian cancer development remains unclear. This study aims to explore the transcription patterns of main regulators, including 19 EMT and 22 m6A, in ovarian cancer samples from TCGA datasets and normal samples from GTEx datasets. After conducting a LASSO regression analysis, ten prognostic signatures were identified, namely KIAA1429, WTAP, SNAI1, AXL, IGF2BP1, ELAVL1, CBLL1, CDH2, NANOG and ALKBH5. These signatures were found to have a comprehensive effect on immune infiltrating signatures and the final prognostic outcome. Next, utilizing the ssGSEA algorithm and conducting overall survival analyses, we have identified the key prognosis-related immunological signatures in ovarian cancer to be ALKBH5, WTAP, ELAVL1, and CDH2 as the regulators. The characteristic immune response and related genetic expression have revealed a significant correlation between the alteration of m6A regulators and EMT regulators, indicating a synergistic effect between these two factors in the development of ovarian cancer. In summary, our research offers a novel perspective and strategy to enhance the occurrence, progression, and prognosis of ovarian cancer.

Herbal Medicines as Adjuvants for the Treatment of Chemotherapy-Induced Diarrhea.

BACKGROUND: Chemotherapeutic drugs used in cancer treatment often result in gastrointestinal toxicity, notably diarrhea, impacting patients' quality of life. Complementary and Alternative Medicine (CAM) has garnered increasing interest as an alternative to conventional approaches as a potential solution for managing chemotherapyinduced diarrhea (CID). OBJECTIVE: To summarize current research focusing on herbal medicines as adjuvant therapy to prevent or treat chemotherapy-induced diarrhea, including clinical assessments, mechanism of actions, active components, and potential pharmacokinetic interactions between herbal medicines and chemotherapeutic drugs. METHODS: We performed the literature review from PubMed, CNKI, Google Scholar, Web of Science, and Scopus using "Chemotherapy", "Diarrhea," and "Complementary and Alternative Medicine" as the search keywords. RESULTS: Using herbal medicines as adjuvants provides an effective approach to treating or preventing CID with improved or unaffected antitumor activity of chemotherapeutic drugs. Among these herbal formulations, scutellaria, ginger, and ginseng are the most frequently used herbs in the prescriptions for CID. The main antidiarrheal components in herbs include wogonin, baicalin, chrysin, quercetin, gingerol, and ginsenosides. These herbs, formulations, and bioactive components relieved CID through different mechanisms, including directly decreasing local drug exposure, anti-inflammation, inhibiting epithelial apoptosis, or promoting epithelium stem cell regeneration. The application of herbal medicines as adjunctive therapies showed efficacy in preventing or treating CID in multiple clinical trials. However, more well-designed clinical studies are expected to validate the results further. Despite some clinical studies demonstrating that certain herbal medicines could potentially attenuate CID and improve efficacy, it remains necessary to evaluate herbal safety. The interactions between herbs and drugs are also potential concerns, but few clinical trials have focused on investigating this aspect. CONCLUSION: In clinical practise, herbal medications show potential as adjuvant treatments for gastrointestinal toxicities induced by chemotherapy, particularly diarrhoea. Further well-designed clinical studies are needed to validate their efficacy, ensure safety, and explore potential drug-herb interactions.

Discovery, Optimization, and Evaluation of Novel N-(Benzimidazol-5-yl)-1,3,4-thiadiazol-2-amine Analogues as Potent STAT3 Inhibitors for Cancer Treatment.

Signal transducer and activator of transcription 3 (STAT3) is an attractive target for cancer therapy. However, identifying potent and selective STAT3 small-molecule inhibitors with drug-like properties remains challenging. Based on a scaffold combination strategy, compounds with a novel N-(benzimidazol-5-yl)-1,3,4-thiadiazol-2-amine scaffold were designed and their inhibition of the interleukin-6 (IL-6)/JAK/STAT3 pathway was tested in HEK-Blue IL-6 reporter cells. After optimization of lead compound 12, compound 40 was identified as a selective STAT3 inhibitor that directly binds the SH2 domain to inhibit STAT3 phosphorylation, translocation, and downstream gene transcription. Compound 40 exhibited antiproliferative activities against STAT3-overactivated DU145 (IC50 value = 2.97 µM) and MDA-MB-231 (IC50 value = 3.26 µM) cancer cells and induced cell cycle arrest and apoptosis. In the DU145 xenograft model, compound 40 showed in vivo antitumor efficacy following intraperitoneal administration, with a tumor growth inhibition rate of 65.3% at 50 mg/kg, indicating promise for further development.

[Effects of pre-electroacupuncture on blood pressure and cardiac function in high-salt-induced hypertension rats].

OBJECTIVE: To observe the effects of pre-electroacupuncture at "Taichong"(LR3), "Neiguan"(PC6) and "Waiguan"(TE5) on blood pressure and cardiac function of high-salt-induced hypertension rats, so as to explore the possible mechanism of pre-electroacupuncture in improving hypertension. METHODS: Twenty-four SD rats were randomly divided into control group, high-salt group and pre-electroacupuncture group, with 8 rats in each group. The hypertension model was established by feeding high-salt diet for 7 weeks. In the pre-electroacupuncture group, rats received electroacupuncture intervention at bilate-ral LR3, PC6 and TE5 (2 Hz/15 Hz, 2 mA) for 30 min, once a day, from the first day of modeling, for a total of 7 weeks. The blood pressure of rats was monitored by caudal artery noninvasive blood pressure measurement technique before and at the 1st, 3rd, 5th and 7th week of modeling. At the 8th week of the experiment, left ventricular catheterization was performed and biological signal acquisition system was used to detect left ventricular hemodynamics indexes and analyze left ventricular function, the car-diac mass ratio was measured to evaluate the degree of myocardial hypertrophy. The mRNA expressions of atrial natriuretic peptide(ANP), myosin heavy chain 7(MYH7), α-smooth muscle actin(α-SMA), interleukin(IL)-1ß, and IL-6 of myocardial tissues were detected by quantitative real-time PCR. Sirius red staining was used to observe the degree of myocardial fibrosis. RESULTS: Compared with the control group, systolic blood pressure, diastolic blood pressure, mean arterial pressure, left ventricular end-diastolic pressure (LVEDP), cardiac mass ratio，and the mRNA expressions of ANP, MYH7, α-SMA, IL-1ß, and IL-6, and sirius red staining area of myocardium were all significantly increased(P<0.01,P<0.05)，maximal rate of rise and descent of left ventricular pressure(LVP±dP/dtmax) were decreased (P<0.05,P<0.01) in the high-salt group. Compared with the high-salt group, rats in the pre-electroacupuncture group had lower systolic blood pressure, diastolic blood pressure, mean arterial pressure, LVEDP，cardiac mass ratio，higher LVP±dP/dtmax,down-regulated mRNA expressions of ANP, MYH7, α-SMA, IL-1ß, IL-6, and smaller area of sirius red staining(P<0.05, P<0.01). CONCLUSION: Pre-electroacupuncture tends to lower blood pressure, improve cardiac function and reduce myocardial fibrosis in high-salt-induced hypertension rats, which may be associated with inhibiting inflammatory response.

C21 steroids from the roots of Marsdenia tenacissima.

A phytochemical investigation of the dichloromethane soluble fraction of the ethanolic extract obtained from the roots of Marsdenia tenacissima led to the discovery of the sixteen undescribed pregnane C21 steroids (1-16) and isolation of eleven known C21 steroidal analogues (17-27). Their chemical structures were elucidated by one- and two-dimensional nuclear magnetic resonance spectroscopy and, high resolution-electrospray ionization mass spectrometry and their absolute configurations were determined using electronic circular dichroism or single-crystal X-ray diffraction. The in vitro anti-proliferative effects of 1-16 were evaluated against HepG2 (human hepatocellular cancer), A549 (lung cancer), and MCF-7 (human breast cancer) cell lines. Even though some of them showed moderate cytotoxic activities, marsectohexol derivative 12 exhibited significant cytotoxicity against A549 cells with an IC50 value of 5.2 µM.

Chlorogenic Acid Induced Neuroblastoma Cells Differentiation via the ACAT1-TPK1-PDH Pathway.

BACKGROUND: Chlorogenic acid (CHA) has been shown to have substantial biological activities, including anti-inflammatory, antioxidant, and antitumor effects. However, the pharmacological role of CHA in neuroblastoma has not yet been assessed. Neuroblastoma is a type of cancer that develops in undifferentiated sympathetic ganglion cells. This study aims to assess the antitumor activity of CHA against neuroblastoma and reveal its mechanism of action in cell differentiation. METHODS: Be(2)-M17 and SH-SY5Y neuroblastoma cells were used to confirm the differentiation phenotype. Subcutaneous and orthotopic xenograft mouse models were also used to evaluate the antitumor activity of CHA. Seahorse assays and metabolomic analyses were further performed to investigate the roles of CHA and its target ACAT1 in mitochondrial metabolism. RESULTS: CHA induced the differentiation of Be(2)-M17 and SH-SY5Y neuroblastoma cells in vivo and in vitro. The knockdown of mitochondrial ACAT1, which was inhibited by CHA, also resulted in differentiation characteristics in vivo and in vitro. A metabolomic analysis revealed that thiamine metabolism was involved in the differentiation of neuroblastoma cells. CONCLUSIONS: These results provide evidence that CHA shows good antitumor activity against neuroblastoma via the induction of differentiation, by which the ACAT1-TPK1-PDH pathway is involved. CHA is a potential drug candidate for neuroblastoma therapy.

Artificial intelligence in thyroid ultrasound.

Artificial intelligence (AI), particularly deep learning (DL) algorithms, has demonstrated remarkable progress in image-recognition tasks, enabling the automatic quantitative assessment of complex medical images with increased accuracy and efficiency. AI is widely used and is becoming increasingly popular in the field of ultrasound. The rising incidence of thyroid cancer and the workload of physicians have driven the need to utilize AI to efficiently process thyroid ultrasound images. Therefore, leveraging AI in thyroid cancer ultrasound screening and diagnosis cannot only help radiologists achieve more accurate and efficient imaging diagnosis but also reduce their workload. In this paper, we aim to present a comprehensive overview of the technical knowledge of AI with a focus on traditional machine learning (ML) algorithms and DL algorithms. We will also discuss their clinical applications in the ultrasound imaging of thyroid diseases, particularly in differentiating between benign and malignant nodules and predicting cervical lymph node metastasis in thyroid cancer. Finally, we will conclude that AI technology holds great promise for improving the accuracy of thyroid disease ultrasound diagnosis and discuss the potential prospects of AI in this field.

Synthesis and Bioactivity Evaluation of Nepetaefolin F and Its Analogues.

Nepetaefolin F (5), an abietane diterpenoid, showed significant inhibitory activity against human cancer cells in vitro with an IC50 value of 6.3 µM. The syntheses of nepetaefolin F and its analogues are presented herein. The cytotoxicity against various cancer cell lines was evaluated; notably, the cyclopropanecarboxylate ester 42 displayed significant antitumor activity against MGC 803 cells with an IC50 value of 20.9 µM. Further studies revealed that 42 could upregulate the expression of p62, microtubule-associated protein 1 light-chain 3 ß (LC3 B-I), cleaved caspase-3, and cleaved caspase-9 and downregulate the expression of Beclin-1 and LC3B-II. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that 42 could modulate multiple signaling pathways, especially for peroxisome proliferator-activated receptor (PPAR) and AMP-activated protein kinase (AMPK), which are closely related to autophagy. These results suggested that compound 42 is a promising lead by inhibiting cell proliferation and autophagy, as inducing cell apoptosis in MGC 803 cells.

PTEN inhibitor VO-OHpic protects endplate chondrocytes against apoptosis and calcification via activating Nrf-2 signaling pathway.

Cartilage endplate (CEP) degeneration and calcification is an important contributor to the onset and pathogenesis of intervertebral disc degeneration (IDD). However, the underlying mechanisms of CEP degeneration remain elusive, let alone according treatment strategies to prevent CEP degeneration. Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene that promotes cell apoptosis, and recent studies indicated that PTEN is overexpressed in degenerated intervertebral disc. However, whether direct inhibition of PTEN attenuates CEP degeneration and IDD development remains largely unknown. In the present study, our in vivo experiments demonstrated that VO-OHpic could attenuate IDD progression and CEP calcification. We also found that VO-OHpic inhibited oxidative stress induced chondrocytes apoptosis and degeneration by activating Nrf-2/HO-1 pathway, thus promoted parkin mediated mitophagy process and inhibited chondrocytes ferroptosis, alleviated redox imbalance and eventually improved cell survival. Nrf-2 siRNA transfection significantly reversed the protective effect of VO-OHpic on endplate chondrocytes. In conclusion, our study demonstrated that inhibition of PTEN with VO-OHpic attenuates CEP calcification and IDD progression. Moreover, VO-OHpic protects endplate chondrocytes against apoptosis and degeneration via activating Nrf-2/HO-1 mediated mitophagy process and ferroptosis inhibition. Our results suggest that VO-OHpic may be a potential effective medicine for IDD prevention and treatment.