A novel FAK-degrading PROTAC molecule exhibited both anti-tumor activities and efficient MDR reversal effects.

FAK (focal adhesion kinase) is widely involved in cancer growth and drug resistance development. Thus, FAK inhibition has emerged as an effective strategy for tumor treatment both as a monotherapy or in combination with other treatments. But the current FAK inhibitors mainly concentrate on its kinase activity, overlooking the potential significance of FAK scaffold proteins. In this study we employed the PROTAC technology, and designed a novel PROTAC molecule F2 targeting FAK based on the FAK inhibitor IN10018. F2 exhibited potent inhibitory activities against 4T1, MDA-MB-231, MDA-MB-468 and MDA-MB-435 cells with IC50 values of 0.73, 1.09, 5.84 and 3.05 µM, respectively. On the other hand, F2 also remarkably reversed the multidrug resistance (MDR) in HCT8/T, A549/T and MCF-7/ADR cells. Both the effects of F2 were stronger than the FAK inhibitor IN10018. To our knowledge, F2 was the first reported FAK-targeted PROTAC molecule exhibiting reversing effects on chemotherapeutic drug resistance, and its highest reversal fold could reach 158 times. The anti-tumor and MDR-reversing effects of F2 might be based on its inhibition on AKT (protein kinase B, PKB) and ERK (extracellular signal-regulated kinase) signaling pathways, as well as its impact on EMT (epithelial-mesenchymal transition). Furthermore, we found that F2 could reduce the protein level of P-gp in HCT8/T cells, thereby contributing to reverse drug resistance from another perspective. Our results will boost confidence in future research focusing on targeting FAK and encourage further investigation of PROTAC with potent in vivo effects.

Gossypol acetic acid regulates leukemia stem cells by degrading LRPPRC via inhibiting IL-6/JAK1/STAT3 signaling or resulting mitochondrial dysfunction.

BACKGROUND: Leukemia stem cells (LSCs) are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia (AML), as they are protected by the bone marrow microenvironment (BMM) against conventional therapies. Gossypol acetic acid (GAA), which is extracted from the seeds of cotton plants, exerts anti-tumor roles in several types of cancer and has been reported to induce apoptosis of LSCs by inhibiting Bcl2. AIM: To investigate the exact roles of GAA in regulating LSCs under different microenvironments and the exact mechanism. METHODS: In this study, LSCs were magnetically sorted from AML cell lines and the CD34+CD38- population was obtained. The expression of leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) and forkhead box M1 (FOXM1) was evaluated in LSCs, and the effects of GAA on malignancies and mitochondrial function were measured. RESULTS: LRPPRC was found to be upregulated, and GAA inhibited cell proliferation by degrading LRPPRC. GAA induced LRPPRC degradation and inhibited the activation of interleukin 6 (IL-6)/janus kinase (JAK) 1/signal transducer and activator of transcription (STAT) 3 signaling, enhancing chemosensitivity in LSCs against conventional chemotherapies, including L-Asparaginase, Dexamethasone, and cytarabine. GAA was also found to downregulate FOXM1 indirectly by regulating LRPPRC. Furthermore, GAA induced reactive oxygen species accumulation, disturbed mitochondrial homeostasis, and caused mitochondrial dysfunction. By inhibiting IL-6/JAK1/STAT3 signaling via degrading LRPPRC, GAA resulted in the elimination of LSCs. Meanwhile, GAA induced oxidative stress and subsequent cell damage by causing mitochondrial damage. CONCLUSION: Taken together, the results indicate that GAA might overcome the BMM protective effect and be considered as a novel and effective combination therapy for AML.

Cardiac lipotoxicity and fibrosis underlie impaired contractility in a mouse model of metabolic dysfunction-associated steatotic liver disease.

The leading cause of death among patients with metabolic dysfunction-associated steatotic liver disease (MASLD) is cardiovascular disease. A significant percentage of MASLD patients develop heart failure driven by functional and structural alterations in the heart. Previously, we observed cardiac dysfunction in hepatocyte-specific peroxisome proliferator-activated receptor alpha knockout (Ppara HepKO), a mouse model that exhibits hepatic steatosis independent of obesity and insulin resistance. The goal of the present study was to determine mechanisms that underlie hepatic steatosis-induced cardiac dysfunction in Ppara HepKO mice. Experiments were performed in 30-week-old Ppara HepKO and littermate control mice fed regular chow. We observed decreased cardiomyocyte contractility (0.17 ± 0.02 vs. 0.24 ± 0.02 µm, p < 0.05), increased cardiac triglyceride content (0.96 ± 0.13 vs. 0.68 ± 0.06 mM, p < 0.05), collagen type 1 (4.65 ± 0.25 vs. 0.31 ± 0.01 AU, p < 0.001), and collagen type 3 deposition (1.32 ± 0.46 vs. 0.05 ± 0.03 AU, p < 0.05). These changes were associated with increased apoptosis as indicated by terminal deoxynucleotidyl transferase dUTP nick end labeling staining (30.9 ± 4.7 vs. 13.1 ± 0.8%, p < 0.006) and western blots showing increased cleaved caspase-3 (0.27 ± 0.006 vs. 0.08 ± 0.01 AU, p < 0.003) and pro-caspase-3 (5.4 ± 1.5 vs. 0.5 ± 0.3 AU, p < 0.02), B-cell lymphoma protein 2-associated X (0.68 ± 0.07 vs. 0.04 ± 0.04 AU, p < 0.001), and reduced B-cell lymphoma protein 2 (0.29 ± 0.01 vs. 1.47 ± 0.54 AU, p < 0.05). We further observed elevated circulating natriuretic peptides and exercise intolerance in Ppara HepKO mice when compared to controls. Our data demonstrated that lipotoxicity, and fibrosis underlie cardiac dysfunction in MASLD.

Identification and Validation of SLC9A2 as A Potential Tumor Suppressor in Colorectal Cancer: Integrating Bioinformatics Analysis with Experimental Confirmation.

OBJECTIVE: To uncover the mechanisms underlying the development of colorectal cancer (CRC), we applied bioinformatic analyses to identify key genes and experimentally validated their possible roles in CRC onset and progression. METHODS: We performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis on differentially expressed genes (DEGs), constructed a protein-protein interaction (PPI) network to find the top 10 hub genes, and analyzed their expression in colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ). We also studied the correlation between these genes and immune cell infiltration and prognosis and validated the expression of SLC9A2 in CRC tissues and cell lines using qRT-PCR and Western blotting. Functional experiments were conducted in vitro to investigate the effects of SLC9A2 on tumor growth and metastasis. RESULTS: We found 130 DEGs, with 45 up-regulated and 85 down-regulated in CRC. GO analysis indicated that these DEGs were primarily enriched in functions related to the regulation of cellular pH, zymogen granules, and transmembrane transporter activity. KEGG pathway analysis revealed that the DEGs played pivotal roles in pancreatic secretion, rheumatoid arthritis, and the IL-17 signaling pathway. We identified 10 hub genes: CXCL1, SLC26A3, CXCL2, MMP7, MMP1, SLC9A2, SLC4A4, CLCA1, CLCA4, and ZG16. GO enrichment analysis showed that these hub genes were predominantly involved in the positive regulation of transcription. Gene expression analysis revealed that CXCL1, CXCL2, MMP1, and MMP7 were highly expressed in CRC, whereas CLCA1, CLCA4, SLC4A4, SLC9A2, SLC26A3, and ZG16 were expressed at lower levels. Survival analysis revealed that 5 key genes were significantly associated with the prognosis of CRC. Both mRNA and protein expression levels of SLC9A2 were markedly reduced in CRC tissues and cell lines. Importantly, SLC9A2 overexpression in SW480 cells led to a notable inhibition of cell proliferation, migration, and invasion. Western blotting analysis revealed that the expression levels of phosphorylated ERK (p-ERK) and phosphorylated JNK (p-JNK) proteins were significantly increased, whereas there were no significant changes in the expression levels of ERK and JNK following SLC9A2 overexpression. Correlation analysis indicated a potential link between SLC9A2 expression and the MAPK signaling pathway. CONCLUSION: Our study suggests that SLC9A2 acts as a tumor suppressor through the MAPK pathway and could be a potential target for CRC diagnosis and therapy.

A simplified herbal decoction attenuates myocardial infarction by regulating macrophage metabolic reprogramming and phenotypic differentiation via modulation of the HIF-1α/PDK1 axis.

BACKGROUND: Myocardial infarction (MI) poses a global public health challenge, often associated with elevated mortality rates and a grim prognosis. A crucial aspect of the inflammatory injury and healing process post-MI involves the dynamic differentiation of macrophages. A promising strategy to alleviate myocardial damage after MI is by modulating the inflammatory response and orchestrating the shift from pro-inflammatory (M1) to anti-inflammatory (M2) macrophages, aiming to achieve a reduced M1/M2 ratio. Nuanxinkang (NXK), a simplified herbal decoction, has demonstrated noteworthy cardioprotective, inflammation-regulating, and myocardial energy metabolism-regulating properties. METHODS: In this study, we constructed an MI model by ligating coronary arteries to investigate the efficacy of NXK in improving ventricular remodeling and cardiac function. Mice were administered NXK (1.65 g/kg/d) or an equivalent volume of regular saline via gavage for 28 consecutive days, commencing the day after surgery. Then, we conducted echocardiography to assess the cardiac function, Masson staining to illustrate the extent of myocardial fibrosis, TUNEL staining to reveal myocardial apoptosis, and flow cytometry to analyze the polarization of M1 and M2 macrophages in the hearts. Besides, a lipopolysaccharide (LPS)-induced pro-inflammatory macrophage (M1) polarization model was implemented in RAW264.7 cells to elucidate the underlying mechanism of NXK in regulating macrophage polarization. RAW264.7 cells were pre-treated with or without NXK-containing serum. Oxidative stress was detected by MitoSox staining, followed by Seahorse energy metabolism assay to evaluate alterations in mitochondrial metabolic patterns and ATP production. Both In vivo and in vitro, HIF-1α and PDK1 were detected by fluorescent quantitative PCR and Western blotting. RESULTS: In vivo, MI mice exhibited a decline in cardiac function, adverse ventricular remodeling, and an increase in glycolysis, coupled with M1-dominant polarization mediated by the HIF-1α/PDK1 axis. Notably, robust responses were evident with high-dose NXK treatment (1.65 g/kg/day), leading to a significant enhancement in cardiac function, inhibition of cardiac remodeling, and partial suppression of macrophage glycolysis and the inflammatory phenotype in MI mice. This effect was achieved through the modulation of the HIF-1α/PDK1 axis. In vitro, elevated levels of mitochondrial ROS production and glycolysis were observed in LPS-induced macrophages. Conversely, treatment with NXK notably reduced the oxidative stress damage induced by LPS and enhanced oxidative phosphorylation (OXPHOS). Furthermore, NXK demonstrated the ability to modify the energy metabolism and inflammatory characteristics of macrophages by modulating the HIF-1α/PDK1 axis. The influence of NXK on this axis was partially counteracted by the HIF-1α agonist DMOG. And NXK downregulated PDK1 expression, curtailed glycolysis, and reversed LPS-induced M1 polarization in macrophages, similar to the PDK1 inhibitor DCA. CONCLUSION: In conclusion, NXK protects against MI-induced cardiac remodeling by inducing metabolic reprogramming and phenotypic differentiation of macrophages, achieved through the modulation of the HIF-1α/PDK1 axis. This provides a novel and promising strategy for the treatment of MI.

Pyroptotic macrophages induce disruption of glutamate metabolism in periodontal ligament stem cells contributing to their compromised osteogenic potential.

Macrophage pyroptosis is of key importance to host defence against pathogen infections and may participate in the progression and recovery of periodontitis. However, the role of pyroptotic macrophages in regulating periodontal ligament stem cells (PDLSCs), the main cell source for periodontium renewal, remains unclear. First, we found that macrophage pyroptosis were enriched in gingiva tissues from periodontitis patients compared with those of healthy people through immunofluorescence. Then the effects of pyroptotic macrophages on the PDLSC osteogenic differentiation were investigated in a conditioned medium (CM)-based coculture system in vitro. CM derived from pyroptotic macrophages inhibited the osteogenic differentiation-related gene and protein levels, ALP activity and mineralized nodule formation of PDLSCs. The osteogenic inhibition of CM was alleviated when pyroptosis was inhibited by VX765. Further, untargeted metabolomics showed that glutamate limitation may be the underlying mechanism. However, exogenous glutamate supplementation aggravated the CM-inhibited osteogenic differentiation of PDLSCs. Moreover, CM increased extracellular glutamate and decreased intracellular glutamate levels of PDLSCs, and enhanced the gene and protein expression levels of system xc - (a cystine/glutamate antiporter). After adding cystine to CM-based incubation, the compromised osteogenic potency of PDLSCs was rescued. Our data suggest that macrophage pyroptosis is related to the inflammatory lesions of periodontitis. Either pharmacological inhibition of macrophage pyroptosis or nutritional supplements to PDLSCs, can rescue the compromised osteogenic potency caused by pyroptotic macrophages.

The impact of fear of cancer recurrence on the quality of life of breast cancer patients: A longitudinal study of the mediation effect of cortisol and hope.

OBJECTIVE: This longitudinal study sought to explore the impact of cortisol and hope levels on Fear of Cancer Recurrence (FCR) and Quality of Life (QOL) in a cohort of 552 breast cancer patients from three centers in Wuhan City. METHOD: A longitudinal study involving 552 breast cancer patients from three centers in Wuhan City utilized Chinese versions of the Fear of Progression Questionnaire-Short Form (FoP-Q-SF), the Herth Hope Index (HHI), and the Functional Assessment of Cancer Therapy-Breast (FACT-B) scale. Cortisol levels were measured thrice daily, and data was collected longitudinally three times. Data analysis was conducted using SPSS 26.0 and Mplus 8.3, employing a longitudinal path model constructed via the cross-lagged method. RESULTS: The results showed there were significant correlations between FCR, cortisol levels, and QOL at different time points. A significant mediating model was found with outcomes related to hope levels. Specifically, FCR predicted a decrease in hope levels (ß = -0.163, p < 0.001), which in turn led to a decrease in overall QOL (ß = -0.078, p < 0.001), with a mediation effect accounting for 10.34%. Although there were correlations between FCR, cortisol levels, and QOL at different time points, further analysis revealed that cortisol levels did not exhibit a mediating effect between the two (95% confidence interval: -0.002 to 0.001). CONCLUSION: This study demonstrated there were significant correlations among FCR, QOL, and hope levels. Considering hope as a crucial mediator between FCR and QOL, potential intervention strategies for optimizing the QOL of breast cancer patients are proposed.

A 3'-pre-tRNA-derived small RNA tRF-1-Ser regulated by 25(OH)D promotes proliferation and stemness by inhibiting the function of MBNL1 in breast cancer.

BACKGROUND: We explored the potential novel anticancer mechanisms of 25-hydroxyvitamin D (25(OH)D), a vitamin D metabolite with antitumour effects in breast cancer. It is stable in serum and is used to assess vitamin D levels in clinical practice. Transfer RNA-derived small RNAs are small noncoding RNAs that generate various distinct biological functions, but more research is needed on their role in breast cancer. METHODS: Small RNA microarrays were used to explore the novel regulatory mechanism of 25(OH)D. High-throughput RNA-sequencing technology was used to detect transcriptome changes after 25(OH)D treatment and tRF-1-Ser knockdown. RNA pull-down and high-performance liquid chromatography-mass spectrometry/mass spectrometry were used to explore the proteins bound to tRF-1-Ser. In vitro and in vivo functional experiments were conducted to assess the influence of 25(OH)D and tRF-1-Ser on breast cancer. Semi-quantitative PCR was performed to detect alternative splicing events. Western blot assay and qPCR were used to assess protein and mRNA expression. RESULTS: The expression of tRF-1-Ser is negatively regulated by 25(OH)D. In our breast cancer (BRCA) clinical samples, we found that the expression of tRF-1-Ser was higher in cancer tissues than in paired normal tissues, and was significantly associated with tumour invasion. Moreover, tRF-1-Ser inhibits the function of MBNL1 by hindering its nuclear translocation. Functional experiments and transcriptome data revealed that the downregulation of tRF-1-Ser plays a vital role in the anticancer effect of 25(OH)D. CONCLUSIONS: In brief, our research revealed a novel anticancer mechanism of 25(OH)D, unveiled the vital function of tRF-1-Ser in BRCA progression, and suggested that tRF-1-Ser could emerge as a new therapeutic target for BRCA.

Simultaneous removal of nitrogen, phosphorus, and organic matter from oligotrophic water in a system containing biochar and construction waste iron: Performances and biotic community analysis.

The issue of combined pollution in oligotrophic water has garnered increasing attention in recent years. To enhance the pollutant removal efficiency in oligotrophic water, the system containing Zoogloea sp. FY6 was constructed using polyester fiber wrapped sugarcane biochar and construction waste iron (PWSI), and the denitrification test of simulated water and actual oligotrophic water was carried out for 35 days. The experimental findings from the systems indicated that the removal efficiencies of nitrate (NO3--N), total nitrogen (TN), chemical oxygen demand (COD), and total phosphorus (TP) in simulated water were 88.61%, 85.23%, 94.28%, and 98.90%, respectively. The removal efficiencies of actual oligotrophic water were 83.06%, 81.39%, 81.66%, and 97.82%, respectively. Furthermore, the high-throughput sequencing data demonstrated that strain FY6 was successfully loaded onto the biological carrier. According to functional gene predictions derived from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, the introduction of PWSI enhanced intracellular iron cycling and nitrogen metabolism.

SARS-CoV-2 Antibodies in Human Milk After mRNA and Adenovector-Based Vaccination: A Systematic Review and Meta-Analysis.

BACKGROUND: SARS-CoV-2 specific antibodies exist in human milk expressed by lactating parents after vaccination. In the existing research, the effects of vaccine types on human milk are inconsistent. RESEARCH AIM: This study aims to perform a systematic review and meta-analysis of the existing observational studies to compare the positive rates of SARS-CoV-2 specific antibodies in human milk according to mRNA and adenovector-based vaccination. METHODS: PubMed, Web of Science, Elsevier Science Direct and Cochrane Library databases were systematically searched for relevant articles published from December 30, 2019 to February 15, 2023. Observational studies were considered eligible provided they reported data on SARS-CoV-2 specific antibodies in human milk. The risk of bias in non-randomized studies of interventions (ROBINS-I) tool, the Newcastle-Ottawa Scale (NOS), and the Agency for Healthcare Research and Quality (AHRQ) were used to assess risk of bias. Seven studies, including 511 lactating participants, were included in this review and meta-analysis. RESULTS: The positive rate of SARS-CoV-2 IgA is higher in mRNA vaccine groups than in adenovector-based vaccine groups (OR = 4.80, 95% CI [3.04, 7.58], p < 0.001). The positive rate of SARS-CoV-2 IgG was higher in mRNA vaccines than in adenovector-based vaccines. CONCLUSIONS: Compared to adenovector-based vaccines, mRNA vaccines present a higher positivity rate of IgA and IgG in human milk after vaccination. In other words, mRNA vaccinations may offer breastfed children a higher level of protection than adenovector-based vaccinations. Further high-quality data is still required to substantiate these findings.

[Application of iliac vein molding and stent implantation through the ipsilateral great saphenous vein approach in daytime treatment mode].

OBJECTIVE: To explore the feasibility and recent efficacy of iliac vein molding and stenting in daytime treatment mode in patients with iliac vein stenosis. METHODS: Medical records of iliac vein molding and stenting performed in the ipsilateral great saphenous vein approach conducted from February 2017 to March 2022 were retrospective reviewed. There were 21 cases, 6 males and 15 females. Age ranged from 37 to 79 years [(62.5 ± 10.2) years]. The stenosis in the 21 limbs simply involved the common iliac veins in 16 patients, 2 patients had the simple and external iliac veins, and both the total and external iliac veins in 3 patients. Both iliac vein molding and iliac vein stenting were performed through the ipsilateral great saphenous vein approach. The patients with simple iliac vein stenosis with great saphenous vein valve insufficiency also underwent radiofrequency closure of great saphenous vein and flexural vein sclerosis therapy simultaneously. Regular postoperative direct oral anticoagulants therapy and stress therapy were followed. All the patients were hospitalized for less than 24 h. RESULTS: All the 21 patients operations were successful (the success rate was 100%), without any intraoperative complications. Immediate postoperative complications were puncture point bleeding in 1 case. The bandage gauze was completely wet. The bleeding was stopped after 5min of recompression. All the patients were hospitalized for less than 24 h. Follow-up results: The 3-month follow-up rate after operation was 100%. Absolute effective 18 cases (18/21, 85.7%). Relatively effective(postmentation still after surgery, but with less extent) in 3 cases (3/21, 14.3%). The iliac vein stents were unobstructed, and the trunk of the great saphenous vein was well closed in the patients with great saphenous vein radiofrequency treatment. The 6-month follow-up rate after operation was 71.4%(15/21). Of these, 14 cases (14/15, 93.3%) were absolutely effective. Relatively effective(postmentation still after surgery, but with less extent) in 1 case (1/15, 6.7%). The iliac vein stents were no restenosis or obstruction, and the trunk of the great saphenous vein was well closed in the patients with great saphenous vein radiofrequency treatment. CONCLUSION: The interventional treatment technique of iliac vein stenosis is feasible in the daytime treatment mode, with clear advantages and satisfactory recent efficacy.

Clinical study on the relationship between liver cirrhosis, ascites, and hyponatremia.

BACKGROUND: Cirrhosis is a common liver disease, and ascites is one of the common clinical conditions. However, the clinical manifestations of ascites combined with hyponatremia as a high-risk condition and its relationship to patient prognosis have not been fully studied. AIM: To explore the clinical manifestations, prognostic factors, and relationships of ascites with hyponatremia in patients with cirrhosis to provide better diagnostic and treatment strategies. METHODS: In this study, we retrospectively analyzed the clinical data of 150 patients diagnosed with cirrhosis and ascites between 2017 and 2022. Patients were divided into two groups: ascites combined with hyponatremia group and ascites group. We compared the general characteristics, degree of hyponatremia, complications, treatment, and prognosis between the two groups. RESULTS: In the study results, patients in the ascites combined with hyponatremia group showed an older average age (58.2 ± 8.9 years), 64.4% were male, and had a significantly longer hospitalization time (12.7 ± 5.3 d). Hyponatremia was more severe in this group, with a mean serum sodium concentration of 128.5 ± 4.3 mmol/L, which was significantly different from the ascites group of 137.6 ± 2.1 mmol/L. Patients with ascites and hyponatremia were more likely to develop hepatic encephalopathy (56.2% vs 39.0%), renal impairment (45.2% vs 28.6%) and infection (37.0% vs 23.4%). Regarding treatment, this group more frequently used diuretics (80.8% vs 62.3%) and salt supplements (60.3% vs 38.9%). Multiple logistic regression analysis identified older age [Odds ratio (OR) = 1.06, P = 0.025] and male gender (OR = 1.72, P = 0.020) as risk factors for hyponatremia combined with ascites. Overall, patients with ascites and hyponatremia present a clear high-risk status, accompanied by severe complications and poor prognosis. CONCLUSION: In patients with cirrhosis, ascites with hyponatremia is a high-risk condition that is often associated with severe complications.

Cadmium exposure activates mitophagy through downregulating thyroid hormone receptor/PGC1α signal in preeclampsia.

Gestational cadmium exposure increases the risk of preeclampsia. Placenta mitophagy was activated in preeclampsia. The aim of present study was to explore the mechanism of cadmium-induced mitophagy activation and its association with preeclampsia. Mitophagy markers expression levels were detected by quantitative real-time PCR, Western blot, immunofluorescence and immunochemistry in preeclampsia placenta. JEG3 cells were treated with CdCl2, iopanoic acid (IOP), 3-methyladenine and PGC1α SiRNA to verify mechanism of cadmium-induced mitophagy. Mitophagy marker LC3BII/I and P62 expression were increased and mitochondrial membrane receptor protein TOM20 and FUNDC1 expression were decreased in preeclampsia placenta as compared with that in normotension control. Mitophagy marker LC3BII/I and P62 expression were increased and TOM20 and FUNDC1 expression was decreased in CdCl2-treated JEG3 cells. Meanwhile, mitochondrial biogenesis regulator, PGC1α expression was decreased in preeclampsia and CdCl2-treated JEG3 cells. The expressions of LC3B and P62 were increased and the expressions of TOM20, FUNDC1 and PGC1α were decreased in IOP-treated cell. PGC1α SiRNA transfection led to increased expression of LC3BII/I and P62 and decreased expression of TOM20 and FUNDC1. The expression of sFlt1 was increased in preeclampsia placenta, CdCl2-treated cells, in IOP-treated cells and in PGC1α SiRNA transfected cells. 3-methyladenine treatment protected the increased expression of sFlt1 in CdCl2-treated cells, in IOP-treated cells and in PGC1α SiRNA transfected cells. Meanwhile, co-treatment of cadmium and IOP or PGC1αSiRNA led to a reduce expressions of OPA1, MFN1, MFN2 and FUNDC1 as compared to cadmium-treated, IOP-treated and PGC1α SiRNA-treated cells. These results elucidated that maternal cadmium exposure activated placenta mitophagy through downregulation of thyroid hormone receptor signal mediated decreased expression of PGC1α and was associated with the occurrence of preeclampsia.

Viscoelastic hydrogels regulate adipose-derived mesenchymal stem cells for nucleus pulposus regeneration.

Low back pain is a leading cause of disability worldwide, often attributed to intervertebral disc (IVD) degeneration with loss of the functional nucleus pulposus (NP). Regenerative strategies utilizing biomaterials and stem cells are promising for NP repair. Human NP tissue is highly viscoelastic, relaxing stress rapidly under deformation. However, the impact of tissue-specific viscoelasticity on the activities of adipose-derived stem cells (ASC) remains largely unexplored. Here, we investigated the role of matrix viscoelasticity in regulating ASC differentiation for IVD regeneration. Viscoelastic alginate hydrogels with stress relaxation time scales ranging from 100 s to 1000s were developed and used to culture human ASCs for 21 days. Our results demonstrated that the fast-relaxing hydrogel significantly enhanced ASCs long-term cell survival and NP-like extracellular matrix secretion of aggrecan and type-II collagen. Moreover, gene expression analysis revealed a substantial upregulation of the mechanosensitive ion channel marker TRPV4 and NP-specific markers such as SOX9, HIF-1α, KRT18, CDH2 and CD24 in ASCs cultured within the fast-relaxing hydrogel, compared to slower-relaxing hydrogels. These findings highlight the critical role of matrix viscoelasticity in regulating ASC behavior and suggest that viscoelasticity is a key parameter for novel biomaterials design to improve the efficacy of stem cell therapy for IVD regeneration. STATEMENT OF SIGNIFICANCE: Systematically characterized the influence of tissue-mimetic viscoelasticity on ASC. NP-mimetic hydrogels with tunable viscoelasticity and tissue-matched stiffness. Long-term survival and metabolic activity of ASCs are substantially improved in the fast-relaxing hydrogel. The fast-relaxing hydrogel allows higher rate of cell protrusions formation and matrix remodeling. ASC differentiation towards an NP-like cell phenotype is promoted in the fast-relaxing hydrogel, with more CD24 positive expression indicating NP committed cell fate. The expression of TRPV4, a molecular sensor of matrix viscoelasticity, is significantly enhanced in the fast-relaxing hydrogel, indicating ASC sensing matrix viscoelasticity during cell development. The NP-specific ECM secretion of ASC is considerably influenced by matrix viscoelasticity, where the deposition of aggrecan and type-II collagen are significantly enhanced in the fast-relaxing hydrogel.

Simultaneous removal of ammonia nitrogen, calcium and cadmium in a biofilm reactor based on microbial-induced calcium precipitation: Optimization of conditions, mechanism and community biological response.

With the enhancement of environmental governance regulations, the discharge requirements for reverse osmosis wastewater have become increasingly stringent. This study proposes an innovative approach utilizing heterotrophic nitrification and aerobic denitrification (HNAD)-based biomineralization technology, combined with coconut palm silk loaded biochar, to offer a novel solution for resource-efficient and eco-friendly treatment of reverse osmosis wastewater. Zobellella denitrificans sp. LX16 were loaded onto modified coir silk and showed removal efficiencies of up to 97.38, 94.58, 86.24, and 100% for NH4+-N (65 mg L-1), COD (900 mg L-1), Ca2+ (180 mg L-1), and Cd2+ (25 mg L-1). Analysis of the metabolites of microorganisms reveals that coconut palm silk loaded with deciduous biochar (BCPS) not only exerts a protective effect on microorganisms, but also enhances their growth, metabolism, and electron transfer capabilities. Characterization of precipitation phenomena elucidated the mechanism of Cd2+ removal via ion exchange, precipitation, and adsorption. Employing high-throughput and KEGG functional analyses has confirmed the biota environmental response strategies and the identification of key genes like HNAD.

Therapeutic potential: The role of mesenchymal stem cells from diverse sources and their derived exosomes in diabetic nephropathy.

Diabetic nephropathy (DN) is one of the most common microvascular complications in diabetic patients, with its incidence continuously increasing in recent years. DN causes renal tissue damage and functional decline, expedites the aging process of the kidneys, and may ultimately progress leading to end-stage renal disease, severely impacting the patient's quality of life and prognosis. Mesenchymal stem cells (MSCs) are highly valued for their multipotent differentiation, paracrine functions, immunomodulatory effects, and capacity for tissue repair. Particularly, exosomes (Exo) derived from MSCs (MSCs-Exo) are rich in bioactive molecules and facilitate intercellular communication, participating in various physiological and pathological processes. MSCs and MSCs-Exo, in particular, have been demonstrated to have therapeutic effects in DN treatment research by encouraging tissue repair, fibrosis inhibition, and inflammation reduction. Research has shown that MSCs and MSCs-Exo have therapeutic effects in DN treatment by promoting tissue repair, inhibiting fibrosis, and reducing inflammation. Recent studies underscore the potential of MSCs and MSCs-Exo, highlighting their broad applicability in DN treatment. This review aims to provide a comprehensive summary of the scientific developments in treating DN using MSCs and MSCs-Exo from diverse sources, while also exploring their future therapeutic possibilities in detail.