Atherosclerosis (AS) is characterized by impairment and apoptosis of endothelial cells, continuous systemic and focal inflammation and dysfunction of vascular smooth muscle cells, which is documented as the traditional cellular paradigm. However, the mechanisms appear much more complicated than we thought since a bulk of studies on efferocytosis, transdifferentiation and novel cell death forms such as ferroptosis, pyroptosis, and extracellular trap were reported. Discovery of novel pathological cellular landscapes provides a large number of therapeutic targets. On the other side, the unsatisfactory therapeutic effects of current treatment with lipid-lowering drugs as the cornerstone also restricts the efforts to reduce global AS burden. Stem cell- or nanoparticle-based strategies spurred a lot of attention due to the attractive therapeutic effects and minimized adverse effects. Given the complexity of pathological changes of AS, attempts to develop an almighty medicine based on single mechanisms could be theoretically challenging. In this review, the top stories in the cellular landscapes during the initiation and progression of AS and the therapies were summarized in an integrated perspective to facilitate efforts to develop a multi-targets strategy and fill the gap between mechanism research and clinical translation. The future challenges and improvements were also discussed.
Copper is an essential trace element, and plays a vital role in numerous physiological processes within the human body. During normal metabolism, the human body maintains copper homeostasis. Copper deficiency or excess can adversely affect cellular function. Therefore, copper homeostasis is stringently regulated. Recent studies suggest that copper can trigger a specific form of cell death, namely, cuproptosis, which is triggered by excessive levels of intracellular copper. Cuproptosis induces the aggregation of mitochondrial lipoylated proteins, and the loss of iron-sulfur cluster proteins. In neurodegenerative diseases, the pathogenesis and progression of neurological disorders are linked to copper homeostasis. This review summarizes the advances in copper homeostasis and cuproptosis in the nervous system and neurodegenerative diseases. This offers research perspectives that provide new insights into the targeted treatment of neurodegenerative diseases based on cuproptosis.
Ferroptosis, a type of regulated cell death driven by iron-dependent lipid peroxidation, is mainly initiated by extramitochondrial lipid peroxidation due to the accumulation of iron-dependent reactive oxygen species. Ferroptosis is a prevalent and primitive form of cell death. Numerous cellular metabolic processes regulate ferroptosis, including redox homeostasis, iron regulation, mitochondrial activity, amino acid metabolism, lipid metabolism, and various disease-related signaling pathways. Ferroptosis plays a pivotal role in cancer therapy, particularly in the eradication of aggressive malignancies resistant to conventional treatments. Multiple studies have explored the connection between ferroptosis and bladder cancer, focusing on its incidence and treatment outcomes. Several biomolecules and tumor-associated signaling pathways, such as p53, heat shock protein 1, nuclear receptor coactivator 4, RAS-RAF-MEK, phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin, and the Hippo-tafazzin signaling system, exert a moderating influence on ferroptosis in bladder cancer. Ferroptosis inducers, including erastin, artemisinin, conjugated polymer nanoparticles, and quinazolinyl-arylurea derivatives, hold promise for enhancing the effectiveness of conventional anticancer medications in bladder cancer treatment. Combining conventional therapeutic drugs and treatment methods related to ferroptosis offers a promising approach for the treatment of bladder cancer. In this review, we analyze the research on ferroptosis to augment the efficacy of bladder cancer treatment.
Infectious diseases are the common enemies of mankind. In the course of historical development, they persistently threaten human health and safety. Even today, despite the developments in medical science, we cannot escape the fear and suffering caused by infectious diseases. Whether in ancient or modern times, the source of infection, route of transmission, and a susceptible population are the three key conditions for the prevalence and spread of infectious diseases. All factors closely related to these three conditions can affect the prevalence of infectious diseases. China is one of the cradles of world civilization. The ancient people accumulated a great deal of experience and lessons in the long struggle against infectious diseases. In the face of the current threat posed by widespread infectious disease, it is imperative to review and summarize ancient Chinese ideas and health policies on epidemic prevention and control to inspire contemporary efforts in the prevention and control of infectious disease. The combination of prevention-oriented epidemic prevention ideology and traditional medicine provides valuable insights, especially for impoverished and medically underserved regions.
Cancer patients are at high risk of malnutrition, which can lead to adverse health outcomes such as prolonged hospitalization, increased complications, and increased mortality. Accurate and timely nutritional assessment plays a critical role in effectively managing malnutrition in these patients. However, while many tools exist to assess malnutrition, there is no universally accepted standard. Although different tools have their own strengths and limitations, there is a lack of narrative reviews on nutritional assessment tools for cancer patients. To address this knowledge gap, we conducted a non-systematic literature search using PubMed, Embase, Web of Science, and the Cochrane Library from their inception until May 2023. A total of 90 studies met our selection criteria and were included in our narrative review. We evaluated the applications, strengths, and limitations of 4 commonly used nutritional assessment tools for cancer patients: the Subjective Global Assessment (SGA), Patient-Generated Subjective Global Assessment (PG-SGA), Mini Nutritional Assessment (MNA), and Global Leadership Initiative on Malnutrition (GLIM). Our findings revealed that malnutrition was associated with adverse health outcomes. Each of these 4 tools has its applications, strengths, and limitations. Our findings provide medical staff with a foundation for choosing the optimal tool to rapidly and accurately assess malnutrition in cancer patients. It is essential for medical staff to be familiar with these common tools to ensure effective nutritional management of cancer patients.
YAP1 plays a dual role as an oncogene and tumor suppressor gene in several tumors; differentiating between these roles may depend on the YAP1 phosphorylation pattern. The specific function of YAP1 in B cell acute lymphoblastic leukemia (B-ALL), however, is currently unclear. Thus, in the present study, the role of YAP1 in B-ALL was investigated using relevant cell lines and patient datasets.
The effects of shRNA-mediated knockdown on YAP1 and LATS1 levels in the NALM6 and MOLT-4 cell lines were examined using Western blotting, quantitative real-time polymerase chain reaction, flow cytometry, immunostaining, and nude mouse subcutaneous tumorigenesis experiments. Gene expression levels of Hippo pathway-related molecules before and after verteporfin (VP) treatment were compared using RNA-Seq to identify significant Hippo pathway-related genes in NALM6 cells.
Patients with ALL showing high YAP1 expression and low YAP1-Ser127 phosphorylation levels had worse prognoses than those with low YAP1 protein expression and high YAP1-Ser127 phosphorylation levels. YAP1-Ser127 phosphorylation levels were lower in NALM6 cells than in MOLT-4 and control cells; YAP1 was distributed in the nuclei in NALM6 cells. Knockdown of YAP1 inhibited MOLT-4 and NALM6 cell proliferation and arrested the NALM6 cell cycle in the G0/G1 phase. Before and after VP treatment, the expression of the upstream gene LATS1 was upregulated; its overexpression promoted YAP1-Ser127 phosphorylation. Further, YAP1 was distributed in the plasma.
LATS1 may downregulate YAP1-Ser127 phosphorylation and maintain B-ALL cell function; thus, VP, which targets this axis, may serve as a new therapeutic method for improving the outcomes for B-ALL patients.
Keshan disease (KD) is a myocardial mitochondrial disease closely related to insufficient selenium (Se) and protein intake. PTEN induced putative kinase 1 (PINK1)/Parkin mediated mitochondrial autophagy regulates various physiological and pathological processes in the body. This study aimed to elucidate the relationship between PINK1/Parkin-regulated mitochondrial autophagy and KD-related myocardial injury.
A low Se and low protein animal model was established. One hundred Wistar rats were randomly divided into 5 groups (control group, low Se group, low protein group, low Se + low protein group, and corn from KD area group). The JC-1 method was used to detect the mitochondrial membrane potential (MMP). ELISA was used to detect serum creatine kinase MB (CK-MB), cardiac troponin I (cTnI), and mitochondrial-glutamicoxalacetic transaminase (M-GOT) levels. RT-PCR and Western blot analysis were used to detect the expression of PINK1, Parkin, sequestome 1 (P62), and microtubule-associated proteins1A/1B light chain 3B (MAP1LC3B).
The MMP was significantly decreased and the activity of CK-MB, cTnI, and M-GOT significantly increased in each experimental group (low Se group, low protein group, low Se + low protein group and corn from KD area group) compared with the control group ( P<0.05 for all). The mRNA and protein expression levels of PINK1, Parkin and MAP1LC3B were profoundly increased, and those of P62 markedly decreased in the experimental groups compared with the control group ( P<0.05 for all).
Low Se and low protein levels exacerbate myocardial damage in KD by affecting the PINK1/Parkin-mediated mitochondrial autophagy pathway.
This study aimed to investigate the changes of follicular helper T (TFH) and follicular regulatory T (TFR) cell subpopulations in patients with non-small cell lung cancer (NSCLC) and their significance.
Peripheral blood was collected from 58 NSCLC patients at different stages and 38 healthy controls. Flow cytometry was used to detect TFH cell subpopulation based on programmed death 1 (PD-1) and inducible co-stimulator (ICOS), and TFR cell subpopulation based on cluster determinant 45RA (CD45RA) and forkhead box protein P3 (FoxP3). The levels of interleukin-10 (IL-10), interleukin-17a (IL-17a), interleukin-21 (IL-21), and transforming growth factor-β (TGF-β) in the plasma were measured, and changes in circulating B cell subsets and plasma IgG levels were also analyzed. The correlation between serum cytokeratin fragment antigen 21-1 (CYFRA 21-1) levels and TFH, TFR, or B cell subpopulations was further explored.
The TFR/TFH ratio increased significantly in NSCLC patients. The CD45RA +FoxP3 int TFR subsets were increased, with their proportions increasing in stages II to III and decreasing in stage IV. PD-1 +ICOS +TFH cells showed a downward trend with increasing stages. Plasma IL-21 and TGF-β concentrations were increased in NSCLC patients compared with healthy controls. Plasmablasts, plasma IgG levels, and CD45RA +FoxP3 int TFR cells showed similar trends. TFH numbers and plasmablasts were positively correlated with CYFRA 21-1 in stages I–III and negatively correlated with CYFRA 21-1 in stage IV.
Circulating TFH and TFR cell subpopulations and plasmablasts dynamically change in different stages of NSCLC, which is associated with serum CYFRA 21-1 levels and reflects disease progression.
The function of Bcl-6 in T follicular helper (Tfh) cell maturation is indispensable, and Tfh cells play a pivotal role in asthma. This study investigated the impact of Bcl-6 on asthmatic traits.
The microscopic pathological alterations, airway resistance (AR), and lung compliance (LC) were determined in asthmatic mice and Bcl-6 interference mice. The surface molecular markers of Tfh cells and the Bcl-6 mRNA and protein expression were determined by flow cytometry, RT-qPCR, and Western blotting, respectively. The relationships between the Tfh cell ratio and the IgE and IgG 1 concentrations in peripheral blood mononuclear cells (PBMCs) and bronchoalveolar lavage fluid (BALF) were determined.
Asthmatic inflammatory changes were observed in the lung tissue and were attenuated by Bcl-6 siRNA and dexamethasone (DXM). Asthmatic mice exhibited an increased AR and a decreased LC, while Bcl-6 siRNA or DXM mitigated these changes. The percentages of Tfh cells and eosinophils were significantly increased in the asthmatic mice, and they significantly decreased after Bcl-6 inhibition or DXM treatment. RT-qPCR and Western blotting analyses revealed that the Bcl-6 expression level in PBMCs was significantly higher in asthmatic mice, and it decreased following Bcl-6 inhibition or DXM treatment. The IgE expression in the serum and BALF and the B cell expression in PBMCs exhibited a similar trend. In asthmatic mice, the ratio of Tfh cells in the peripheral blood showed a strong positive correlation with the IgE levels in the serum and BALF, but not with the IgG 1 levels.
The amelioration of airway inflammation and airway hyper-responsiveness is achieved through Bcl-6 suppression, which effectively hinders Tfh cell differentiation, ultimately resulting in a concurrent reduction in IgE production.
Human adenovirus (HAdV) infection is common and can develop to serious conditions with high mortality, yet the mechanism of HAdV infection remains unclear. In the present study, the serum metabolite profiles of HAdV-7-infected patients with pneumonia or upper respiratory tract infection (URTI) were explored.
In total, 35 patients were enrolled in the study following an outbreak of HAdV-7 in the army, of whom 14 had pneumonia and 21 had URTI. Blood samples were collected at the acute stage and at the recovery stage and were analyzed by untargeted metabolomics.
Over 90% of the differential metabolites identified between the pneumonia patients and URTI patients were lipids and lipid-like molecules, including glycerophospholipids, fatty acyls, and sphingolipids. The metabolic pathways that were significantly enriched were primarily the lipid metabolism pathways, including sphingolipid metabolism, glycerophospholipid metabolism, and linoleic acid metabolism. The sphingolipid metabolism was identified as a significantly differential pathway between the pneumonia patients and URTI patients and between the acute and recovery stages for the pneumonia patients, but not between the acute and recovery stages for the URTI patients. Ceramide and lactosylceramide, involved in sphingolipid metabolism, were significantly higher in the pneumonia patients than in the URTI patients with good discrimination abilities [area under curve (AUC) 0.742 and 0.716, respectively; combination AUC 0.801].
Our results suggested that HAdV modulated lipid metabolism for both the patients with URTI and pneumonia, especially the sphingolipid metabolism involving ceramide and lactosylceramide, which might thus be a potential intervention target in the treatment of HAdV infection.
SUMO-specific protease 3 (SENP3), a member of the SUMO-specific protease family, reverses the SUMOylation of SUMO-2/3 conjugates. Dysregulation of SENP3 has been proven to be involved in the development of various tumors. However, its role in mantle cell lymphoma (MCL), a highly aggressive lymphoma, remains unclear. This study was aimed to elucidate the effect of SENP3 in MCL.
The expression of SENP3 in MCL cells and tissue samples was detected by RT-qPCR, Western blotting or immunohistochemistry. MCL cells with stable SENP3 knockdown were constructed using short hairpin RNAs. Cell proliferation was assessed by CCK-8 assay, and cell apoptosis was determined by flow cytometry. mRNA sequencing (mRNA-seq) was used to investigate the underlying mechanism of SENP3 knockdown on MCL development. A xenograft nude mouse model was established to evaluate the effect of SENP3 on MCL growth in vivo.
SENP3 was upregulated in MCL patient samples and cells. Knockdown of SENP3 in MCL cells inhibited cell proliferation and promoted cell apoptosis. Meanwhile, the canonical Wnt signaling pathway and the expression of Wnt10a were suppressed after SENP3 knockdown. Furthermore, the growth of MCL cells in vivo was significantly inhibited after SENP3 knockdown in a xenograft nude mouse model.
SENP3 participants in the development of MCL and may serve as a therapeutic target for MCL.
Diabetic cardiomyopathy (DCM) represents a substantial risk factor for heart failure and increased mortality in individuals afflicted with diabetes mellitus (DM). DCM typically manifests as myocardial fibrosis, myocardial hypertrophy, and impaired left ventricular diastolic function. While the clinical utility of the Jianpi Qinghua (JPQH) formula has been established in treating diabetes and insulin resistance, its potential efficacy in alleviating diabetic cardiomyopathy remains uncertain. This study aims to investigate the impact and underlying molecular mechanisms of the JPQH formula (JPQHF) in ameliorating myocardial injury in nonobese diabetic rats, specifically focusing on apoptosis and inflammation.
Wistar rats were assigned as the normal control group (CON), while Goto-Kakizaki (GK) rats were randomly divided into three groups: DM, DM treated with the JPQHF, and DM treated with metformin (MET). Following a 4-week treatment regimen, various biochemical markers related to glucose metabolism, cardiac function, cardiac morphology, and myocardial ultrastructure in GK rats were assessed. RNA sequencing was utilized to analyze differential gene expression and identify potential therapeutic targets. In vitro experiments involved high glucose to induce apoptosis and inflammation in H9c2 cells. Cell viability was evaluated using CCK-8 assay, apoptosis was monitored via flow cytometry, and the production of inflammatory cytokines was measured using quantitative real-time PCR (qPCR) and ELISA. Protein expression levels were determined by Western blotting analysis. The investigation also incorporated the use of MAPK inhibitors to further elucidate the mechanism at both the transcriptional and protein levels.
The JPQHF group exhibited significant reductions in interventricular septal thickness at end-systole (IVSs) and left ventricular internal diameter at end-systole and end-diastole (LVIDs and LVIDd). JPQHF effectively suppressed high glucose-induced activation of IL-1β and caspase 3 in cardiomyocytes. Furthermore, JPQHF downregulated the expression of myocardial JunB/c-Fos, which was upregulated in both diabetic rats and high glucose-treated H9c2 cells.
The JPQH formula holds promise in mitigating diabetic myocardial apoptosis and inflammation in cardiomyocytes by inhibiting JunB/c-Fos expression through suppressing the MAPK (p38 and ERK1/2) pathway.
Anthracycline-containing regimens are irreplaceable in neoadjuvant chemotherapy (NAC) for breast cancer (BC) at present. However, 30% of early breast cancer (EBC) patients are resistant to anthracycline-containing chemotherapy, leading to poor prognosis and higher mortality. Ki-67 is associated with the prognosis and response to therapy, and it changes after NAC.
A total of 105 BC patients who received anthracycline-containing NAC were enrolled. Then, the optimal model of Ki-67 was selected, and its predictive efficacy was analyzed. Immunohistochemistry (IHC) was used to determine the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) status and Ki-67 level. Fluorescent in situ hybridization (FISH) was used to verify the HER-2 when the IHC score was 2+.
The post-NAC Ki67 level after treatment with anthracycline drugs was lower than pre-NAC Ki-67 (19.6%±23.3% vs. 45.6%±23.1%, P<0.001). Furthermore, patients with the Ki-67 decrease had a border line higher pathological complete response (pCR) rate (17.2% vs. 0.0%, P=0.068), and a higher overall response rate (ORR) (73.6% vs. 27.8%, P<0.001), when compared to patients without the Ki-67 decrease. The ΔKi-67 and ΔKi-67% were valuable markers for the prediction of both the pCR rate and ORR. The area under the curve (AUC) for ΔKi-67 on pCR and ORR was 0.809 (0.698–0.921) and 0.755 (0.655–0.855), respectively, while the AUC for ΔKi-67% on pCR and ORR was 0.857 (0.742–0.972) and 0.720 (0.618–0.822), respectively. Multivariate logistic regression model 1 revealed that ΔKi-67 was an independent predictor for both pCR [odds ratio (OR)=61.030, 95% confidence interval (CI)=4.709–790.965; P=0.002] and ORR (OR=10.001, 95% CI: 3.044–32.858; P<0.001). Multivariate logistic regression model 2 revealed that ΔKi-67% was also an independent predictor for both pCR (OR=408.922, 95% CI=8.908–18771.224; P=0.002) and ORR (OR=5.419, 95% CI=1.842–15.943; P=0.002).
The present study results suggest that ΔKi67 and ΔKi67% are candidate predictors for anthracycline-containing NAC response, and that they may provide various information for further systematic therapy after surgery in clinical practice.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-associated death worldwide. As a first-line drug for advanced HCC treatment, lenvatinib faces a significant hurdle due to the development of both intrinsic and acquired resistance among patients, and the underlying mechanism remains largely unknown. The present study aims to identify the pivotal gene responsible for lenvatinib resistance in HCC, explore the potential molecular mechanism, and propose combinatorial therapeutic targets for HCC management.
Cell viability and colony formation assays were conducted to evaluate the sensitivity of cells to lenvatinib and dicoumarol. RNA-Seq was used to determine the differences in transcriptome between parental cells and lenvatinib-resistant (LR) cells. The upregulated genes were analyzed by GO and KEGG analyses. Then, qPCR and Western blotting were employed to determine the relative gene expression levels. Afterwards, the intracellular reactive oxygen species (ROS) and apoptosis were detected by flow cytometry.
PLC-LR and Hep3B-LR were established. There was a total of 116 significantly upregulated genes common to both LR cell lines. The GO and KEGG analyses indicated that these genes were involved in oxidoreductase and dehydrogenase activities, and reactive oxygen species pathways. Notably, NAD(P)H:quinone oxidoreductase 1 (NQO1) was highly expressed in LR cells, and was involved in the lenvatinib resistance. The high expression of NQO1 decreased the production of ROS induced by lenvatinib, and subsequently suppressed the apoptosis. The combination of lenvatinib and NQO1 inhibitor, dicoumarol, reversed the resistance of LR cells.
The high NQO1 expression in HCC cells impedes the lenvatinib-induced apoptosis by regulating the ROS levels, thereby promoting lenvatinib resistance in HCC cells.
Brain metastases significantly impact the clinical course of patients with hepatocellular carcinoma (HCC). This study aimed to examine the age-related incidence, demographics, and survival of patients with HCC and brain metastases.
Data of HCC patients from 2010 to 2015 in the Surveillance, Epidemiology, and End Results (SEER) Registry were screened for the presence of brain metastases. They were stratified by age and ethnicity. Multivariable logistic and Cox regression analyses were used to identify factors associated with brain metastases and those with overall survival (OS) and liver cancer-specific survival (CSS), respectively.
A total of 141 HCC patients presenting with brain metastases were identified, accounting for 0.35% of all HCC patients and 2.37% of patients with metastatic disease. Among all HCC patients, the incidence rate was the highest among patients aged 30–49 years old (0.47%). Ethnicity was not associated with the presence of brain metastases at the time of HCC diagnosis. However, African-American patients presented with a significantly lower disease-specific survival [median time: 1 month; interquartile range (IQR): 0–3.0 months)]. Initial lung or bone metastasis was independently associated with an increased risk of the presence of brain metastases [odds ratio (OR): 12.62, 95% confidence interval (CI): 8.40–18.97] but was not associated with a worse OS or CSS among those with brain metastases.
This study identified the age-related incidence and risk factors of brain metastases in HCC patients. These results may contribute to the consideration of brain screening among patients with initial metastatic HCC with lung or bone metastases, and influence the counseling of this patient population regarding their prognosis.
Premature rupture of membranes (PROM) is a common pregnancy disorder that is closely associated with structural weakening of fetal membranes. Studies have found that formyl peptide receptor 1 (FPR1) activates inflammatory pathways and amniotic epithelialmesenchymal transition (EMT), stimulates collagen degradation, and leads to membrane weakening and membrane rupture. The purpose of this study was to investigate the anti-inflammatory and EMT inhibitory effects of FPR1 antagonist (BOC-MLF) to provide a basis for clinical prevention of PROM.
The relationship between PROM, FPR1, and EMT was analyzed in human fetal membrane tissue and plasma samples using Western blotting, PCR, Masson staining, and ELISA assays. Lipopolysaccharide (LPS) was used to establish a fetal membrane inflammation model in pregnant rats, and BOC-MLF was used to treat the LPS rat model. We detected interleukin (IL)-6 in blood from the rat hearts to determine whether the inflammatory model was successful and whether the anti-inflammatory treatment was effective. We used electron microscopy to analyze the structure and collagen expression of rat fetal membrane.
Western blotting, PCR and Masson staining indicated that the expression of FPR1 was significantly increased, the expression of collagen was decreased, and EMT appeared in PROM. The rat model indicated that LPS caused the collapse of fetal membrane epithelial cells, increased intercellular gaps, and decreased collagen. BOC-MLF promoted an increase in fetal membrane collagen, inhibited EMT, and reduced the weakening of fetal membranes.
The expression of FPR1 in the fetal membrane of PROM was significantly increased, and EMT of the amniotic membrane was obvious. BOC-MLF can treat inflammation and inhibit amniotic EMT.
Innate lymphoid cells (ILCs) are a class of newly discovered immunocytes. Group 1 ILCs (ILC1s) are identified in the decidua of humans and mice. High mobility group box 1 (HMGB1) is predicted to be one of the target genes of miR-142-3p, which is closely related to pregnancy-related diseases. Furthermore, miR-142-3p and HMGB1 are involved in regulating the NF-κB signaling pathway. This study aimed to examine the regulatory effect of miR-142-3p on ILC1s and the underlying mechanism involving HMGB1 and the NF-κB signaling pathway.
Mouse models of normal pregnancy and abortion were constructed, and the alterations of ILC1s, miR-142-3p, ILC1 transcription factor (T-bet), and pro-inflammatory cytokines of ILC1s (TNF-α, IFN-γ and IL-2) were detected in mice from different groups. The targeting regulation of HMGB1 by miR-142-3p in ILC1s, and the expression of HMGB1 in normal pregnant mice and abortive mice were investigated. In addition, the regulatory effects of miR-142-3p and HMGB1 on ILC1s were detected in vitro by CCK-8, Annexin-V/PI, ELISA, and RT-PCR, respectively. Furthermore, changes of the NF-κB signaling pathway in ILC1s were examined in the different groups. For the in vivo studies, miR-142-3p-Agomir was injected in the uterus of abortive mice to evaluate the abortion rate and alterations of ILC1s at the maternal-fetal interface, and further detect the expression of HMGB1, pro-inflammatory cytokines, and the NF-κB signaling pathway.
The number of ILC1s was significantly increased, the level of HMGB1 was significantly upregulated, and that of miR-142-3p was considerably downregulated in the abortive mice as compared with the normal pregnant mice (all P<0.05). In addition, miR-142-3p was found to drastically inhibit the activation of the NF-κB signaling pathway ( P<0.05). The number of ILC1s and the levels of pro-inflammatory cytokines were significantly downregulated and the activation of the NF-κB signaling pathway was inhibited in the miR-142-3p Agomir group (all P<0.05).
miR-142-3p can regulate ILC1s by targeting HMGB1 via the NF-κB signaling pathway, and attenuate the inflammation at the maternal-fetal interface in abortive mice.
Both sequential embryo transfer (SeET) and double-blastocyst transfer (DBT) can serve as embryo transfer strategies for women with recurrent implantation failure (RIF). This study aims to compare the effects of SeET and DBT on pregnancy outcomes.
Totally, 261 frozen-thawed embryo transfer cycles of 243 RIF women were included in this multicenter retrospective analysis. According to different embryo quality and transfer strategies, they were divided into four groups: group A, good-quality SeET (GQ-SeET, n=38 cycles); group B, poor-quality or mixed-quality SeET (PQ/MQ-SeET, n=31 cycles); group C, good-quality DBT (GQ-DBT, n=121 cycles); and group D, poor-quality or mixed-quality DBT (PQ/MQ-DBT, n=71 cycles). The main outcome, clinical pregnancy rate, was compared, and the generalized estimating equation (GEE) model was used to correct potential confounders that might impact pregnancy outcomes.
GQ-DBT achieved a significantly higher clinical pregnancy rate (aOR 2.588, 95% CI 1.267–5.284, P=0.009) and live birth rate (aOR 3.082, 95% CI 1.482–6.412, P=0.003) than PQ/MQ-DBT. Similarly, the clinical pregnancy rate was significantly higher in GQ-SeET than in PQ/MQ-SeET (aOR 4.047, 95% CI 1.218–13.450, P=0.023). The pregnancy outcomes of GQ-SeET were not significantly different from those of GQ-DBT, and the same results were found between PQ/MQ-SeET and PQ/MQ-DBT.
SeET relative to DBT did not seem to improve pregnancy outcomes for RIF patients if the embryo quality was comparable between the two groups. Better clinical pregnancy outcomes could be obtained by transferring good-quality embryos, no matter whether in SeET or DBT. Embryo quality plays a more important role in pregnancy outcomes for RIF patients.
Retinoblastoma (RB) is a prevalent type of eye cancer in youngsters. Prospero homeobox 1 (Prox1) is a homeobox transcriptional repressor and downstream target of the proneural gene that is relevant in lymphatic, hepatocyte, pancreatic, heart, lens, retinal, and cancer cells. The goal of this study was to investigate the role of Prox1 in RB cell proliferation and drug resistance, as well as to explore the underlying Notch1 mechanism.
Human RB cell lines (SO-RB50 and Y79) and a primary human retinal microvascular endothelial cell line (ACBRI-181) were used in this study. The expression of Prox1 and Notch1 mRNA and protein in RB cells was detected using quantitative real time-polymerase chain reaction (RT-qPCR) and Western blotting. Cell proliferation was assessed after Prox1 overexpression using the Cell Counting Kit-8 and the MTS assay. Drug-resistant cell lines (SO-RB50/vincristine) were generated and treated with Prox1 to investigate the role of Prox1 in drug resistance. We employed pcDNA-Notch1 to overexpress Notch1 to confirm the role of Notch1 in the protective function of Prox1. Finally, a xenograft model was constructed to assess the effect of Prox1 on RB in vivo.
Prox1 was significantly downregulated in RB cells. Overexpression of Prox1 effectively decreased RB cell growth while increasing the sensitivity of drug-resistant cells to vincristine. Notch1 was involved in Prox1’s regulatory effects. Notch1 was identified as a target gene of Prox1, which was found to be upregulated in RB cells and repressed by increased Prox1 expression. When pcDNA-Notch1 was transfected, the effect of Prox1 overexpression on RB was removed. Furthermore, by downregulating Notch1, Prox1 overexpression slowed tumor development and increased vincristine sensitivity in vivo.
These data show that Prox1 decreased RB cell proliferation and drug resistance by targeting Notch1, implying that Prox1 could be a potential therapeutic target for RB.
Secoemestrin C (SC), an epitetrathiodioxopiperazine isolated from Aspergillus nidulans, has been previously reported to have immunomodulatory and hepatoprotective effects against acute autoimmune hepatitis. However, the effect of SC on regulating the inflammation and its underlying mechanisms in the pathogenesis of psoriasis remain unclear. This study aimed to evaluate the effects of SC on inflammatory dermatosis both in vitro and in vivo.
In vitro, HaCaT cells were induced with tumor necrosis factor-alpha (TNF-α, 10 ng/mL) to establish an inflammatory injury model, and the expression of nuclear transcription factor-κB (NF-κB) pathway components was measured using qRT-PCR and Western blotting. An in vivo mouse model of imiquimod (IMQ)-induced psoriasis-like skin inflammation was used to evaluate the effectiveness of SC in alleviating psoriasis.
SC significantly blocked the activation of NF-κB signaling in TNF-α-stimulated HaCaT cells. In addition, systemic and local administration of SC improved psoriatic dermatitis in the IMQ-induced mouse model. SC reduced skin scale and significantly inhibited the secretion of inflammatory factors in skin lesions.
The protective effect of SC against psoriatic-associated inflammation reveals its potential therapeutic value for treating psoriasis.