[Incidence and risk factors of deep vein thrombosis in patients with rheumatoid arthritis].

OBJECTIVE: To investigate the incidence and risk factors of deep vein thrombosis (DVT) in patients with rheumatoid arthritis (RA). METHODS: The clinical data of RA patients who were hospi-talized in the Department of Rheumatology and Immunology of Aerospace Center Hospital from May 2015 to September 2021 was retrospectively analyzed, including demographic characteristics, concomitant diseases, laboratory examinations (blood routine, biochemistry, coagulation, inflammatory markers, rheumatoid factor, antiphospholipid antibodies and lupus anticoagulant, etc.) and treatment regimens. The patients were compared according to the presence or absence of DVT, and the t test, Mann-Whitney U test or Chi-square test were applied to screen for relevant factors for DVT, followed by Logistic regression analysis to determine risk factors for DVT in patients with RA. RESULTS: The incidence of DVT in the RA patients was 9.6% (31/322); the median age of RA in DVT group was significantly older than that in non-DVT group [64 (54, 71) years vs. 50 (25, 75) years, P < 0.001]; the level of disease activity score using 28 joints (DAS28)-erythrocyte sedimentation rate (ESR) in DVT group was higher than that in non-DVT group [5.2 (4.5, 6.7) vs. 4.5(4.5, 5.0), P < 0.001]; the incidence of hypertension, chronic kidney disease, fracture or surgery history within 3 months, and varicose veins of the lower extremities in DVT group was higher than that in non-DVT group (P < 0.001). The levels of hemoglobin and albumin in DVT group were significantly lower than that in non-DVT group (P=0.009, P=0.004), while the D-dimer level and rheumatoid factor positive rate in DVT group were significantly higher than that in non-DVT group (P < 0.001). The use rate of glucocorticoid in DVT group was higher than that in non-DVT group (P=0.009). Logistic regression analysis showed that the age (OR=1.093, P < 0.001), chronic kidney disease (OR=7.955, P=0.005), fracture or surgery history within 3 months (OR=34.658, P=0.002), DAS28-ESR (OR=1.475, P=0.009), and the use of glucocorticoid (OR=5.916, P=0.003) were independent risk factors for DVT in RA patients. CONCLUSION: The incidence of DVT in hospitalized RA patients was significantly increased, in addition to traditional factors, such as age and chronic kidney disease, increased DAS28-ESR level and the use of glucocorticoid were also independent risk factors for DVT.

Enhancer in cancer pathogenesis and treatment.

Enhancers are essential cis-acting regulatory elements that determine cell identity and tumor progression. Enhancer function is dependent on the physical interaction between the enhancer and its target promoter inside its local chromatin environment. Enhancer reprogramming is an important mechanism in cancer pathogenesis and can be driven by both cis and trans factors. Super enhancers are acquired at oncogenes in numerous cancer types and represent potential targets for cancer treatment. BET and CDK inhibitors act through mechanisms of enhancer function and have shown promising results in therapy for various types of cancer. Genome editing is another way to reprogram enhancers in cancer treatment. The relationship between enhancers and cancer has been revised by several authors in the past few years, which mainly focuses on the mechanisms by which enhancers can impact cancer. Here, we emphasize SE's role in cancer pathogenesis and the new therapies involving epigenetic regulators (BETi and CDKi). We suggest that understanding mechanisms of activity would aid clinical success for these anti-cancer agents.

Integrated single-cell and spatial transcriptomic profiling reveals higher intratumour heterogeneity and epithelial-fibroblast interactions in recurrent bladder cancer.

BACKGROUND: Recurrent bladder cancer is the most common type of urinary tract malignancy; nevertheless, the mechanistic basis for its recurrence is uncertain. Innovative technologies such as single-cell transcriptomics and spatial transcriptomics (ST) offer new avenues for studying recurrent tumour progression at the single-cell level while preserving spatial data. METHOD: This study integrated single-cell RNA (scRNA) sequencing and ST profiling to examine the tumour microenvironment (TME) of six bladder cancer tissues (three from primary tumours and three from recurrent tumours). FINDINGS: scRNA data-based ST deconvolution analysis revealed a much higher tumour heterogeneity along with TME in recurrent tumours than in primary tumours. High-resolution ST analysis further identified that while the overall natural killer/T cell and malignant cell count or the ratio of total cells was similar or even lower in the recurrent tumours, a higher interaction between epithelial and immune cells was detected. Moreover, the analysis of spatial communication reveals a marked increase in activity between cancer-associated fibroblasts (CAFs) and malignant cells, as well as other immune cells in recurrent tumours. INTERPRETATION: We observed an enhanced interplay between CAFs and malignant cells in bladder recurrent tumours. These findings were first observed at the spatial level.

Spinal Cord Stimulation for the Treatment of Refractory Pain From Tarlov Cysts: A Case Report.

Tarlov cysts are extradural meningeal cysts with a collection of cerebrospinal fluid that most often affects sacral nerve roots, causing chronic low back pain and radiculopathy. Still, there is no consensus regarding the best treatment for symptomatic cysts. We describe a patient who developed worsening lower back pain and radiculopathy after interventional drainage and surgical management. Medication and various procedures failed to relieve the pain. Subsequently, the patient received significant pain relief from spinal cord stimulation (SCS). This case provides evidence that SCS could be used to manage refractory pain from Tarlov cysts that have failed to respond to other treatment modalities.

Skullcapflavone II, a novel NQO1 inhibitor, alleviates aristolochic acid I-induced liver and kidney injury in mice.

Aristolochic acid I (AAI) is a well established nephrotoxin and human carcinogen. Cytosolic NAD(P)H quinone oxidoreductase 1 (NQO1) plays an important role in the nitro reduction of aristolochic acids, leading to production of aristoloactam and AA-DNA adduct. Application of a potent NQO1 inhibitor dicoumarol is limited by its life-threatening side effect as an anticoagulant and the subsequent hemorrhagic complications. As traditional medicines containing AAI remain available in the market, novel NQO1 inhibitors are urgently needed to attenuate the toxicity of AAI exposure. In this study, we employed comprehensive 2D NQO1 biochromatography to screen candidate compounds that could bind with NQO1 protein. Four compounds, i.e., skullcapflavone II (SFII), oroxylin A, wogonin and tectochrysin were screened out from Scutellaria baicalensis. Among them, SFII was the most promising NQO1 inhibitor with a binding affinity (KD = 4.198 µmol/L) and inhibitory activity (IC50 = 2.87 µmol/L). In human normal liver cell line (L02) and human renal proximal tubular epithelial cell line (HK-2), SFII significantly alleviated AAI-induced DNA damage and apoptosis. In adult mice, oral administration of SFII dose-dependently ameliorated AAI-induced renal fibrosis and dysfunction. In infant mice, oral administration of SFII suppressed AAI-induced hepatocellular carcinoma initiation. Moreover, administration of SFII did not affect the coagulation function in short term in adult mice. In conclusion, SFII has been identified as a novel NQO1 inhibitor that might impede the risk of AAI to kidney and liver without obvious side effect.

One-pot double annulations to confer diastereoselective spirooxindolepyrrolothiazoles.

A novel four-component reaction in one pot as an atom- and step-economic process was developed to synthesize diastereoselectively spirooxindolepyrrolothiazoles through sequential N,S-acetalation of aldehydes with cysteine and decarboxylative [3 + 2] cycloaddition with olefinic oxindoles. High synthetic efficiency, operational simplification and reaction process economy using EtOH as solvent, and only releasing CO2 and H2O as side products confer this approach favorable in green chemistry metrics analysis.

ß-Hydroxybutyrate upregulates FGF21 expression through inhibition of histone deacetylases in hepatocytes.

Fibroblast growth factor 21 (FGF21) is secreted by hepatocytes as a peptide hormone to regulate glucose and lipid metabolism. FGF21 promotes hepatic ketogenesis and increases ketone body utilization in starvation. Histones are the target molecules of nutrients in regulating hepatic metabolic homeostasis. However, the effect of ketone bodies on FGF21 expression and the involvement of histones in it is not clear yet. The present study observed the effects of ß-hydroxybutyrate (ß-OHB), the main physiological ketone body, on FGF21 expression in human hepatoma HepG2 cells in vitro and in mice in vivo, and the role of histone deacetylases (HDACs) in ß-OHB-regulated FGF21 expression was investigated. The results showed that ß-OHB significantly upregulated FGF21 gene expression and increased FGF21 protein levels while it inhibited HDACs' activity in HepG2 cells. HDACs' inhibition by entinostat upregulated FGF21 expression and eliminated ß-OHB-stimulated FGF21 expression in HepG2 cells. Intraperitoneal injections of ß-OHB in mice resulted in the elevation of serum ß-OHB and the inhibition of hepatic HDACs' activity. Meanwhile, hepatic FGF21 expression and serum FGF21 levels were significantly increased in ß-OHB-treated mice compared with the control. It is suggested that ß-OHB upregulates FGF21 expression through inhibition of HDACs' activity in hepatocytes.

Ecological niche modeling based on ensemble algorithms to predicting current and future potential distribution of African swine fever virus in China.

African swine fever (ASF) is a tick-borne infectious disease initially described in Shenyang province China in 2018 but is now currently present nationwide. ASF has high infectivity and mortality rates, which often results in transportation and trade bans, and high expenses to prevent and control the, hence causing huge economic losses and a huge negative impact on the Chinese pig farming industry. Ecological niche modeling has long been adopted in the epidemiology of infectious diseases, in particular vector-borne diseases. This study aimed to establish an ecological niche model combined with data from ASF incidence rates in China from August 2018 to December 2021 in order to predict areas for African swine fever virus (ASFV) distribution in China. The model was developed in R software using the biomod2 package and ensemble modeling techniques. Environmental and topographic variables included were mean diurnal range (°C), isothermality, mean temperature of wettest quarter (°C), precipitation seasonality (cv), mean precipitation of warmest quarter(mm), mean precipitation of coldest quarter (mm), normalized difference vegetation index, wind speed (m/s), solar radiation (kJ /day), and elevation/altitude (m). Contribution rates of the variables normalized difference vegetation index, mean temperature of wettest quarter, mean precipitation of coldest quarter, and mean precipitation of warmest quarter were, respectively, 47.61%, 28.85%, 10.85%, and 7.27% (according to CA), which accounted for over 80% of contribution rates related to variables. According to model prediction, most of areas revealed as suitable for ASF distribution are located in the southeast coast or central region of China, wherein environmental conditions are suitable for soft ticks' survival. In contrast, areas unsuitable for ASFV distribution in China are associated with arid climate and poor vegetation, which are less conducive to soft ticks' survival, hence to ASFV transmission. In addition, prediction spatial suitability for future ASFV distribution suggests narrower areas for ASFV spread. Thus, the ensemble model designed herein could be used to conceive more efficient prevention and control measure against ASF according to different geographical locations in China.

A novel fatty acid metabolism-related signature identifies features of the tumor microenvironment and predicts clinical outcome in acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is the most common malignancy of the hematological system, and there are currently a number of studies regarding abnormal alterations in energy metabolism, but fewer reports related to fatty acid metabolism (FAM) in AML. We therefore analyze the association of FAM and AML tumor development to explore targets for clinical prognosis prediction and identify those with potential therapeutic value. METHODS: The identification of AML patients with different fatty acid metabolism characteristics was based on a consensus clustering algorithm. The CIBERSORT algorithm was used to calculate the proportion of infiltrating immune cells. We used Cox regression analysis and least absolute shrinkage and selection operator (LASSO) regression analysis to construct a signature for predicting the prognosis of AML patients. The Genomics of Drug Sensitivity in Cancer database was used to predict the sensitivity of patient samples in high- and low-risk score groups to different chemotherapy drugs. RESULTS: The consensus clustering approach identified three molecular subtypes of FAM that exhibited significant differences in genomic features such as immunity, metabolism, and inflammation, as well as patient prognosis. The risk-score model we constructed accurately predicted patient outcomes, with area under the receiver operating characteristic curve values of 0.870, 0.878, and 0.950 at 1, 3, and 5 years, respectively. The validation cohort also confirmed the prognostic evaluation performance of the risk score. In addition, higher risk scores were associated with stronger fatty acid metabolisms, significantly higher expression levels of immune checkpoints, and significantly increased infiltration of immunosuppressive cells. Immune functions, such as inflammation promotion, para-inflammation, and type I/II interferon responses, were also significantly activated. These results demonstrated that immunotherapy targeting immune checkpoints and immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) and M2 macrophages, are more suitable for patients with high-risk scores. Finally, the prediction results of chemotherapeutic drugs showed that samples in the high-risk score group had greater treatment sensitivity to four chemotherapy drugs in vitro. CONCLUSIONS: The analysis of the molecular patterns of FAM effectively predicted patient prognosis and revealed various tumor microenvironment (TME) characteristics.

α-Lipoic acid up-regulates gene expression but reduces protein levels of fibroblast growth factor 21 in HepG2 cells.

Fibroblast growth factor 21 (FGF21) is a metabolism-regulating hepatokine, and its expression is finely controlled by the nutrients and cellular stressors. α-Lipoic acid (ALA) regulates fuel metabolism as a nutrient, but it also arouses mitochondrial and endoplasmic reticulum (ER) stress as well as oxidative stress in hepatocytes. However, the role of cellular stress in ALA-regulated FGF21 expression has not been demonstrated as yet. The present study found that ALA up-regulated FGF21 gene expression while it reduced FGF21 protein levels in HepG2 cells, which was accompanied by mitochondrial damage that was shown by ATP reduction and ROS elevation. ALA led to mitochondrial stress and ER stress as shown by the increased expression of HSP60, ATF6 and ATF4. Inhibition of ER stress by 4-PBA significantly attenuated ALA-stimulated FGF21 gene expression while it did not influence the reduction of FGF21 protein levels. H2 O2 -induced oxidative stress reduced FGF21 protein levels in HepG2 cells, and anti-oxidation by Tempol blocked ALA-induced reduction of FGF21 proteins. In conclusion, ALA up-regulates FGF21 gene expression through the stimulation of mitochondrial and ER stress while it reduces FGF21 protein levels through the induction of oxidative stress in HepG2 cells. Further studies are needed to demonstrate the in vivo effect of ALA on hepatic FGF21 expression.

Pyruvate Upregulates Hepatic FGF21 Expression by Activating PDE and Inhibiting cAMP-Epac-CREB Signaling Pathway.

Fibroblast growth factor 21 (FGF21) functions as a polypeptide hormone to regulate glucose and lipid metabolism, and its expression is regulated by cellular metabolic stress. Pyruvate is an important intermediate metabolite that acts as a key hub for cellular fuel metabolism. However, the effect of pyruvate on hepatic FGF21 expression and secretion remains unknown. Herein, we examined the gene expression and protein levels of FGF21 in human hepatoma HepG2 cells and mouse AML12 hepatocytes in vitro, as well as in mice in vivo. In HepG2 and AML12 cells, pyruvate at concentrations above 0.1 mM significantly increased FGF21 expression and secretion. The increase in cellular cAMP levels by adenylyl cyclase activation, phosphodiesterase (PDE) inhibition and 8-Bromo-cAMP administration significantly restrained pyruvate-stimulated FGF21 expression. Pyruvate significantly increased PDE activities, reduced cAMP levels and decreased CREB phosphorylation. The inhibition of exchange protein directed activated by cAMP (Epac) and cAMP response element binding protein (CREB) upregulated FGF21 expression, upon which pyruvate no longer increased FGF21 expression. The increase in plasma pyruvate levels in mice induced by the intraperitoneal injection of pyruvate significantly increased FGF21 gene expression and PDE activity with a reduction in cAMP levels and CREB phosphorylation in the mouse liver compared with the control. In conclusion, pyruvate activates PDEs to reduce cAMP and then inhibits the cAMP-Epac-CREB signaling pathway to upregulate FGF21 expression in hepatocytes.

Selecting Candidates for Organ-Preserving Strategies After Neoadjuvant Chemoradiotherapy for Rectal Cancer: Development and Validation of a Model Integrating MRI Radiomics and Pathomics.

BACKGROUND: Histopathologic evaluation after surgery is the gold standard to evaluate treatment response to neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC). However, it cannot be used to guide organ-preserving strategies due to poor timeliness. PURPOSE: To develop and validate a multiscale model incorporating radiomics and pathomics features for predicting pathological good response (pGR) of down-staging to stage ypT0-1N0 after nCRT. STUDY TYPE: Retrospective. POPULATION: A total of 153 patients (median age, 55 years; 109 men; 107 training group; 46 validation group) with clinicopathologically confirmed LARC. FIELD STRENGTH/SEQUENCE: A 3.0-T; fast spin echo T2 -weighted and single-shot EPI diffusion-weighted images. ASSESSMENT: The differences in clinicoradiological variables between pGR and non-pGR groups were assessed. Pretreatment and posttreatment radiomics signatures, and pathomics signature were constructed. A multiscale pGR prediction model was established. The predictive performance of the model was evaluated and compared to that of the clinicoradiological model. STATISTICAL TESTS: The χ2 test, Fisher's exact test, t-test, the minimum redundancy maximum relevance algorithm, the least absolute shrinkage and selection operator logistic regression algorithm, regression analysis, receiver operating characteristic curve (ROC) analysis, Delong method. P < 0.05 indicated a significant difference. RESULTS: Pretreatment radiomics signature (odds ratio [OR] = 2.53; 95% CI: 1.58-4.66), posttreatment radiomics signature (OR = 9.59; 95% CI: 3.04-41.46), and pathomics signature (OR = 3.14; 95% CI: 1.40-8.31) were independent factors for predicting pGR. The multiscale model presented good predictive performance with areas under the curve (AUC) of 0.93 (95% CI: 0.88-0.98) and 0.90 (95% CI: 0.78-1.00) in the training and validation groups, those were significantly higher than that of the clinicoradiological model with AUCs of 0.69 (95% CI: 0.55-0.82) and 0.68 (95% CI: 0.46-0.91) in both groups. DATA CONCLUSION: A model incorporating radiomics and pathomics features effectively predicted pGR after nCRT in patients with LARC. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 4.

LncRNA LUADT1 inhibits cell apoptosis in diabetic retinopathy by regulating miR-383/peroxiredoxin 3 axis.

This study aimed to investigate the involvement of long non-coding RNA (lncRNA) lung adenocarcinoma transcript 1 (LUADT1) LUADT1 in diabetic retinopathy (DR). We found LUADT1 may interact with miR-383 by RNA interaction prediction. QPCR analysis showed that lncRNA LUADT1 was downregulated, and miR-383 was upregulated in DR. However, correlation analysis revealed no significant correlation between them. In retinal pigment epithelial cells (RPEpiC, h1RPE7 from Sigma-Aldrich), overexpression of LUADT1 and miR-383 failed to affect the expression of each other. However, LUADT1 overexpression led to increased and miR-383 overexpression led to decreased expression level of peroxiredoxin 3 (PRX3). Cell apoptosis analysis showed that LUADT1 and PRX3 overexpression resulted in the decreased cell apoptosis. MiR-383 played an opposite role and reduced the effects of LUADT1 and PRX3 overexpression. Therefore, LUADT1 regulates PRX3 by serving as the endogenous sponge of miR-383 in DR to regulate cell apoptosis.

Preparation of Near-Infrared/Photoacoustic Dual-Mode Imaging and Photothermal/Chemo Synergistic Theranostic Nanoparticles and Their Imaging and Treating of Hepatic Carcinoma.

At present, the clinical diagnosis of and treatment methods for hepatic carcinoma still fail to fully meet the needs of patients. The integrated theranostic system, in which functional materials are used to load different active molecules, created a new developmental direction for the combination treatment of hepatic carcinoma, realizing the synchronization of diagnosis and treatment. In this study, polydopamine (PDA), which has the functions of self-assembly, encapsulation, photothermal conversion, and photoacoustic interaction, was used as the carrier material. The IR780, a near-infrared fluorescence imaging (NIFI), photoacoustic imaging (PAI), and photothermal therapy (PTT) agent, and paclitaxel (PTX), a broad-spectrum chemotherapy drug, were selected to build the NIF/PA dual-mode imaging and PTT/chemo synergistic theranostic nanoparticles (DIST NPs). The DIST NPs have a 103.4 ± 13.3 nm particle size, a weak negative charge on the surface, good colloidal stability, slow and controlled drug release, and high photothermal conversion ability. The experiments results showed that the DIST NPs have a long circulation in vivo, high bioavailability, high biocompatibility, and low effective dose. DIST NPs showed an excellent NIFI/PAI dual-mode imaging and significant synergistic antitumor effect in hepatic carcinoma models. DIST NPs met the initial design requirements. A set of fast and low-cost preparation methods was established. This study provides an experimental basis for the development of new clinical theranostic methods for hepatic carcinoma.

Salicylic acid in ginseng root alleviates skin hyperpigmentation disorders by inhibiting melanogenesis and melanosome transport.

Abnormal melanogenesis and melanosome transport can cause skin pigmentation disorders that are often treated using ginseng-based formulation. We previously found that phenolic acid compounds in ginseng root could inhibit melanin production and as a skin-whitening agents. However, mechanisms of action underlying effects of ginseng phenolic acid monomers on melanogenesis remain unclear. This study was conducted to investigate effects of salicylic acid, a main ginseng root phenolic acid component, on melanogenesis and melanosome functions in melanocytes of zebrafish and other species. Salicylic acid exhibited no cytotoxicity and reduced melanin levels and tyrosinase activity in B16F10 murine melanoma cells and normal human epidermal melanocytes regardless of prior cell stimulation with α-melanocyte stimulating hormone. Additionally, salicylic acid treatment reduced expression of melanogenic enzymes tyrosinase, tyrosinase-related protein 1 and tyrosinase-related protein 2, while reducing expression of their master transcriptional regulator, microphthalmia-associated transcription factor. Moreover, reduced phosphorylation of cAMP response-element binding protein was observed due to reduced cAMP levels resulting from salicylic acid inhibition of upstream signal regulators (adenylyl cyclase and protein kinase A). Furthermore, salicylic acid treatment suppressed expression of transport complex-associated proteins melanophilin and myosin Va in two UVB-treated melanocytic cell lines, suppressed phagocytosis of fluorescent microspheres by UVB-stimulated human keratinocytes (HaCaT), inhibited protease-activated receptor 2 activation by reducing both Ca2+ release and activation of phosphoinositide 3 kinase/AKT and mitogen-activated protein kinases and induced anti-melanogenic effects in zebrafish. Collectively, these results indicate that salicylic acid within ginseng root can inhibit melanocyte melanogenesis and melanin transport, while also suppressing keratinocyte phagocytic function.

Ubiquitin specific peptidase 33 promotes cell proliferation and reduces apoptosis through regulation of the SP1/PI3K/AKT pathway in retinoblastoma.

Ubiquitin-specific protease 33 (USP33), a deubiquitinating enzyme (DUB), has been identified to serve as a tumor suppressor or an oncogene in different cancers. However, its role in retinoblastoma (RB) remains unknown. Here, we aimed to uncover USP33 expression profile and function in RB, and disclose the underlying mechanism. USP33 levels in RB tissues and cells were determined using RT-qPCR and western blotting assays. USP33 effects on cell growth, cycle, apoptosis and tumorigenesis were studied using MTT, Edu, cycle and western blotting and in vivo assays. The results showed that USP33 expression levels were elevated in RB tissues and cells as compared with normal retinal tissues and cells. Downregulation of USP33 in RB Y79 and WERI-RB1 cells leaded to significant increases in cell apoptosis, G1 phase arrest and tumorigenesis, and reductions in cell growth and G2 and S phase arrest, as well as inhibited the activation of the PI3K/AKT signaling. SP1 overexpression abolished the roles of USP33 downregulation in modulating the activation of PI3K/AKT signaling, cell growth, apoptosis, and cell cycle. This study uncovered that USP33 promoted the progression of RB through regulation of the SP1/PI3K/AKT pathway.

Akt activation-dependent protective effect of wild ginseng adventitious root protein against UVA-induced NIH-3T3 cell damage.

Prolonged skin exposure to ultraviolet radiation can lead to development of several acute and chronic diseases, with UVA exposure considered a primary cause of dermal photodamage. We prepared a wild ginseng adventitious root extract (ARE) that could alleviate UVA irradiation-induced NIH-3T3 cell viability decline. After employing a series of purification methods to isolate main active components of ARE, adventitious root protein mixture (ARP) was identified then tested for protective effects against UVA irradiation-induced NIH-3T3 cell damage. The results showed that ARP treatment significantly reduced UVA-induced cell viability decline and confirmed that the active constituent of ARP was the protein, since proteolytic hydrolysis and heat treatment each eliminated ARP protective activity. Moreover, ARP treatment markedly inhibited UVA-induced apoptosis, cell cycle arrest and DNA fragmentation, while also significantly reversing UVA effects (elevated Bax levels, reduced Bcl-2 expression) by reducing Bax levels and increasing Bcl-2 expression. Mechanistically, ARP promoted Akt phosphorylation regardless of UVA exposure, thus confirming ARP resistance to inactivation by UVA light. Notably, in the presence of Akt inhibitor SC0227, ARP could no longer counteract UVA-induced cell viability decline and DNA fragmentation. Additionally, our results demonstrated that ARP treatment protected UVA-irradiated NIH-3T3 cells by preventing UVA-induced reduction of collagen-I expression. Taken together, these results suggest that ARP treatment of NIH-3T3 cells effectively mitigated UVA-induced cell viability decline by activating intracellular Akt to reduce UVA-induced DNA damage, leading to reduced rates of apoptosis and cell cycle arrest after UVA exposure and restoring collagen expression to normal levels.

Mitophagy and apoptosis mediated by ROS participate in AlCl3-induced MC3T3-E1 cell dysfunction.

Aluminum (Al), as a common environmental pollutant, causes osteoblast (OB) dysfunction and then leads to Al-related bone diseases (ARBD). One of the mechanisms of ARBD is oxidative stress, which leads to an increase in the production of reactive oxygen species (ROS). ROS can induce mitochondrial damage, thereby inducing mitophagy and apoptosis. But whether mitophagy and apoptosis mediated by ROS, and the role of ROS in AlCl3-induced MC3T3-E1 cell dysfunction is still unclear. In this study, MC3T3-E1 cells used 0 mM Al (control group), 2 mM Al (Al group), 5 mM N-acetyl cysteine (NAC) (NAC group), 2 mM Al and 5 mM NAC (Al + NAC group) for 24 h. We found AlCl3-induced MC3T3-E1 cell dysfunction accompanied by oxidative stress, apoptosis, and mitophagy. While NAC, a ROS scavenger treatment, restored cell function and alleviated the mitophagy and apoptosis. These results suggested that mitophagy and apoptosis mediated by ROS participate in AlCl3-induced MC3T3-E1 cell dysfunction.

SET Domain-Containing Protein 5 Enhances the Cell Stemness of Non-Small Cell Lung Cancer via the PI3K/Akt/mTOR Pathway.

BACKGROUND: SET domain-containing protein 5 (SETD5) could promote non-small cell lung cancer (NS-CLC) cell invasion, but the effect of SETD5 on NSCLC cell stemness characteristics is unknown. Thus we attempted to evaluate the effect of SETD5 on NSCLC stemness and its mechanism. METHODS: The expressions of SETD5 and stemness-related genes (SOX2, OCT4, ABCG2) were detected in NSCLC tissues by immunohistochemistry assay, qRT-PCR, and western blot. A SETD5 knockdown cell model was constructed by siRNA transfection in A549 and H1299 cells. A CCK8 assay was used to examine cell viability. A sphere-forming assay and side population cell assay were conducted to measure the cancer cell stem properties. The cells with SETD5 deletion were treated with an activator of AKT, SC79, and the protein expressions of Akt, p-Akt, mTOR, and p-mTOR were assessed. RESULTS: SETD5 and cancer stem-related genes SOX2, OCT4, and ABCG2 were co-expressed and co-localized in tumor tissues and cell lines of NSCLC. The deletion of SETD5 significantly reduced the cell viability, cancer stem properties, and activity of the PI3K/Akt/mTOR pathway, while the decreased SETD5-induced effects were partially restored with SC79 treatment. CONCLUSION: In this study, SETD5 promoted the cancer stem cell property of NSCLC through mitigating the activation of the PI3K/Akt/mTOR pathway, suggesting a candidate target role for SETD5 in NSCLC treatment.