Olfactory Dysfunction as a Marker for Cognitive Impairment in General Paresis of the Insane: A Clinical Study.

BACKGROUND General paresis of the insane (GPI) is characterized by cognitive impairment, neuropsychiatric symptoms, and brain structural abnormalities, mimicking many neuropsychiatric diseases. Olfactory dysfunction has been linked to cognitive decline and neuropsychiatric symptoms in numerous neuropsychiatric diseases. Nevertheless, it remains unclear whether patients with GPI experience olfactory dysfunction and whether olfactory dysfunction is associated with their clinical manifestations. MATERIAL AND METHODS Forty patients with GPI and 37 healthy controls (HCs) underwent the "Sniffin Sticks" test battery, Mini-Mental State Examination, and Neuropsychiatric Inventory to measure olfactory function, cognitive function, and neuropsychiatric symptoms, respectively. Brain structural abnormalities were evaluated using visual assessment scales including the medial temporal lobe atrophy (MTA) visual rating scale and Fazekas scale. RESULTS Compared with HCs, patients with GPI exhibited significant olfactory dysfunction, as indicated by deficits in the odor threshold (OT) (P=0.001), odor discrimination (OD) (P<0.001), and odor identification (OI) (P<0.001). In patients with GPI, the OI was positively correlated with cognitive function (r=0.57, P<0.001), but no significant correlation was found between olfactory function and neuropsychiatric symptoms, blood, or cerebrospinal fluid biomarkers (rapid plasma reagin circle card test and Treponema pallidum particle agglutination test), or brain structural abnormalities (MTA and Fazekas scale scores). Mediation analysis indicated that the impaired OI in patients with GPI was mediated by cognitive impairment and impaired OT respectively. CONCLUSIONS Patients with GPI exhibited overall olfactory dysfunction. OI is correlated with cognitive function and the impaired OI is mediated by cognitive impairment in patients with GPI. Thus, OI may serve as a marker for reflecting cognitive function in patients with GPI.

Disrupted dynamic functional connectivity of hippocampal subregions mediated the slowed information processing speed in late-life depression.

BACKGROUND: Slowed information processing speed (IPS) is the core contributor to cognitive impairment in patients with late-life depression (LLD). The hippocampus is an important link between depression and dementia, and it may be involved in IPS slowing in LLD. However, the relationship between a slowed IPS and the dynamic activity and connectivity of hippocampal subregions in patients with LLD remains unclear. METHODS: One hundred thirty-four patients with LLD and 89 healthy controls were recruited. Sliding-window analysis was used to assess whole-brain dynamic functional connectivity (dFC), dynamic fractional amplitude of low-frequency fluctuations (dfALFF) and dynamic regional homogeneity (dReHo) for each hippocampal subregion seed. RESULTS: Cognitive impairment (global cognition, verbal memory, language, visual-spatial skill, executive function and working memory) in patients with LLD was mediated by their slowed IPS. Compared with the controls, patients with LLD exhibited decreased dFC between various hippocampal subregions and the frontal cortex and decreased dReho in the left rostral hippocampus. Additionally, most of the dFCs were negatively associated with the severity of depressive symptoms and were positively associated with various domains of cognitive function. Moreover, the dFC between the left rostral hippocampus and middle frontal gyrus exhibited a partial mediation effect on the relationships between the scores of depressive symptoms and IPS. CONCLUSIONS: Patients with LLD exhibited decreased dFC between the hippocampus and frontal cortex, and the decreased dFC between the left rostral hippocampus and right middle frontal gyrus was involved in the underlying neural substrate of the slowed IPS.

CircRNA circ_POLA2 overexpression suppresses cell apoptosis by downregulating PTEN in glioblastoma.

The oncogenic role of circ_POLA2 has only been explored in lung cancer, whereas the role of which in glioblastoma (GBM) is unclear. Our research explored the involvement of circ_POLA2 in GBM. Circ_POLA2 and phosphatasetensinhomolog (PTEN) mRNA levels in GBM and paired nontumor tissues collected from 58 GBM patients were analyzed by real-time quantitative PCR (RT-qPCR). Circ_POLA2 and PTEN were overexpressed in GBM cells to study their interaction by RT-qPCR and Western blot. The roles of circ_POLA2 and PTEN in regulating GBM cell apoptosis were explored using cell apoptosis assay. Our data revealed that circ_POLA2 was upregulated and PTEN was downregulated in GBM. PTEN showed an inverse correlation to circ_POLA2 across GBM tissues, In GBM cells, circ_POLA2 overexpression decreased PTEN accumulation, but PTEN overexpression failed to significantly affect circ_POLA2 expression. Moreover, PTEN reduced the inhibitory effects of circ_POLA2 on GBM cell apoptosis. Circ_POLA2 is overexpressed in MCL and might promote GBM cell apoptosis through downregulating PTEN.

Lower Dorsal Lateral Prefrontal Cortex Functional Connectivity in Late-Life Depression With Suicidal Ideation.

OBJECTIVE: The dorsal lateral prefrontal cortex (DLPFC) has been identified as a neuromodulation target for alleviating suicidal ideation. Dysfunctional DLPFC has been implicated in suicidality in depression. This study aimed to investigate the functional connectivity (FC) of the DLPFC in late-life depression (LLD) with suicidal ideation. METHODS: Resting-state functional magnetic resonance imaging (fMRI) data from 32 LLD patients with suicidal ideation (LLD-S), 41 LLD patients without suicidal ideation (LLD-NS), and 54 healthy older adults (HOA) were analyzed using DLPFC seed-based FC analyses. Group differences in FC were examined, and machine learning was applied to explore the potential of DLPFC-FC for classifying LLD-S from LLD-NS. RESULTS: Abnormal DLPFC-FC patterns were observed in LLD-S, characterized by lower connectivity with the angular gyrus, precuneus, and superior frontal gyrus compared to LLD-NS and healthy controls. A classification model based on the identified DLPFC-FC achieved an accuracy of 75%. CONCLUSION: The lower FC of DLPFC networks may contribute to the neurobiological mechanism of suicidal ideation in late-life depression. These findings may facilitate suicide prevention for LLD by providing potential neuroimaging markers and network-based neuromodulation targets. However, further confirmation with larger sample sizes and experimental designs is warranted.

Recovery of polyhydroxyalkanoates (PHAs) polymers from a mixed microbial culture through combined ultrasonic disruption and alkaline digestion.

PHAs are a form of cellular storage polymers with diverse structural and material properties, and their biodegradable and renewable nature makes them a potential green alternative to fossil fuel-based plastics. PHAs are obtained through extraction via various mechanical, physical and chemical processes after their intracellular synthesis. Most studies have until now focused on pure cultures, while information on mixed microbial cultures (MMC) remains limited. In this study, ultrasonic (US) disruption and alkaline digestion by NaOH were applied individually and in combination to obtain PHAs products from an acclimated MMC using phenol as the carbon source. Various parameters were tested, including ultrasonic sound energy density, NaOH concentration, treatment time and temperature, and biomass density. US alone caused limited cell lysis and resulted in high energy consumption and low efficiency. NaOH of 0.05-0.2 M was more efficient in cell disruption, but led to PHAs degradation under elevated temperature and prolonged treatment. Combining US and NaOH significantly improved the overall process efficiency, which could reduce energy consumption by 2/3rds with only minimal PHAs degradation. The most significant factor was identified to be NaOH dosage and treatment time, with US sound energy density playing a minor role. Under the semi-optimized condition (0.2 M NaOH, 1300 W L-1, 10 min), over 70% recovery and 80% purity were achieved from a 3 g L-1 MMC slurry of approximately 50% PHAs fraction. The material and thermal properties of the products were analyzed, and the polymers obtained from US + NaOH treatments showed comparable or higher molecular weight to previously reported results. The products also exhibited good thermal stability and rheological properties, compared to the commercial standard. In conclusion, the combined US and NaOH method has the potential in real application as an efficient process to obtain high quality PHAs from MMC, and cost-effectiveness can be further optimized.

Deficit irrigation combined with nitrogen application in the early growth stage of sugar beet increases the production capacity of canopy and avoids yield loss.

BACKGROUND: Properly reduced irrigation combined with nitrogen (N) application can be used to improve crop water use efficiency (WUE) in arid regions, but its effect on sugar beet is unknown at present. A two-year field experiment was conducted to evaluate the effects of N application (N0, 0; N1, 150; N2, 225 kg N ha-1 ) on the canopy production capacity (CPC), yield and WUE of sugar beet under normal irrigation (W1, 70% of field capacity (FC)) and deficit irrigation (DI) (W2, 50% FC) in the early growth stage (EGS). RESULTS: The results showed that the W2 treatment reduced the CPC by reducing gas exchange, leaf area index (LAI) and chlorophyll content (SPAD value) of sugar beet leaves compared to the W1 treatment. However, DI combined with N application increased these parameters. Specifically, N application increased the net photosynthetic rate by 40.7% by increased gas exchange, SPAD and LAI compared to the N0 treatment. In addition, N application increased WUE by 12.5% by increasing thickness of upper surface, stomatal aperture and cross-sectional area of petiole. This ultimately led to a significant increase in taproot yield (TY; 19.7%) and sugar yield (SY; 57.6%). Although the TY of the N2 treatment was higher than that of the N1 treatment, the SY and WUE did not increase significantly and the harvest index decreased significantly by 9.3%. CONCLUSION: DI combined with 150 kg N ha-1 in the EGS of sugar beet increases the WUE in arid areas while avoiding yield loss by improving the CPC. © 2023 Society of Chemical Industry.

LDHA promotes osteoblast differentiation through histone lactylation.

Osteoblast cells tend to metabolize glucose to lactate via aerobic glycolysis during osteogenic differentiation. However, the function of lactate in this process is still elusive. As a newly discovered protein posttranslational modification, lactate-derived histone lactylation has been found to play important roles in gene regulation and have profound effects on diverse biological processes. Here, we found that the expression of lactate dehydrogenase A (LDHA), intracellular lactate, and histone lactylation levels were all gradually increased during osteogenic differentiation. Knockdown of LDHA impaired the formation of mineralized nodules and ALP activity. RNA-sequencing and subsequent validation experiments showed that JunB expression was decreased in LDHA knockdown cells. Mechanistically, knockdown of LDHA decreased histone lactylation mark enrichment on JunB promoter, and exogenous lactate treatment rescued this effect. Our study revealed a non-canonical function of lactate during osteogenic differentiation.

The protective role of glucocerebrosidase/ceramide in rheumatoid arthritis.

OBJECTIVE: To clarify the role of glucocerebrosidase (GBA) and Ceramide (Cer) in rheumatoid arthritis (RA). METHODS: GBA-expressing lentivirus were constructed and injected into collagen-induced arthritis (CIA) mice, and compared with CIA mice injected with empty vector. The severity of arthritis and inflammatory mediators were evaluated. Fibroblast-like synoviocytes (FLS) from RA patients were transfected with GBA-expressing lentivirus, or pretreated with C6-Cer. The migration and invasion of FLS, the production of inflammatory cytokines, and the relevant signaling pathways were assessed. RESULTS: In CIA mice, GBA markedly improved arthritis compared to that in the CIA mice, with increased content of proteoglycan and integral cartilage surfaces and tidemarks. The circulating inflammatory mediators, including interleukin (IL)-1ß, IL-6, IL-18, and matrix metalloproteinase (MMP)-1, were significantly reduced in CIA mice with GBA overexpression compared to those in CIA mice. GBA and C6-Cer treatment inhibited migration and invasion of FLS, and suppressed production of inflammatory cytokines and activation of the MAPK pathways. CONCLUSION: GBA/Cer exhibited a protective role in CIA mice and RA FLS. These results highlight the potential of targeting GBA/Cer as a therapeutic strategy in RA and warrant further investigation.

Treatment of primary cardiac angiosarcoma in a 35 weeks pregnant woman.

BACKGROUND: Cardiac angiosarcoma is a rare but highly malignant cardiac tumor. It is characterized by poor prognosis, and current treatment approaches are not effective. CASE PRESENTATION: A 37-year-old female with 35 weeks pregnancy experienced chest tightness and shortness of breath for 1 month. She was diagnosed with primary cardiac angiosarcoma. Delivery of fetus was performed early to treat the mother. The patient underwent resection of the tumor then she was treated with chemotherapy. However, the tumor recurred 11 months after surgery. CONCLUSION: Angiosarcoma is a highly malignant tumor explaining recurrence of the tumor recurred after surgery. Cardiac angiosarcoma should be treated through a comprehensive treatment plan, comprising surgery, radiotherapy, and chemotherapy approaches.

Association of urate deposition shown by ultrasound and frequent gout attacks.

BACKGROUND: There are few data demonstrating the association between urate burden assessed by ultrasound (US) and gout flares. The aim of this study was to determine the association of urate deposition shown by US and frequent gout attacks. MATERIALS AND METHODS: Patients with gout were divided into two groups according to the frequency of gout attacks in the previous 12 months: frequent (>2 attacks) and infrequent (0-2 attacks). Urate deposition in the hands, knees, and feet was assessed by US. RESULTS: Overall, 106 patients were enrolled in this study, of whom 32 (30.1%) had had frequent gout attacks (>2 attacks) in the previous 12 months (the average number of gout attacks was 4.7, range 3-12). Those with frequent gout attacks had significantly longer gout duration, a higher serum urate level, and more urate deposition shown by US than those with infrequent gout attacks (P < 0.05). In both univariate and logistic regression analyses, frequent gout attacks were correlated with gout duration, serum urate level, and urate deposition as shown by US (P < 0.05). CONCLUSION: These findings indicate that urate deposition shown by US is independently associated with frequent gout attacks. Special attention should be given to the prevention of flares in patients with an initially high urate burden as assessed by US.

The Clinical Significance of Dickkopf Wnt Signaling Pathway Inhibitor Gene Family in Head and Neck Squamous Cell Carcinoma.

BACKGROUND Dickkopf Wnt signaling pathway inhibitor (DKK) gene family, which is known to inhibit the Wnt regulation process, is widely found in cancers. However, the roles and functions of specific family members in head and neck squamous cell carcinoma (HNSCC) are still unclear. MATERIAL AND METHODS Online bioinformatics tools (Oncomine, UALCAN, Kaplan-Meier plotter, GEPIA, Metascape, and STRING) were used to analyze the relationships between distinct DKKs and HNSCC. The transcriptome expression, clinical association, functions, pathways, and protein-protein interaction networks of DKKs in HNSCC were explored. RESULTS The mRNA expression of DKK1, DKK3, and Dickkopf-like acrosomal protein 1 (DKKL1) in HNSCC was significantly higher than in normal tissues, while that of DKK4 was lower. The mRNA expression of DKK1, DKK3, and DKKL1 was elevated in higher-grade HNSCC. The mRNA expression of DKK1 and DKK3 was elevated in human papillomavirus (HPV)-negative HNSCC, while DKKL1 had a higher mRNA expression in HPV-positive HNSCC. In addition, DKK1 was significantly associated with unfavorable overall survival in HNSCC patients. DKK3 was more likely to be a negative factor for the 5-year survival rate, while DKK4 was the opposite. DKK1 function was mainly enriched in GTPase-mediated signal transduction. Porcupine O-acyltransferase, a key regulator of the Wnt signaling pathway, was also associated with DKK1 in the protein-protein interaction network. CONCLUSIONS With regard to improving the therapeutic strategies of HNSCC in the future, DKK1 could be an unfavorable prognostic biomarker. DKK3, DKK4, and DKKL1 might be potential biomarkers for HNSCC.

A SERS-based lateral flow assay for the stroke biomarker S100-ß.

A surface-enhanced Raman scattering (SERS)-based lateral flow assay (LFA) is described for the quantitative analysis of the proteinic stroke biomarker S100-ß that has to be detected at very low concentration levels. The Raman reporter 5,5'-dithiobis-2-nitrobenzoic acid (DTNB) on gold nanoparticles (GNPs) was employed as the SERS tags. They are shown to perform much better than bare GNPs in LF strips. The S100-ß protein can be detected by this method with very low detection limits by monitoring the intensity of the characteristic Raman peak of the S100-ß protein-conjugated GNPs at 1332 cm-1. Under optimized conditions, the assay works in the 1 pg·mL-1 to 40 ng·mL-1 S100-ß concentration range, and the detection limit is as low as 0.14 pg·mL-1. This is lower by a factor of 3 compared to colorimetric or fluorimetric methods. Graphical abstract Schematic illustration of the configuration (A) and the principle of the SERS-based lateral flow assay for quantification of S100-ß (B).

Rhizobia promote the growth of rice shoots by targeting cell signaling, division and expansion.

KEY MESSAGE: The growth-promotion of rice seedling following inoculation with Sinorhizobium meliloti 1021 was a cumulative outcome of elevated expression of genes that function in accelerating cell division and enhancing cell expansion. Various endophytic rhizobacteria promote the growth of cereal crops. To achieve a better understanding of the cellular and molecular bases of beneficial cereal-rhizobia interactions, we performed computer-assisted microscopy and transcriptomic analyses of rice seedling shoots (Oryza sativa) during early stages of endophytic colonization by the plant growth-promoting Sinorhizobium meliloti 1021. Phenotypic analyses revealed that plants inoculated with live rhizobia had increased shoot height and dry weight compared to control plants inoculated with heat-killed cells of the same microbe. At 6 days after inoculation (DAI) with live cells, the fourth-leaf sheaths showed significant cytological differences including their enlargement of parenchyma cells and reduction in shape complexity. Transcriptomic analysis of shoots identified 2,414 differentially-expressed genes (DEGs) at 1, 2, 5 and 8 DAI: 195, 1390, 1025 and 533, respectively. Among these, 46 DEGs encoding cell-cycle functions were up-regulated at least 3 days before the rhizobia ascended from the roots to the shoots, suggesting that rhizobia are engaged in long-distance signaling events during early stages of this plant-microbe interaction. DEGs involved in phytohormone production, photosynthetic efficiency, carbohydrate metabolism, cell division and wall expansion were significantly elevated at 5 and 8 DAI, consistent with the observed phenotypic changes in rice cell morphology and shoot growth-promotion. Correlation analysis identified 104 height-related DEGs and 120 dry-weight-related DEGs that represent known quantitative-trait loci for seedling vigor and increased plant height. These findings provide multiple evidences of plant-microbe interplay that give insight into the growth-promotion processes associated with this rhizobia-rice beneficial association.

A Novel NAC-Type Transcription Factor, NAC87, from Oilseed Rape Modulates Reactive Oxygen Species Accumulation and Cell Death.

Reactive oxygen species (ROS) are thought to play a dual role in plants by functioning as signaling molecules and toxic by-products of aerobic metabolism. The hypersensitive response (HR) is a typical feature of immune responses in plants and also a type of programmed cell death (PCD). How these two processes are regulated in oilseed rape (Brassica napus L.) at the transcriptional level remains largely unknown. In this study, we report that an oilseed rape (Brassica napus L.) NAM-ATAF-CUC (NAC)-type transcription factor NAC87 modulates ROS and cell death accompanied by typical changes at the morphological and cellular levels. The BnaNAC87 gene was induced by multiple stress and hormone treatments and was highly expressed in senescent leaves by quantitative reverse transcription-PCR (qRT-PCR). BnaNAC87 is located in nuclei and has transcriptional activation activity. Expression of BnaNAC87 promoted significant ROS production, cell death as well as death of protoplasts, as indicated by histological staining. In addition, putative downstream target genes of NAC87 were identified through both qRT-PCR and dual luciferase reporter assays. We found that genes implicated in ROS generation (RbohB), cell death (VPE1a, ZEN1), leaf senescence (WRKY6, ZAT12) and defense (PR2, PR5 and HIN1) were significantly induced. Through an electrophoretic mobility shift assay (EMSA), we confirmed that BnaNAC87 directly binds to the NACRS-containing promoter fragments of ZEN1, ZAT12, HIN1 and PR5 genes. From these results, we conclude that oilseed rape NAC87 is a novel NAC transcription factor that acts as a positive regulator of ROS metabolism and cell death.

Adoptive Regulatory T-cell Therapy Attenuates Perihematomal Inflammation in a Mouse Model of Experimental Intracerebral Hemorrhage.

The CD4+CD25+ regulatory T cells (Tregs), an innate immunomodulator, suppress cerebral inflammation and maintain immune homeostasis in multiple central nervous system injury, but its role in intracerebral hemorrhage (ICH) has not been fully characterized. This study investigated the effect of Tregs on brain injury using the mouse ICH model, which is established by autologous blood infusion. The results showed that tail intravenous injection of Tregs significantly reduced brain water content and Evans blue dye extravasation of perihematoma at day (1, 3 and 7), and improved short- and long-term neurological deficits following ICH in mouse model. Tregs treatment reduced the content of pro-inflammatory cytokines interleukin (IL)-1ß, IL-6, tumor necrosis factor-α, and malondialdehyde, while increasing the superoxide dismutase (SOD) enzymatic activity at day (1, 3 and 7) following ICH. Furthermore, Tregs treatment obviously reduced the number of NF-κB+, IL-6+, TUNEL+ and active caspase-3+ cells at day 3 after ICH. These results indicate that adoptive transfer of Tregs may provide neuroprotection following ICH in mouse models.

Reversal of Beta-Amyloid-Induced Neurotoxicity in PC12 Cells by Curcumin, the Important Role of ROS-Mediated Signaling and ERK Pathway.

Progressive accumulation of beta-amyloid (Aß) will form the senile plaques and cause oxidative damage and neuronal cell death, which was accepted as the major pathological mechanism to the Alzheimer's disease (AD). Hence, inhibition of Aß-induced oxidative damage and neuronal cell apoptosis by agents with potential antioxidant properties represents one of the most effective strategies in combating human AD. Curcumin (Cur) a natural extraction from curcuma longa has potential of pharmacological efficacy, including the benefit to antagonize Aß-induced neurotoxicity. However, the molecular mechanism remains elusive. The present study evaluated the protective effect of Cur against Aß-induced cytotoxicity and apoptosis in PC12 cells and investigated the underlying mechanism. The results showed that Cur markedly reduced Aß-induced cytotoxicity by inhibition of mitochondria-mediated apoptosis through regulation of Bcl-2 family. The PARP cleavage, caspases activation, and ROS-mediated DNA damage induced by Aß were all significantly blocked by Cur. Moreover, regulation of p38 MAPK and AKT pathways both contributed to this protective potency. Our findings suggested that Cur could effectively suppress Aß-induced cytotoxicity and apoptosis by inhibition of ROS-mediated oxidative damage and regulation of ERK pathway, which validated its therapeutic potential in chemoprevention and chemotherapy of Aß-induced neurotoxicity.

Carnosine Attenuates Brain Oxidative Stress and Apoptosis After Intracerebral Hemorrhage in Rats.

Carnosine, an endogenous dipeptide (ß-alanyl-L-histidine), exerts multiple neuroprotective properties, but its role in intracerebral hemorrhage (ICH) remains unclear. This study investigates the effect of Carnosine on brain injury using the rat ICH model, which is established by type IV collagenase caudatum infusion. The results indicate that intraperitoneal administration of Carnosine (1000 mg/kg) significantly attenuates brain edema, blood-brain barrier (BBB) disruption, oxidative stress, microglia activation and neuronal apoptosis of perihematoma at 72 h following ICH in rats models, as convinced by preventing the disruption of tight junction protein ZO-1, occludin and claudin-5, followed by the decrease of ROS, MDA, 3-NT, 8-OHDG level and the increase of GSH-Px and SOD activity, then followed by the decline of Iba-1, ED-1, active caspase-3 and TUNEL positive cells and the decrease of IL-1ß, IL-6, TNF-α, active caspase-3 and cytochrome c level. Our results suggest that Carnosine may provide neuroprotective effect after experimental ICH in rat models.

Enhanced Neuroprotection of Minimally Invasive Surgery Joint Local Cooling Lavage against ICH-induced Inflammation Injury and Apoptosis in Rats.

Hypothermia treatment is one of the neuroprotective strategies that improve neurological outcomes effectively after brain damage. Minimally invasive surgery (MIS) has been an important treatment of intracerebral hemorrhage (ICH). Herein, we evaluated the neuroprotective effect and mechanism of MIS joint local cooling lavage (LCL) treatment on ICH via detecting the inflammatory responses, oxidative injury, and neuronal apoptosis around the hematoma cavity in rats. ICH model was established by type IV collagenase caudatum infusion. The rats were treated with MIS 6 h after injection, and then were lavaged by normothermic (37 °C) and hypothermic (33 °C) normal saline in brain separately. The results indicated that MIS joint LCL treatment showed enhanced therapeutic effects against ICH-induced inflammation injury and apoptosis in rats, as convinced by the decline of TUNEL-positive cells, followed by the decrease of IL-1ß and LDH and increase of IL-10 and SOD. This study demonstrated that the strategy of using MIS joint LCL may achieve enhanced neuroprotection against ICH-induced inflammation injury and apoptosis in rats with potential clinic application.

Induction of S-Phase Arrest in Human Glioma Cells by Selenocysteine, a Natural Selenium-Containing Agent Via Triggering Reactive Oxygen Species-Mediated DNA Damage and Modulating MAPKs and AKT Pathways.

Selenocysteine (SeC) a natural available selenoamino acid exhibits novel anticancer activities against human cancer cell lines. However, the growth inhibitory effect and mechanism of SeC in human glioma cells remain unclear. The present study reveals that SeC time- and dose-dependently inhibited U251 and U87 human glioma cells growth by induction of S-phase cell cycle arrest, followed by the marked decrease of cyclin A. SeC-induced S-phase arrest was achieved by inducing DNA damage through triggering generation of reactive oxygen species (ROS) and superoxide anion, with concomitant increase of TUNEL-positive cells and induction of p21waf1/Cip1 and p53. SeC treatment also caused the activation of p38MAPK, JNK and ERK, and inactivation of AKT. Four inhibitors of MAPKs and AKT pathways further confirmed their roles in SeC-induced S-phase arrest in human glioma cells. Our findings advance the understanding on the molecular mechanisms of SeC in human glioma management.

Caudatin induces caspase-dependent apoptosis in human glioma cells with involvement of mitochondrial dysfunction and reactive oxygen species generation.

Caudatin as one species of C-21 steroidal from Cynanchum bungei decne displays potential anticancer activity. However, the underlying mechanisms remain elusive. In the present study, the growth suppressive effect and mechanism of caudatin on human glioma U251 and U87 cells were evaluated in vitro. The results indicated that caudatin significantly inhibited U251 and U87 cell growth in both a time- and dose-dependent manner. Flow cytometry analysis revealed that caudatin-induced cell growth inhibition was achieved by induction of cell apoptosis, as convinced by the increase of Sub-G1 peak, PARP cleavage and activation of caspase-3, caspase-7 and caspase-9. Caudatin treatment also resulted in mitochondrial dysfunction which correlated with an imbalance of Bcl-2 family members. Further investigation revealed that caudatin triggered U251 cell apoptosis by inducing reactive oxygen species (ROS) generation through disturbing the redox homeostasis. Moreover, pretreatment of caspase inhibitors apparently weakens caudatin-induced cell killing, PARP cleavage and caspase activation and eventually reverses caudatin-mediated apoptosis. Importantly, caudatin significantly inhibited U251 tumour xenografts in vivo through induction of cell apoptosis involving the inhibition of cell proliferation and angiogenesis, which further validate its value in combating human glioma in vivo. Taken together, the results described above all suggest that caudatin inhibited human glioma cell growth by induction of caspase-dependent apoptosis with involvement of mitochondrial dysfunction and ROS generation.