Osteoclastogenesis Inhibitory Polyketides from the Sponge-Associated Fungus Xylaria feejeensis.

A new ten-membered macrolide (1) and a new α-pyrone derivative, (-)-annularin C (2), together with 14 known analogs (3-16) were isolated from the AcOEt extract of the fungus Xylaria feejeensis isolated from the South China Sea sponge Stylissa massa. The structures of the new compounds were elucidated by the spectroscopic analysis and by comparison with reported data. The absolute configuration was determined by the optical rotation and ECD experiments. In an in vitro test, compounds 1, 5 and 9 exhibited significant down-regulating activity of osteoclast cell differentiation at 0.5 and 1 µm. This is the first report of the fungus X. feejeensis from a marine sponge and of osteoclastogenesis inhibitory activity for the metabolites of these kinds.

Scutellaria Baicalensis Georgi Stem and Leaf Flavonoids Ameliorate the Learning and Memory Impairment in Rats Induced by Okadaic Acid.

AIM: The objective of this study is to explore the impact and underlying mechanism of Scutellaria baicalensis Georgi stem and leaf flavonoids (SSFs) on cognitive impairment caused by intracerebroventricular injection of okadaic acid (OA) in rats. METHODS: An experimental model of Alzheimer's disease (AD) was induced in rats by intracerebroventricular injection of OA, resulting in memory impairment. The Morris water maze test was employed to confirm the successful establishment of the memory impairment model. The rats that exhibited significant memory impairment were randomly divided into different groups, including a model group, three SSFs dose groups (25, 50, and 100 mg/kg), and a positive control group treated with Ginkgo biloba tablets (GLT) at a dose of 200 mg/kg. To evaluate the learning and memory abilities of the rats, the Morris water maze test was conducted. Hematoxylin-eosin (HE) staining was used to observe any morphological changes in neurons. Immunohistochemistry (IHC) was performed to measure the expression of choline acetyltransferase (ChAT) protein. Western blotting (WB) was utilized to assess the phosphorylation levels of tau protein at Ser262 and Ser396. The activities of inducible nitric oxide synthase (iNOS) and constitutive nitric oxide synthase (cNOS) were quantified using ultraviolet spectrophotometry. The levels of inflammatory factors, including interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), were measured using ELISA. RESULTS: In rats, the administration of OA via intracerebroventricular injection resulted in cognitive impairment, neuropathological changes, and alterations in protein expression and activity levels. Specifically, the protein expression of ChAT was significantly reduced (P<0.01), while the phosphorylation levels of tau protein at Ser262 and Ser396 were significantly increased (P<0.01). Moreover, iNOS activity in the hippocampus and cerebral cortex exhibited a significant increase (P<0.01), whereas cNOS activity showed a decrease (P<0.05). Furthermore, the levels of IL-1ß and TNF-α in the cerebral cortex were elevated (P<0.01), while the level of IL-6 was decreased (P<0.05). The administration of three doses of SSFs and GLT to rats exhibited varying degrees of improvement in the aforementioned pathological alterations induced by OA. CONCLUSION: SSFs demonstrated the ability to enhance cognitive function and mitigate memory deficits in rats following intracerebroventricular injection of OA. This beneficial effect may be attributed to the modulation of ChAT protein expression, tau hyperphosphorylation, NOS activity, and inflammatory cytokine levels by SSFs.

Safety, immunogenicity, and efficacy of a modified COVID-19 mRNA vaccine, SW-BIC-213, in healthy people aged 18 years and above: a phase 3 double-blinded, randomized, parallel controlled clinical trial in Lao PDR (Laos).

Background: The mRNA vaccine has demonstrated significant effectiveness in protecting against SARS-CoV-2 during the pandemic, including against severe forms of the disease caused by emerging variants. In this study, we examined safety, immunogenicity, and relative efficacy of a heterologous booster of the lipopolyplex (LPP)-based mRNA vaccine (SW-BIC-213) versus a homologous booster of an inactivated vaccine (BBIBP) in Laos. Methods: In this phase 3 clinical trial, which was randomized, parallel controlled and double-blinded, healthy adults aged 18 years and above were recruited from the Southern Savannakhet Provincial Hospital and Champhone District Hospital. The primary outcomes were safety and immunogenicity, with efficacy as an exploratory endpoint. Participants who were fully immunized with a two-dose inactivated vaccine for more than 6 months were assigned equally to either the SW-BIC-213 group (25 µg) or BBIBP group. The primary safety endpoint was to describe the safety profile of all participants in each group up to 6 months post-booster immunization. The primary immunogenic outcome was to demonstrate the superiority of the neutralizing antibody response, in terms of geometric mean titers (GMTs) of SW-BIC-213, compared with BBIBP 28 days after the booster dose. The exploratory efficacy endpoint aimed to assess the relative efficacy of SW-BIC-213 compared to BBIBP against virologically confirmed symptomatic COVID-19 over a 6-month period. The trial was registered with ClinicalTrials.gov (NCT05580159). Findings: Between October 10, 2022, and January 13, 2023, 1200 participants were assigned to SW-BIC-213 group and 1203 participants in the BBIBP group. All adverse reactions observed during the study were tolerable, transient, and resolved spontaneously. Solicited local reactions were the main adverse reactions in both the SW-BIC-213 group (43.8%) and BBIBP group (14.8%) (p < 0.001). Heterologous boosting with SW-BIC-213 induced higher live virus neutralizing antibodies to SARS-CoV-2 wildtype and BA.5 strains with GMTs reaching 750.1 and 192.9 than homologous boosting with BBIBP with GMTs of 131.5 (p < 0.001) and 47.5 (p < 0.001) on day 29. The statistical findings revealed that, following a period of 14-day to 6-month after booster vaccination, the SW-BIC-213 group exhibited a relative vaccine efficacy (VE) of 70.1% (95% CI: 34.2-86.4) against symptomatic COVID-19 when compared to the BBIBP group. Interpretation: A heterologous booster with the COVID-19 mRNA vaccine SW-BIC-213 manifests a favorable safety profile and proves highly immunogenic and efficacious in preventing symptomatic COVID-19 in individuals who have previously received two doses of inactivated vaccine. Funding: Shanghai Strategic Emerging Industries Development Special Fund, Biomedical Technology Support Special Project of Shanghai "Science and Technology Innovation Action Plan", Shanghai Municipal Science and Technology Commission.

Long non-coding RNA expression identified by microarray analysis: Candidate biomarkers in human acral lentiginous melanoma.

Melanoma is a rare but fatal form of skin cancer and acral lentiginous melanoma (ALM) is one of its most common types. Long non-coding RNA (lncRNA) has emerged as a crucial molecule in the development and progression of human cancers, and several studies have revealed that lncRNAs may be associated with the pathogenesis, progression and metastasis of melanoma. To demonstrate the association between ALM and lncRNAs, microarray analysis was performed in tumor and adjacent non-tumor tissues. A total of 4,488 lncRNAs and 3,913 mRNAs were identified to be differentially expressed in these samples. Among them, 2,211 and 2,277 lncRNAs were upregulated and downregulated in the ALM samples compared with adjacent tissues, respectively. In addition, 1,191 and 2,722 mRNAs were upregulated and downregulated, respectively. Additionally, five randomly selected lncRNAs (fold-change >2; P<0.05) were validated by reverse transcription-quantitative PCR. An lncRNA and mRNA co-expression network and competing endogenous network analysis were also constructed. In summary, the results of the present study may reveal a novel mechanism associated with the pathogenesis and malignant biological processes of ALM and indicate that lncRNAs may serve as potential targets for the treatment of ALM.

Optimizing prostate cancer accumulating model: combined PI-RADS v2 with prostate specific antigen and its derivative data.

BACKGROUND: To establish a new accumulating model to enhance the accuracy of prostate cancer (PCa) diagnosis by incorporating prostate-specific antigen (PSA) and its derivative data into the Prostate Imaging-Reporting and Data System version 2 (PI-RADS v2). METHODS: A total of 357 patients who underwent prostate biopsy between January 2014 and December 2017 were included in this study. All patients had 3.0 T multiparametric magnetic resonance imaging (MRI) and complete laboratory examinations. PI-RADS v2 was used to assess the imaging. PSA, PSA density (PSAD), the free/total PSA ratio (f/t PSA) and the Gleason score (GS) were classified into four-tiered levels, and optimal weights were pursued on these managed levels to build a PCa accumulating model. A receiver operating characteristic curve was generated. RESULTS: In all, 174 patients (48.7%) had benign prostatic hyperplasia, and 183 (51.3%) had PCa, among whom 149 (81.4%, 149/183) had clinically significant PCa. The established model 6 (PI-RADS v2 + level of PSAD + level of f/t PSA+ level of PSA) had a sensitivity and specificity of 81.4 and 84.5%, respectively, at the cut-off point of 11 in PCa diagnosis. Correspondingly, at the 12 cut-off point, the sensitivity and specificity were 87.7 and 83.0%, respectively, in diagnosing clinically significant PCa. The score of the new accumulating system was significantly different among the defined GS groups (p < 0.001). The mean values and 95% confidence intervals for GS 1-4 groups were 10.20 (9.63-10.40), 12.03 (11.19-12.87), 14.12 (13.60-14.64) and 15.44 (15.09-15.79). CONCLUSIONS: A new PCa accumulating model may be useful in improving the accuracy of the primary diagnosis of PCa and helpful in the clinical decision to perform a biopsy when MRI results are negative.

Atorvastatin downregulates HSP22 expression in an atherosclerotic model in vitro and in vivo.

One of the pathological functions of heat shock protein 22 (HSP22) is the association with inflammatory diseases and atherosclerosis. However, the effects of a high­fat diet (HFD) or oxidized low­density lipoprotein (ox­LDL) combined with atorvastatin (ATV) on HSP22 expression are entirely unknown. The present study investigated the effects of ATV on HSP22 expression in HFD­induced atherosclerotic apolipoprotein E­deficient (ApoE­/­) mice and in ox­LDL­induced human umbilical vein endothelial cells (HUVECs). Furthermore, the influence of HSP22­knockdown on the HFD- or ox­LDL­induced atherosclerotic model was also examined. It was found that HFD or ox­LDL treatment significantly increased HSP22 expression in the serum and aorta, accompanied by decreased phosphorylated (p)­endothelial nitric oxide synthase (p-eNOS) activity and activated p38 mitogen­activated protein kinase (MAPK). However, these effects were suppressed by treatment with ATV. Furthermore, HSP22-knockdown showed reduced ox­LDL­induced lesions, evidenced by increased p­eNOS activity and inactivated p38 MAPK, while suppression of cell proliferation inhibition and cell cycle arrest were also observed. Taken together, the results of this study suggest that HFD or ox­LDL increased the expression of HSP22 and p­p38 MAPK, and decreased the p­eNOS activity in vitro and in vivo, and ATV could reduce the effects by downregulating HSP22 expression.

Role of heat shock protein 22 in the protective effect of geranylgeranylacetone in response to oxidized-LDL.

OBJECTIVE: The aim was to investigate the role and potential mechanism of geranylgeranylacetone (GGA) in the development of atherosclerosis, and to explore the role of heat shock protein 22 (HSP22) in mediating GGA effect. METHODS: Human coronary artery endothelial cell (HCAEC) was used for in vitro study. RNA interference was applied to suppress HSP22 in the cells. Cellular apoptosis and intracellular level of reactive oxygen species (ROS) were detected by flow cytometer, and proteins of HSP22, NF-κB, eNOS, and ICAM-1 were assessed by immunoblotting. HSP22-/-//ApoE-/-, and HSP22+/+//ApoE-/- mice were used to investigate the effect of GGA in the animal model of atherosclerosis. Atherosclerotic lesion of the mice aortas was evaluated by Oil Red O staining and H&E staining. RESULTS: GGA significantly inhibited HCAEC apoptosis in response to oxidized-LDL (ox-LDL), but stimulated HSP22 synthesis in the cells. Transfection of HSP22-siRNA in the cells resulted in complete blockage of the GGA effect on apoptosis. GGA also significantly inhibited ROS, NF-κB, and ICAM-1 in the cells transfected control siRNA, but not in the cells transfected with HSP22-siRNA. Atherosclerotic plaque in the aorta was significantly less in the wild type (WT) animals treated with GGA as stained either by Oil Red O or by H&E staining, but not in the HSP22-KO mice. GGA significantly inhibited expression of NF-κB and ICAM-1 in the WT mice, but not in the HSP22-KO mice. CONCLUSION: GGA-induced HSP22, and inhibited ox-LDL-induced apoptosis as well as expression of NF-κB and ICAM-1 in the HCAECs. GGA also attenuated formation of atherosclerotic plaques in mice aorta. Suppression of HSP22 by siRNA resulted in blockage of the GGA inhibition on apoptosis or stimulation on NF-κB and ICAM-1. These findings suggested that GGA protects endothelial cells from injury in response to ox-LDL and block atherosclerotic development in mice aorta through induction of HSP22.

Improving the detection rate of prostate cancer in the gray zone of PI-RADS v2 and serum tPSA by using prostate-specific antigen-age volume.

To improve the detection of prostate cancer (PCa) by combining the Prostate Imaging Reporting and Data System version 2 (PI-RADS v2) and prostate-specific antigen-age volume (PSA-AV), especially among those in gray zone with PI-RADS v2 score 3 or serum total prostate-specific antigen (tPSA) 4 to 10 ng/mL.The 357 patients were enrolled in this study. The PI-RADS v2 scoring system was used to represent characteristics on multiparametric magnetic resonance imaging (mpMRI). PI-RADS v2 score 3 or tPSA 4 to 10 ng/mL were defined as the gray zone in detecting PCa. The formula equates to the patient age multiplied by the prostate volume, which is divided by the tPSA level. Univariate and multivariate analyses were done to ascertain significant predictors of prostate cancer.In all, 174 (48.7%) were benign prostatic hyperplasia, 183 (51.3%) had PCa. The results showed that PI-RADS v2, tPSA, and PSA-AV were significant independent predictors of prostate cancer. PI-RADS v2 score ≥4 could detect PCa with rate of 82.1%. Serum tPSA ≥10 ng/mL could detect PCa with rate of 66.2%, PSA density (PSAD) ≥0.15 ng/mL/cc with rate of 62.8%, and PSA-AV ≤250 with rate of 83.5%. Combining with PSA-AV ≤250, patients those with tPSA 4 to 10 ng/mL could improve the detection from 36.0% up to 81%, those with PI-RADS v2 score 3 from 28.6% up to 60.0%.PI-RADS v2 and PSA-AV are faithful variables for detecting PCa. And for patients, those in gray zones of PI-RADS v2 and tPSA, PSA-AV can improve detection rate of PCa.

Advances in extraction and analysis of phenolic compounds from plant materials.

Phenolic compounds, the most abundant secondary metabolites in plants, have received more and more attention in recent years because of their distinct bioactivities. This review summarizes different types of phenolic compounds and their extraction and analytical methods used in the recent reports, involving 59 phenolic compounds from 52 kinds of plants. The extraction methods include solid-liquid extraction, ultrasound-assisted extractions, microwave-assisted extractions, supercritical fluid extraction, and other methods. The analysis methods include spectrophotometry, gas chromatography, liquid chromatography, thin-layer chromatography, capillary electrophoresis, and near-infrared spectroscopy. After illustrating the specific conditions of the analytical methods, the advantages and disadvantages of each method are also summarized, pointing out their respective suitability. This review provides valuable reference for identification and/or quantification of phenolic compounds from natural products.

Significance of TFF3 protein and Her-2/neu status in patients with gastric adenocarcinoma.

Increased knowledge of molecular alterations involved in gastric carcinogenesis has provided useful information for diagnosis and prediction. In this study, we investigated the clinicopathological significance of TFF3 expression and Her-2/neu status in gastric adenocarcinoma and explored the correlation between TFF3 expression and Her-2/neu status. A hundred and twenty-six (126) patients having undergone curative gastrectomy were enrolled. Immunohistochemistry for TFF3 was performed on tumor tissues and non-neoplastic resection margins. Her-2/neu status was assessed by immunohistochemical staining and fluorescence in situ hybridization (FISH) on tumor tissues. As a result, TFF3 expression and Her-2/neu positivity were detected in 46.8% and 11.9% of the cases, respectively. Patients with negative TFF3 exhibited longer survival than the positive group (P=0.0142), while patients with positive Her-2/neu only showed a tendency toward longer overall survival (P>0.05). However, Her-2/neu was significantly associated with improved disease-free survival (P=0.0234). Multivariate analysis demonstrated Her-2/neu and TFF3 to be independent prognostic indicators of recurrence, and a significantly poor prognosis for expression of TFF3 in patients with Her-2/neu negative tumors. TFF3 is an independent indicator for overall survival in gastric cancer, while Her-2/neu, as a marker of long time survival prediction, seems to be limited.

Valproic acid improves outcome after rodent spinal cord injury: potential roles of histone deacetylase inhibition.

Histone deacetylases (HDAC) inhibitors including valproic acid (VPA) have emerged as a promising therapeutic intervention in neurological disorders. We investigated the levels of acetylated histone and the therapeutic potential of VPA in a rat model of spinal cord injury (SCI). At different time points (12 h, 1 day, 3 days, 1 week and 2 weeks) after SCI or sham surgery, the spinal cords were collected to evaluate the levels of acetylated histone H3 (Ac-H3) and H4 (Ac-H4). VPA or vehicle was injected for 1 week starting immediately after SCI and histone acetylation, apoptosis, as well as neurobehavior were observed to test the effect of VPA. The levels of Ac-H3 and Ac-H4 in the injured spinal cord started to significantly decrease as early as day 1, and remained below those in uninjured controls for at least 2 weeks after SCI. Injection of VPA markedly prevented the reductions of Ac-H3 and Ac-H4, upregulated the expressions of Hsp70 and Bcl-2, reduced apoptosis and finally promoted locomotion recovery. Our data demonstrated that SCI led to marked reduction in histone acetylation; VPA was neuroprotective in the SCI model, and the mechanism may involve HDAC inhibition and protective proteins induction.