Comparison between sub-chronic and chronic sleep deprivation-induced behavioral and neuroimmunological abnormalities in mice: Focusing on glial cell phenotype polarization.

BACKGROUND: Sleep disorders, depression, and Alzheimer's disease (AD) are extensively reported as comorbidity. Although neuroinflammation triggered by microglial phenotype M1 activation, leading to neurotransmitter dysfunction and Aß aggregation, is considered as the leading cause of depression and AD, whether and how sub-chronic or chronic sleep deprivation (SD) contribute to the onset and development of these diseases remains unclear. METHODS: Memory and depression-like behaviors were evaluated in both SDs, and then circadian markers, glial cell phenotype polarization, cytokines, depression-related neurotransmitters, and AD-related gene/protein expressions were measured by qRT-PCR, enzyme-linked immunosorbent assay, high-performance liquid chromatography, and western-blotting respectively. RESULTS: Both SDs induced give-up behavior and anhedonia and increased circadian marker period circadian regulator 2 (PER2) expression, which were much worse in chronic than in the sub-chronic SD group, while brain and muscle ARNT-like protein-1 only decreased in the chronic-SD. Furthermore, increased microglial M1 and astrocyte A1 expression and proinflammatory cytokines, interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α was observed in both SDs, which were more significant in chronic SD. Similarly, decreased norepinephrine and 5-hydroxytryptamine/5-hydroxyindoleacetic acid ratio were more significant, which corresponds to the worse depression-like behavior in chronic than sub-chronic-SD. With regard to AD, increased amyloid precursor protein (APP) and soluble (s)-APPß and decreased sAPPα in both SDs were more significant in the chronic. However, sAPPα/sAPPß ratio was only decreased in chronic SD. CONCLUSION: These findings suggest that both SDs induce depression-like changes by increasing PER2, leading to neuroinflammation and neurotransmitter dysfunction. However, only chronic SD induced memory impairment likely due to severer circadian disruption, higher neuroinflammation, and dysregulation of APP metabolism.

Neuroprotective azaphilones from a deep-sea derived fungus Penicillium sp. SCSIO41030.

Ten azaphilones including one pair of new epimers and three new ones, penineulones A-E (1-5) with the same structural core of angular deflectin, were obtained from a deep-sea derived Penicillium sp. SCSIO41030 fermented on a liquid medium. Their structures including absolute configurations were elucidated using chiral-phase HPLC analysis, extensive NMR spectroscopic and HRESIMS data, ECD and NMR calculations, and by comparing NMR data with literature data. Biological assays showed that the azaphilones possessed no antitumor and anti-viral (HSV-1/2) activities at concentrations of 5.0 µM and 20 µM, respectively. In addition, azaphilones 8 and 9 showed neuroprotective effects against Aß25-35-induced neurotoxicity in primary cultured cortical neurons at a concentration of 10 µM. Azaphilones 8 and 9 dramatically promoted axonal regrowth against Aß25-35-induced axonal atrophy. Our study indicated that azaphilones could be promising lead compounds for neuroprotection.

Isolation and Identification of a Novel Anti-Dry Eye Peptide from Tilapia Skin Peptides Based on In Silico, In Vitro, and In Vivo Approaches.

Tilapia skin is a great source of collagen. Here, we aimed to isolate and identify the peptides responsible for combating dry eye disease (DED) in tilapia skin peptides (TSP). In vitro cell DED model was used to screen anti-DED peptides from TSP via Sephadex G-25 chromatography, LC/MS/MS, and in silico methods. The anti-DED activity of the screened peptide was further verified in the mice DED model. TSP was divided into five fractions (TSP-I, TSP-II, TSP-III, TSP-IV, and TSP-V), and TSP-II exerted an effective effect for anti-DED. A total of 131 peptides were identified using LC/MS/MS in TSP-II, and NGGPSGPR (NGG) was screened as a potential anti-DED fragment in TSP-II via in silico methods. In vitro, NGG restored cell viability and inhibited the expression level of Cyclooxygenase-2 (COX-2) protein in Human corneal epithelial cells (HCECs) induced by NaCl. In vivo, NGG increased tear production, decreased tear ferning score, prevented corneal epithelial thinning, alleviated conjunctival goblet cell loss, and inhibited the apoptosis of corneal epithelial cells in DED mice. Overall, NGG, as an anti-DED peptide, was successfully identified from TSP, and it may be devoted to functional food ingredients or medicine for DED.

Omega-3 Polyunsaturated Fatty Acid Eicosapentaenoic Acid or Docosahexaenoic Acid Improved Ageing-Associated Cognitive Decline by Regulating Glial Polarization.

Neuroinflammation induced by microglial and astrocyte polarizations may contribute to neurodegeneration and cognitive impairment. Omega (n)-3 polyunsaturated fatty acids (PUFAs) have anti-inflammatory and neuroprotective effects, but conflicting results were reported after different n-3 PUFA treatments. This study examined both the change in glial polarizations in ageing rats and the differential effects of two omega-3 PUFAs. The results showed that both PUFAs improved spatial memory in ageing rats, with docosahexaenoic acid (DHA) being more effective than eicosapentaenoic acid (EPA). The imbalance between microglial M1/M2 polarizations, such as up-regulating ionized calcium binding adaptor molecule 1 (IBA1) and down-regulating CD206 and arginase-1 (ARG-1) was reversed in the hippocampus by both n-3 PUFAs, while the DHA effect on CD206 was stronger. Astrocyte A1 polarization presented increasing S100B and C3 but decreasing A2 parameter S100A10 in the ageing brain, which were restored by both PUFAs, while DHA was more effective on S100A10 than EPA. Consistent with microglial M1 activation, the concentration of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-6 were significantly increased, which were attenuated by DHA, while EPA only suppressed IL-6. In correlation with astrocyte changes, brain-derived neurotrophic factor precursor was increased in ageing rats, which was more powerfully down-regulated by DHA than EPA. In summary, enhanced microglial M1 and astrocytic A1 polarizations may contribute to increased brain pro-inflammatory cytokines, while DHA was more powerful than EPA to alleviate ageing-associated neuroimmunological changes, thereby better-improving memory impairment.

The Ethnopharmacological, Phytochemical, and Pharmacological Review of Euryale ferox Salisb.: A Chinese Medicine Food Homology.

Euryale ferox Salisb. (prickly water lily) is the only extent of the genus Euryale that has been widely distributed in China, India, Korea, and Japan. The seeds of E. ferox (EFS) have been categorized as superior food for 2000 years in China, based on their abundant nutrients including polysaccharides, polyphenols, sesquineolignans, tocopherols, cyclic dipeptides, glucosylsterols, cerebrosides, and triterpenoids. These constituents exert multiple pharmacological effects, such as antioxidant, hypoglycemic, cardioprotective, antibacterial, anticancer, antidepression, and hepatoprotective properties. There are very few summarized reports on E. ferox, albeit with its high nutritional value and beneficial activities. Therefore, we collected the reported literature (since 1980), medical classics, database, and pharmacopeia of E. ferox, and summarized the botanical classification, traditional uses, phytochemicals, and pharmacological effects of E. ferox, which will provide new insights for further research and development of EFS-derived functional products.

Low L3 skeletal muscle index associated with the clinicopathological characteristics and prognosis of ovarian cancer: a meta-analysis.

Sarcopenia is a syndrome characterized by progressive loss of skeletal muscle mass, strength and function, which is one of the most important clinical features of cancer malnutrition, representing a poor prognostic indicator in oncology. Sarcopenia is commonly assessed by measuring the skeletal muscle index (SMI) of the third lumbar spine (L3) using computed tomography (CT). The primary aim of this meta-analysis was to study the association between low SMI and comprehensive clinicopathological characteristics as well as prognosis in patients with ovarian cancer. Data were searched in PubMed, EMBASE and Cochrane databases from inception to 10 June 2022. Studies evaluating the prognostic effect of SMI on ovarian cancer survival or chemotherapy-related side effects were included. The risk of bias and study quality were assessed via the Newcastle-Ottawa Scale (NOS). The search strategy yielded 1286 hits in all three databases combined. Thirteen studies were included for qualitative and quantitative analysis, comprising 1814 patients. Our meta-analysis revealed the significant association between low SMI and progression-free survival (PFS) [P = 0.02; hazard ratio (HR): 1.40, 95% confidence interval (CI): 1.06-1.85], as well as 5-year overall survival (OS) [P = 0.02; odds ratio (OR): 1.35, 95% CI: 1.05-1.74]. Low SMI was also obviously associated with body mass index (BMI) < 25 (P < 0.00001; OR: 5.08, 95% CI: 3.54-7.30), FIGO stage (P = 0.02; OR: 1.62, 95% CI: 1.06-2.45) and R0 cytoreduction (P = 0.04;OR: 1.34, 95% CI: 1.01-1.79). There was no correlation between low SMI and histological types, pathological grades and chemotherapy-related toxicity. The quality of the evidence was relatively high according to NOS. Our meta-analysis indicated that sarcopenia assessed by SMI was associated with poor clinical characteristics and adverse prognosis in patients with ovarian cancer. Consensus should be reached on standardized cut-off values for defining sarcopenia in patients with ovarian cancer.

Targeting the tubulin C-terminal tail by charged small molecules.

The disordered tubulin C-terminal tail (CTT), which possesses a higher degree of heterogeneity, is the target for the interaction of many proteins and cellular components. Compared to the seven well-described binding sites of microtubule-targeting agents (MTAs) that localize on the globular tubulin core, tubulin CTT is far less explored. Therefore, tubulin CTT can be regarded as a novel site for the development of MTAs with distinct biochemical and cell biological properties. Here, we designed and synthesized linear and cyclic peptides containing multiple arginines (RRR), which are complementary to multiple acidic residues in tubulin CTT. Some of them showed moderate induction and promotion of tubulin polymerization. The most potent macrocyclic compound 1f was found to bind to tubulin CTT and thus exert its bioactivity. Such RRR containing compounds represent a starting point for the discovery of tubulin CTT-targeting agents with therapeutic potential.

Hizikia fusiforme functional oil (HFFO) prevents neuroinflammation and memory deficits evoked by lipopolysaccharide/aluminum trichloride in zebrafish.

Background: Oxidative stress, cholinergic deficiency, and neuroinflammation are hallmarks of most neurodegenerative disorders (NDs). Lipids play an important role in brain development and proper functioning. Marine-derived lipids have shown good memory-improving potentials, especially those from fish and microalgae. The cultivated macroalga Hizikia fusiforme is healthy food and shows benefits to memory, but the study is rare on the brain healthy value of its oil. Previously, we had reported that the Hizikia fusiforme functional oil (HFFO) contains arachidonic acid, 11,14,17-eicosatrienoic acid, phytol, and other molecules displaying in vitro acetylcholinesterase inhibitory and nitroxide scavenging activity; however, the in vivo effect remains unclear. In this study, we further investigated its potential effects against lipopolysaccharides (LPS)- or aluminum trichloride (AlCl3)-induced memory deficiency in zebrafish and its drug-related properties in silica. Methods: We established memory deficit models in zebrafish by intraperitoneal (i.p.) injection of lipopolysaccharides (LPS) (75 ng) or aluminum trichloride (AlCl3) (21 µg), and assessed their behaviors in the T-maze test. The interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), acetylcholine (ACh), and malondialdehyde (MDA) levels were measured 24 h after the LPS/AlCl3 injection as markers of inflammation, cholinergic activity, and oxidative stress. Furthermore, the interaction of two main components, 11,14,17-eicosatrienoic acid and phytol, was investigated by molecular docking, with the important anti-inflammatory targets nuclear factor kappa B (NF-κB) and cyclooxygenase 2 (COX-2). Specifically, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) and drug-likeness properties of HFFO were studied by ADMETlab. Results: The results showed that HFFO reduced cognitive deficits in zebrafish T-maze induced by LPS/AlCl3. While the LPS/AlCl3 treatment increased MDA content, lowered ACh levels in the zebrafish brain, and elevated levels of central and peripheral proinflammatory cytokines, these effects were reversed by 100 mg/kg HFFO except for MDA. Moreover, 11,14,17-eicosatrienoic acid and phytol showed a good affinity with NF-κB, COX-2, and HFFO exhibited acceptable drug-likeness and ADMET profiles in general. Conclusion: Collectively, this study's findings suggest HFFO as a potent neuroprotectant, potentially valuable for the prevention of memory impairment caused by cholinergic deficiency and neuroinflammation.

Identification of ellagic acid and urolithins as natural inhibitors of Aß25-35-induced neurotoxicity and the mechanism predication using network pharmacology analysis and molecular docking.

Ellagic acid (EA) is a dietary polyphenol that widely exists in grapes, strawberries, and walnuts. It usually exerts multiple biological activities together with its in vivo metabolites called urolithins. EA and urolithins had been proposed as natural agents for applying on the early intervention of Alzheimer's disease (AD). However, the neuroprotective effects of those small molecules have not been confirmed, and the action mechanism is not clear. Deposition of beta-amyloid (Aß) protein is well documented as being involved in the initiation and pathological process of AD. In the present study, we investigated the attenuating effects of EA and several urolithins on Aß25-35-induced neuronal injury and its underlying molecular mechanism by constructing the in vitro AD cell model of PC12 cells and primary neurons. The results revealed that EA and urolithins especially the UM5 and UM6 exerted promising neuroprotective effects in improving the Aß25-35-induced cell damage and lactate dehydrogenase (LDH) leakage, reducing reactive oxygen species (ROS) production, inhibiting neuronal apoptosis, and promoting neurite outgrowth. These results provide new insights into the development of UM5 and UM6 as anti-AD candidates. A network pharmacology analysis combining molecular docking strategy was further adopted to predict the signaling pathway involved in the anti-AD action of EA and urolithins, and the activation of PI3K-Akt, as well as the inhibition of MAPK was found to be involved.

A review for discovering bioactive minor saponins and biotransformative metabolites in Panax quinquefolius L.

Panax quinquefolius L. has attracted extensive attention worldwide because of its prominent pharmacological properties on type 2 diabetes, cancers, central nervous system, and cardiovascular diseases. Ginsenosides are active phytochemicals of P. quinquefolius, which can be classified as propanaxdiol (PPD)-type, propanaxtriol (PPT)-type, oleanane-type, and ocotillol-type oligo-glycosides depending on the skeleton of aglycone. Recently, advanced analytical and isolated methods including ultra-performance liquid chromatography tandem with mass detector, preparative high-performance liquid chromatography, and high speed counter-current chromatography have been used to isolate and identify minor components in P. quinquefolius, which accelerates the clarification of the material basis. However, the poor bioavailability and undetermined bio-metabolism of most saponins have greatly hindered both the development of medicines and the identification of their real active constituents. Thus, it is essential to consider the bio-metabolism of constituents before and after absorption. In this review, we described the structures of minor ginsenosides in P. quinquefolius, including naturally occurring protype compounds and their in vivo metabolites. The preclinical and clinical pharmacological studies of the ginsenosides in the past few years were also summarized. The review will promote the reacquaint of minor saponins on the growing appreciation of their biological role in P. quinquefolius.

Enteral nutrition provides favorable postoperative outcomes for patients with pseudomyxoma peritonei: a retrospective study.

Background: Pseudomyxoma peritonei (PMP) is a rare malignancy, and many uncertainties regarding its treatment and prognosis still remain. The main treatment for PMP is cytoreductive surgery (CRS) combined with heated intraperitoneal chemotherapy (HIPEC), which can lead to intra-abdominal trauma and systemic reactions. Enteral nutrition (EN) is an important and beneficial perioperative option for major complicated abdominal surgery compared with total parenteral nutrition (TPN). However, the role of EN in PMP after surgery is still unknown. The purpose of this study was to analyze the effects of EN on postoperative outcomes in PMP patients. Methods: The perioperative clinical data of PMP patients from Xiangya Hospital of Central South University who accepted CRS plus HIPEC from January 2011 to December 2018 were collected and analyzed. The effects of EN on the nutritional status, postoperative complications, and hospital stay time of patients with PMP were studied. We further analyzed the risk factors affecting hospital stay and complications in PMP patients after surgery. Results: A total of 51 PMP patients accepted CRS and were enrolled in this study, including 25 cases in the EN group and 26 patients in the TPN group. The baseline demographic characteristics and preoperative nutritional status were not significantly different between the two groups. The postoperative absolute lymphocyte count (P<0.001), hemoglobin (P=0.016), and albumin (P<0.001) levels of the EN group were higher than those of the TPN group, but the postoperative hospital stay time (P=0.008) and the complication rate (P=0.03) in the EN group were less than those in the TPN group. Logistic regression analysis showed that age (P=0.031), American Society of Anesthesiologists (ASA) score (P=0.008), and EN (P=0.024) were independent risk factors for postoperative hospital stay in PMP patients. ASA score (P=0.006), number of prior operations (P=0.021), and EN (P=0.035) were independent risk factors for postoperative complications in PMP patients. Conclusions: EN support results in better outcomes and is an independent protective factor for the postoperative hospital stay time and complications of PMP patients.

Early-phase insulin hypersecretion associated with weight loss outcome after LSG: a prospective cohort study in Asian patients with BMI ≥28 kg/m2.

BACKGROUND: Obesity has become a global problem that poses a serious threat to human health. Laparoscopic sleeve gastrectomy (LSG) is an effective long-term treatment. However, the weight loss of some patients after LSG is still insufficient. It is necessary to investigate the factors associated with inadequate weight loss after LSG. OBJECTIVE: The objective of this study was to explore whether preoperative insulin secretion could be associated with weight loss after LSG in patients with obesity. SETTING: This is a single-center prospective cohort study conducted in a university hospital. METHODS: Patients from a prospective database who underwent LSG were analyzed. All 178 participants underwent a 75-g oral glucose tolerance test (OGTT) to assess preoperative insulin and c-peptide secretion before LSG. The areas under the curve (AUCs) for glucose, insulin, and c-peptide were determined in the OGTT. The percentage of excess weight loss (%EWL) and the percentage of total weight loss (%TWL) were used to estimate the effect of weight loss after LSG. Regression models were used to assess the correlation between preoperative insulin and c-peptide secretion with %EWL ≥75% and TWL ≥35% at 12 months after LSG. RESULTS: The AUCs of insulin and c-peptide were significantly lower in the %EWL ≥75% and %TWL ≥35% groups at 0-30 minutes, 0-60 minutes, and 0-120 minutes during the OGTT. At 30, 60, and 120 minutes during the OGTT, c-peptide levels were significantly lower in the %EWL ≥75% group and %TWL ≥35% group. The preoperative c-peptide level at 30 minutes during the OGTT (C30) was significantly negatively correlated with %EWL (ß = -.37, P < .001) and %TWL (ß = -.28, P = .011). Univariate logistic regression analysis showed that preoperative C30 was associated with %EWL ≥75% and %TWL ≥35% after LSG. According to multiple logistic regression analysis, patients with a low preoperative C30 had an 8-fold higher %TWL ≥35% after LSG than those with a high C30 (odds ratio: 8.41 [95% confidence interval: 1.46-48.58], P = .017). Similarly, patients with a low preoperative C30 had a 7-fold higher EWL% ≥75% after LSG than patients with a high C30 (odds ratio: 7.25 [95% confidence interval: 1.11-47.50], P = .039). CONCLUSIONS: The rate of weight loss after LSG is low among patients with preoperative hyperinsulinemia. The preoperative c-peptide level at 30 minutes during the OGTT is associated with weight loss after LSG.

Marine fungal metabolite butyrolactone I prevents cognitive deficits by relieving inflammation and intestinal microbiota imbalance on aluminum trichloride-injured zebrafish.

BACKGROUND: Mounting evidences indicate that oxidative stress, neuroinflammation, and dysregulation of gut microbiota are related to neurodegenerative disorders (NDs). Butyrolactone I (BTL-I), a marine fungal metabolite, was previously reported as an in vitro neuroprotectant and inflammation inhibitor. However, little is known regarding its in vivo effects, whereas zebrafish (Danio rerio) could be used as a convenient in vivo model of toxicology and central nervous system (CNS) diseases. METHODS: Here, we employed in vivo and in silico methods to investigate the anti-NDs potential of BTL-I. Specifically, we established a cognitive deficit model in zebrafish by intraperitoneal (i.p.) injection of aluminum trichloride (AlCl3) (21 µg) and assessed their behaviors in the T-maze test. The proinflammatory cytokines interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) as well as acetylcholinesterase (AChE) activity or glutathione (GSH) levels were assayed 24 h after AlCl3 injection. The intestinal flora variation of the zebrafish was investigated by 16S rDNA high-throughput analysis. The marine fungal metabolite, butyrolactone I (BTL-I), was used to modulate zebrafish cognitive deficits evoked by AlCl3 and evaluated about its effects on the above inflammatory, cholinergic, oxidative stress, and gut floral indicators. Furthermore, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) and drug-likeness properties of BTL-I were studied by the in silico tool ADMETlab. RESULTS: BTL-I dose-dependently ameliorated AlCl3-induced cognitive deficits in zebrafish. While AlCl3 treatment elevated the levels of central and peripheral proinflammatory cytokines, increased AChE activity, and lowered GSH in the brains of zebrafish, these effects, except GSH reduction, were reversed by 25-100 mg/kg BTL-I administration. Besides, 16S rDNA high-throughput sequencing of the intestinal flora of zebrafish showed that AlCl3 decreased Gram-positive bacteria and increased proinflammatory Gram-negative bacteria, while BTL-I contributed to maintaining the predominance of beneficial Gram-positive bacteria. Moreover, the in silico analysis indicated that BTL-I exhibits acceptable drug-likeness and ADMET profiles. CONCLUSIONS: The present findings suggest that BTL-I is a potential therapeutic agent for preventing CNS deficits caused by inflammation, neurotoxicity, and gut flora imbalance.

ω-3 DPA Protected Neurons from Neuroinflammation by Balancing Microglia M1/M2 Polarizations through Inhibiting NF-κB/MAPK p38 Signaling and Activating Neuron-BDNF-PI3K/AKT Pathways.

Microglia M1 phenotype causes HPA axis hyperactivity, neurotransmitter dysfunction, and production of proinflammatory mediators and oxidants, which may contribute to the etiology of depression and neurodegenerative diseases. Eicosapentaenoic acid (EPA) may counteract neuroinflammation by increasing n-3 docosapentaenoic acid (DPA). However, the cellular and molecular mechanisms of DPA, as well as whether it can exert antineuroinflammatory and neuroprotective effects, are unknown. The present study first evaluated DPA's antineuroinflammatory effects in lipopolysaccharide (LPS)-activated BV2 microglia. The results showed that 50 µM DPA significantly decreased BV2 cell viability after 100 ng/mL LPS stimulation, which was associated with significant downregulation of microglia M1 phenotype markers and proinflammatory cytokines but upregulation of M2 markers and anti-inflammatory cytokine. Then, DPA inhibited the activation of mitogen-activated protein kinase (MAPK) p38 and nuclear factor-κB (NF-κB) p65 pathways, which results were similar to the effects of NF-κB inhibitor, a positive control. Second, BV2 cell supernatant was cultured with differentiated SH-SY5Y neurons. The results showed that the supernatant from LPS-activated BV2 cells significantly decreased SH-SY5Y cell viability and brain-derived neurotrophic factor (BDNF), TrkB, p-AKT, and PI3K expression, which were significantly reversed by DPA pretreatment. Furthermore, DPA neuroprotection was abrogated by BDNF-SiRNA. Therefore, n-3 DPA may protect neurons from neuroinflammation-induced damage by balancing microglia M1 and M2 polarizations, inhibiting microglia-NF-κB and MAPK p38 while activating neuron-BDNF/TrkB-PI3K/AKT pathways.

Isoginkgetin treatment attenuated lipopolysaccharide-induced monoamine neurotransmitter deficiency and depression-like behaviors through downregulating p38/NF-κB signaling pathway and suppressing microglia-induced apoptosis.

BACKGROUND: Microglia activation-induced neuroinflammation may contribute to the etiology of depression. Podocarpus nagi containing high concentration of isoginkgetin could effectively treat mental diseases in ancient times. However, the therapeutic role, peculiarly in the brain-immune modulation in depression is still unclear. This study aimed to determine effects of isoginkgetin on lipopolysaccharide (LPS)-induced depression-like changes. Furthermore, its modulation on the p38/nuclear factor-kappa B (NF-κB) pathway in LPS-activated microglia was evaluated. METHODS: Adult Kunming mice were intraperitoneally injected vehicle or isoginkgetin (4 mg/kg) daily for 14 days before saline or LPS (0.83 mg/kg) administration. Depression-like behavior, neurotransmitter levels, and markers of neuroinflammation were determined. Isoginkgetin effect on LPS-induced microglial activation was then assessed in BV2 cells. Finally, conditioned medium (CM) derived from isoginkgetin-treated BV2 cells was co-cultured with SH-SY5Y cells for 24 h. Cell viability and apoptosis were evaluated. RESULTS: LPS significantly induced helplessness and anxiety, which were associated with decreased 5-HT, noradrenaline, and dopamine concentrations. Meanwhile, LPS increased microglia M1 hallmark Iba1 expression and serum interleukin (IL)-1ß concentration. These changes were attenuated by isoginkgetin treatment. In vitro, isoginkgetin markedly suppressed the production of IL-1ß, IL-6, tumor necrosis factor-alpha, cyclooxygenase-2, inducible nitric oxide, and reactive oxygen species, which are released from LPS-stimulated BV2 cells. More interestingly, CM from isoginkgetin-treated BV2 cells significantly alleviated SH-SY5Y cell apoptosis and restored cell viability compared to LPS-treated group through the inhibition of p38/NF-κB signaling pathway. CONCLUSION: These data demonstrate that isoginkgetin is an effective therapeutic agent for depression-like behaviors and neuropathological changes via potent anti-inflammatory property.

Mechanism underlying the regulation of lncRNA ACTA2-AS1 on CXCL2 by absorbing miRNA-532-5p as ceRNA in the development of ovarian cancer.

OBJECTIVE: To explore the mechanism underlying the regulation of long non-coding RNA (LncRNA) ACTA2-AS1 on CXCL2 as a ceRNA of miR-532-5p in the progression of ovarian cancer (OC). METHODS: A qRT-PCR assay was carried out for analyzing the expression changes of ACTA2-AS1, miR-532-5p, as well as CXCL2 in OC tissues and corresponding healthy paracancerous tissues HOSEpiC (human ovarian epithelial cells), and OC cells. OC cells were grouped and transfected, and the fluorescent in situ hybridization was adopted for evaluating ACTA2-AS1 in the cells. Additionally, a dual luciferase reporter (DLR) assay was carried out for verifying the correlation of ACTA2-AS1 with miR-532-5p and of miR-532-5p with CXCL2. Cells were transfected with si-ACTA2-AS1, miR-532-5p, or CXCL2 overexpression plasmids, and then the cell proliferation, invasion, and apoptosis were determined using MTT, Transwell, and flow cytometry assays, respectively. RESULTS: Compared with paracancerous tissues and HOSEpiC cells, OC tissues and cells showed increased ACTA2-AS1 and CXCL2 expression and decreased miR-532-5p expression (all P<0.05). ACTA2-AS1 acted as ceRNA in OC by negatively regulating miR-532-5p. Additionally, upregulating ACTA2-AS1 intensified the proliferation and invasion of cancer cells and suppressed their apoptosis (all P<0.05), and inhibition of it resulted in opposite results. In contrast, overexpressing miR-532-5p suppressed the proliferation, invasion, and clone formation of the cells and promoted their apoptosis (all P<0.05). The effect of ACTA2-AS1 on OC cells can be partially reversed by overexpressing miR-532-5p. Moreover, CXCL2, positively correlated with ACTA2-AS1 in expression (P<0.0001, r=0.7385), was the target of miR-532-5p, and its overexpression could partially offset the influence of miR-532-5p on OC cells. CONCLUSION: LncRNA ACTA2-AS1 can act as a tumor promoter in OC by absorbing miR-532-5p as ceRNA and regulating CXCL2, and ACTA2-AS1 inhibitor is expected to play a role in targeted therapy of OC.

Low Expression of Circular RNA hsa_circ_0078607 Predicts Poor Prognosis in High-Grade Serous Ovarian Cancer.

OBJECTIVE: Recent studies have shown that circRNAs participate in ovarian cancer progression and act as potential biomarkers for ovarian cancer diagnosis and prognosis. In the present study, we aimed to investigate the expression pattern and prognostic significance of circ_0078607 in high-grade serous ovarian cancer (HGSOC). METHODS: The expression of circ_0078607 was detected by quantitative real-time polymerase chain reaction (qRT-PCR) in 49 cases of HGSOC. Clinical data of patients with HGSOC were retrospectively collected, and those patients were divided according to their expression of circ_0078607. Correlation between circ_0078607 and clinical features as well as the prognosis in patients with HGSOC was analyzed. t-test and chi-square test were used to compare continuous and categorical variables. The Cox hazard regression model was used to assess prognostic factors. Both progression-free survival (PFS) and overall survival (OS) curves were generated by Kaplan-Meier method. RESULTS: The expression of circ_0078607 was significantly downregulated in ovarian cancer tissues compared with adjacent non-cancerous tissues. Besides, patients with low circ_0078607 expression exhibited parameters associated with poor prognosis, including advanced FIGO stage and higher serum CA125 level. Kaplan-Meier survival curve analysis showed that patients with low circ_0078607 expression had shorter PFS and OS. Cox regression analysis showed that low expression of circ_0078607 was a predictor for poor PFS and OS in HGSOC patients. CONCLUSION: Low expression of circ_0078607 might be an adverse prognostic indicator for HGSOC.

Circular RNA hsa_circ_0078607 suppresses ovarian cancer progression by regulating miR-518a-5p/Fas signaling pathway.

BACKGROUND: Increasing researches have demonstrated the critical functions of circular RNAs (circRNAs) in the progression of malignant tumors, including ovarian cancer. In this study, we aim to investigate abnormally expression of hsa_circ_0078607 and the role of hsa_circ_0078607 during ovarian cancer pathogenesis. METHODS: RT-PCR were used to detect the expression of circ_0078607 in ovarian cancer tissues. To determine the functional roles of circ_0078607 in ovarian cancer, cell proliferation and cell invasion assays were performed. Bioinformatics and luciferase reporter analysis were used to predict the target of circ_0078607. RESULTS: In the present study, we first found that circ_0078607 was downregulated in ovarian cancer. Forced circ_0078607 expression significantly suppressed proliferation and promoted apoptosis of ovarian cancer cells. Mechanically, bioinformatics and luciferase reporter analysis identified miR-518a-5p as a direct target of circ_0078607, while Fas as a direct target of miR-518a-5p. MiR-518a-5p negatively regulated Fas in ovarian cancer cells, while overexpression of circ_0078607 could increase the expression of Fas inhibited by miR-518a-5p. Furthermore, overexpression of circ_0078607 could inhibit the proliferation and invasion of ovarian cancer cells caused by miR-518a-5p mimic. CONCLUSION: The results of the present study revealed that circ_0078607 suppressed ovarian cancer progression by sponging oncogenic miR-518a-5p to induce Fas expression, which may provide new therapeutic approach for ovarian cancer.

Artificial Mini Dendritic Cells Boost T Cell-Based Immunotherapy for Ovarian Cancer.

Ovarian cancer is the most lethal gynecological malignancy with high recurrence rates and low survival rates, remaining a disease of high unmet need. Cancer immunotherapy, which harnesses the potential of the immune system to attack tumors, has emerged as one of the most promising treatment options in recent years. As an important form of immunotherapy, dendritic cell (DC)-based vaccines have demonstrated the ability to induce an immune response, while clinical efficacy of DC vaccines remains unsubstantiated as long-term benefit is only reported in a restricted proportion of patients. Here, a biomimetic nanovaccine derived from DCs is developed through cell membrane coating nanotechnology. This nanovaccine, denoted "mini DC," inherits the ability of antigen presentation and T cells' stimulation from DCs and is shown to elicit enhanced activation of T cells both in vitro and in vivo. In a mouse model of ovarian cancer, mini DCs exhibit superior therapeutic and prophylactic efficacy against cancer including delayed tumor growth and reduced tumor metastasis compared with DC vaccine. These findings suggest that mini DCs may serve as a facile and potent vaccine to boost anticancer immunotherapy.

Platycodigenin as Potential Drug Candidate for Alzheimer's Disease via Modulating Microglial Polarization and Neurite Regeneration.

Neuroinflammatory microenvironment, regulating neurite regrowth and neuronal survival, plays a critical role in Alzheimer's disease (AD). During neuroinflammation, microglia are activated, inducing the release of inflammatory or anti-inflammatory factors depending on their polarization into classical M1 microglia or alternative M2 phenotype. Therefore, optimizing brain microenvironment by small molecule-targeted microglia polarization and promoting neurite regeneration might be a potential therapeutic strategy for AD. In this study, we found platycodigenin, a naturally occurring triterpenoid, promoted M2 polarization and inhibited M1 polarization in lipopolysaccharide (LPS)-stimulated BV2 and primary microglia. Platycodigenin downregulated pro-inflammatory molecules such as interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, IL-6 and nitric oxide (NO), while upregulated anti-inflammatory cytokine IL-10. Further investigation confirmed that platycodigenin inhibited cyclooxygenase-2 (Cox2) positive M1 but increased Ym1/2 positive M2 microglial polarization in primary microglia. In addition, platycodigenin significantly decreased LPS-induced the hyperphosphorylation of mitogen-activated protein kinase (MAPK) p38 and nuclear factor-κB (NF-κB) p65 subunits. Furthermore, the inactivation of peroxisome proliferators-activated receptor γ (PPARγ) induced by LPS was completely ameliorated by platycodigenin. Platycodigenin also promoted neurite regeneration and neuronal survival after Aß treatment in primary cortical neurons. Taken together, our study for the first time clarified that platycodigenin effectively ameliorated LPS-induced inflammation and Aß-induced neurite atrophy and neuronal death.