Patchouli alcohol attenuates the cognitive deficits in a transgenic mouse model of Alzheimer's disease via modulating neuropathology and gut microbiota through suppressing C/EBPß/AEP pathway.

BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by progressive cognitive dysfunctions and behavioral impairments. Patchouli alcohol (PA), isolated from Pogostemonis Herba, exhibits multiple pharmacological properties, including neuroprotective effects. This study aimed to investigate the therapeutic effects of PA against AD using the TgCRND8 transgenic AD mouse model, and to explore the underlying mechanisms targeting CCAAT/enhancer-binding protein ß/asparagine endopeptidase (C/EBPß/AEP) signaling pathway. METHODS: After genotyping to confirm the transgenicity, drug treatments were administered intragastrically once daily to 3-month-old TgCRND8 mice for 4 consecutive months. Several behavioral tests were applied to assess different aspects of neurological functions. Then the brain and colon tissues were harvested for in-depth mechanistic studies. To further verify whether PA exerts anti-AD effects via modulating C/EBPß/AEP signaling pathway in TgCRND8 mice, adeno-associated virus (AAV) vectors encoding CEBP/ß were bilaterally injected into the hippocampal CA1 region in TgCRND8 mice to overexpress C/EBPß. Additionally, the fecal microbiota transplantation (FMT) experiment was performed to verify the potential role of gut microbiota on the anti-AD effects of PA. RESULTS: Our results showed that PA treatment significantly improved activities of daily living (ADL), ameliorated the anxiety-related behavioral deficits and cognitive impairments in TgCRND8 mice. PA modulated the amyloid precursor protein (APP) processing. PA also markedly reduced the levels of beta-amyloid (Aß) 40 and Aß42, suppressed Aß plaque burdens, inhibited tau protein hyperphosphorylation at several sites and relieved neuroinflammation in the brains of TgCRND8 mice. Moreover, PA restored gut dysbiosis and inhibited the activation of the C/EBPß/AEP signaling pathway in the brain and colon tissues of TgCRND8 mice. Interestingly, PA strikingly alleviated the AD-like pathologies induced by the overexpression of C/EBPß in TgCRND8 mice. Additionally, the FMT of fecal microbiota from the PA-treated TgCRND8 mice significantly alleviated the cognitive impairments and AD-like pathologies in the germ-free TgCRND8 mice. CONCLUSION: All these findings amply demonstrated that PA could ameliorate the cognitive deficits in TgCRND8 mice via suppressing Aß plaques deposition, hyperphosphorylation of tau protein, neuroinflammation and gut dysbiosis through inhibiting the activation of C/EBPß/AEP pathway, suggesting that PA is a promising naturally occurring chemical worthy of further development into the pharmaceutical treatment of AD.

A nomogram for predicting survival of head and neck mucosal melanoma.

OBJECTIVES: We aimed to understand the clinical characteristics and better predict the prognosis of patients with mucosal melanoma of the head and neck (MMHN) using a nomogram. METHODS: Three hundred patients with nometastatic MMHN were included. Multivariable Cox regression was performed to analyze independent prognostic factors for overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRRFS), and these factors were used to develop a nomogram. Concordance indexes (C-indexes), calibration plots, and receiver operating characteristic (ROC) analysis were performed to test the predictive performance of the nomogram in both the primary (n = 300) and validation cohorts (n = 182). RESULTS: The primary tumor site, T stage and N stage were independent risk factors for survival and were included in the nomogram to predict the 3- and 5-year OS, DFS, DMFS, and LRRFS in the primary cohort. The C-indexes (both > 0.700), well-fit calibration plots, and area under the ROC curve (both > 0.700) indicated the high diagnostic accuracy of the nomogram, in both the primary and validation cohorts. The patients were divided into three groups (high-risk, intermediate-risk, and low-risk groups) according to their nomogram scores. The survival curves of OS, DFS, DMFS, and LRRFS were well separated by the risk groups in both cohorts (all P < 0.001). CONCLUSIONS: The nomogram can stratify MMHN patients into clinically meaningful taxonomies to provide individualized treatment.

Long noncoding RNA MEG3 regulates rheumatoid arthritis by targeting NLRC5.

Rheumatoid arthritis (RA) is one of the chronic systemic autoimmune diseases that cardinally affect the joints. Many people all over the world suffer from the disease. Fibroblast-like synoviocytes (FLSs) play a significant role in the occurrence and development of RA. The long noncoding RNA maternally expressed gene 3 (MEG3) is an imprinted gene, which participates in various cancers as a tumor suppressor. Previous studies have shown that nucleotide oligomerization domain (NOD)-like receptors 5 (NLRC5) plays a key role in inflammatory and autoimmune diseases. Nonetheless, we know very little about the biofunctionality of MEG3 during the development of RA. In this paper, we used complete Freund's adjuvant (CFA)-induced rats as RA animal models. The level of MEG3 significantly reduced in CFA-induced synovial tissues and FLSs, whereas the NLRC5 levels were increased. Enforced expression of MEG3 may be responsible for the decreased level of NLRC5 and inflammatory cytokine level. The results of methylation-specific PCR suggested that the MEG3 gene promoter was significantly methylated in CFA-induced synovial tissues and FLSs. More important, hypermethylation of MEG3 promoter could be inhibited by 5-aza-2-deoxycytidine (5-azadC; methylation inhibitor). Besides, the expression of NLRC5 significantly decreased followed by 5-azadc. Furthermore, DNA methyltransferases 1 (DNMT1) increased in CFA-induced synovial tissues and cells. These results indicated that MEG3 regulates RA by targeting NLRC5 potentially.

Acetyl-11-keto-ß-boswellic acid suppresses docetaxel-resistant prostate cancer cells in vitro and in vivo by blocking Akt and Stat3 signaling, thus suppressing chemoresistant stem cell-like properties.

Acquired docetaxel-resistance of prostate cancer (PCa) remains a clinical obstacle due to the lack of effective therapies. Acetyl-11-keto-ß-boswellic acid (AKBA) is a pentacyclic triterpenic acid isolated from the fragrant gum resin of the Boswellia serrata tree, which has shown intriguing antitumor activity against human cell lines established from PCa, colon cancer, malignant glioma, and leukemia. In this study, we examined the effects of AKBA against docetaxel-resistant PCa in vitro and in vivo as well as its anticancer mechanisms. We showed that AKBA dose-dependently inhibited cell proliferation and induced cell apoptosis in docetaxel-resistant PC3/Doc cells; its IC50 value in anti-proliferation was ∼17 µM. Furthermore, AKBA dose-dependently suppressed the chemoresistant stem cell-like properties of PC3/Doc cells, evidenced by significant decrease in the ability of mammosphere formation and down-regulated expression of a number of stemness-associated genes. The activation of Akt and Stat3 signaling pathways was remarkably enhanced in PC3/Doc cells, which contributed to their chemoresistant stem-like phenotype. AKBA (10-30 µM) dose-dependently suppressed the activation of Akt and Stat3 signaling pathways in PC3/Doc cells. In contrast, overexpression of Akt and Stat3 significantly attenuated the inhibition of AKBA on PC3/Doc cell proliferation. In docetaxel-resistant PCa homograft mice, treatment with AKBA significantly suppresses the growth of homograft RM-1/Doc, equivalent to its human PC3/Doc, but did not decrease their body weight. In summary, we demonstrate that AKBA inhibits the growth inhibition of docetaxel-resistant PCa cells in vitro and in vivo via blocking Akt and Stat3 signaling, thus suppressing their cancer stem cell-like properties.

Transcriptome-guided identification of SprA as a pleiotropic regulator in Streptomyces chattanoogensis.

Quorum sensing molecular γ-butyrolactones (GBL) are widely distributed among the genus Streptomyces. Their cognate receptors have been demonstrated to control secondary metabolism and/or morphological differentiation. ScgA is responsible for the biosynthesis of GBL in Streptomyces chattanoogensis. According to the genome-wide transcriptome analysis of the ΔscgA mutant, we found that the expression of sprA, which encodes a GBL receptor homologue, was shown to be positively regulated by ScgA. Electrophoretic mobility shift assays and DNase I footprinting assays showed that SprA bound to two specific autoregulatory element (ARE) sequences located upstream of the sprA gene, indicating that its expression is self-regulated. SprA was involved in biosynthesis of GBL by repressing the expression of scgA. An Escherichia coli-based luciferase report system demonstrated that SprA directly repressed the expression of scgR, which encodes a GBL receptor. Like deletion of scgA, the disruption of sprA resulted in decreased production of the antibiotic natamycin in liquid culture and retarded morphological differentiation on solid agar. This work indicates that SprA acts as a pleiotropic regulator of both morphogenesis and the production of natamycin.

Secondary metabolites from Aspergillus fumigatus, an endophytic fungus from the liverwort Heteroscyphus tener (Steph.) Schiffn.

Three new metabolites, asperfumigatin (1), isochaetominine (10), and 8'-O-methylasterric acid (21), together with nineteen known compounds, were obtained from the culture of Aspergillus fumigatus, an endophytic fungus from the Chinese liverwort Heteroscyphus tener (Steph.) Schiffn. Their structures were established by extensive analysis of the spectroscopic data. The absolute configurations of 1 and 10 were determined by analysis of their respective CD spectra. Cytotoxicity of these isolates against four human cancer cell lines was also determined.

[Clinical analysis of purulent meningitis in 317 children].

OBJECTIVE: To study the clinical features, treatment, and prognosis of purulent meningitis (PM) in children. METHODS: A retrospective analysis was performed on the clinical data of 317 children with PM aged from 1 month to 15 years. RESULTS: PM was commonly seen in infants (198 cases, 62.6%). Most children with PM had preceding respiratory infection (171 cases, 53.9%). The major clinical manifestations of PM were fever, convulsions, and intracranial hypertension, and convulsions were more commonly seen in infants (152 cases, 93.6%). The major complication was subdural effusion (95 cases, 29.9%). Of the 95 cases of subdural effusion, 22 cases were diagnosed by subdural puncture; 68 cases underwent subdural puncture and 62 cases restored to normal temperature 3-5 days after puncture. Risk factors associated with complications and sequelae were young age and protein≥1 g/L in cerebrospinal fluid (CSF) (OR=0.518, 1.524 respectively; P<0.05). The third-generation cephalosporins were the first choice for PM, and vancomycin or carbapenems were replacement therapy. Thirteen (14.4%) out of 90 children had delayed cerebral vasculitis during a follow-up visit within 3 months after discharge. CONCLUSIONS: PM is more commonly seen in infants, and the infants have a high incidence of convulsions. Young age and protein≥1 g/L in CSF may increase the risk of complications and sequelae. Subdural puncture is not only a diagnostic method but also a therapy for subdural effusion. Some children have delayed cerebral vasculitis during a follow-up visit within 3 months after discharge, so follow-up visits should be performed within 3 months after discharge.

Tianma-Gouteng pair ameliorates the cognitive deficits on two transgenic mouse models of Alzheimer's disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD) is a progressive neurodegenerative disease. Tianma-Gouteng Pair (TGP), commonly prescribed as a pair-herbs, can be found in many Chinese medicine formulae to treat brain diseases. However, the neuroprotective effects and molecular mechanisms of TGP remained unexplored. AIM OF THE STUDY: This study investigated the difference between the TgCRND8 and 5 × FAD transgenic mice, the anti-AD effects of TGP, and underlying molecular mechanisms of TGP against AD through the two mouse models. METHODS: Briefly, three-month-old TgCRND8 and 5 × FAD mice were orally administered with TGP for 4 and 6 months, respectively. Behavioral tests were carried out to determine the neuropsychological functions. Moreover, immunofluorescence and western blotting assays were undertaken to reveal the molecular mechanisms of TGP. RESULTS: Although TgCRND8 and 5 × FAD mice had different beta-amyloid (Aß) burdens, neuroinflammation status, and cognition impairments, TGP exerted neuroprotective effects against AD in the two models. In detail, behavioral tests revealed that TGP treatment markedly ameliorated the anxiety-like behavior, attenuated the recognition memory deficits, and increased the spatial learning ability as well as the reference memory of TgCRND8 and 5 × FAD mice. Moreover, TGP treatment could regulate the beta-amyloid precursor protein (APP) processing by inhibiting the Aß production enzymes such as ß- and γ-secretases and activating Aß degrading enzyme to reduce Aß accumulation. In addition, TGP reduced the Aß42 level, the ratio of Aß42/Αß40, Aß accumulation, and tau hyperphosphorylation in both the 5 × FAD and TgCRND8 mouse models. Furthermore, TGP ameliorated neuroinflammation by decreasing the densities of activated microglia and astrocytes, and inhibiting the production of inflammatory cytokines. TGP upregulated the SIRT1 and AMPK, and downregulated sterol response element binding protein 2 (SREBP2) in the brain of TgCRND8 mice and deactivation of the EPhA4 and c-Abl in the brain tissues of 5 × FAD mice. CONCLUSION: Our experiments for the first time revealed the neuroprotective effects and molecular mechanism of TGP on 5 × FAD and TgCRND8 transgenic mouse models of different AD stages. TGP decreased the level of Aß aggregates, improved the tauopathy, and reduced the neuroinflammation by regulation of the SIRT1/AMPK/SREBP2 axis and deactivation of EPhA4/c-Abl signaling pathway in the brains of TgCRND8 and 5 × FAD mice, respectively. All these findings unequivocally confirmed that the TGP would be promising in developing into an anti-AD therapeutic pharmaceutical.

Modified Qing-Zao-Jiu-Fei decoction attenuated pulmonary fibrosis induced by bleomycin in rats via modulating Nrf2/NF-κB and MAPKs pathways.

BACKGROUND: Qing-Zao-Jiu-Fei Decoction (QZJFD) is a famous herbal formula commonly prescribed for the treatment of lung-related diseases in the ancient and modern times. Trichosanthis Fructus (TF) and Fritillariae Thunbergii Bulbus (FTB) are widely used for treatment of cough and pulmonary disease. In order to identify a more effective formula for treatment of pulmonary fibrosis, we intend to add TF and FTB in QZJFD to form a modified QZJFD (MQZJFD). In this study, we aims to explore MQZJFD as an innovative therapeutic agent for pulmonary fibrosis using bleomycin (BLM)-treated rats and to unravel the underlying molecular mechanisms. METHODS: BLM was given to SD rats by intra-tracheal administration of a single dose of BLM (5 mg/kg). QZJFD (3 g/kg) and MQZJFD (1, 2 and 4 g/kg) was given intragastrically daily to rats for 14 days (from day 15 to 28) after BLM administration for 14 consecutive days. RESULTS: MQZJFD was found to contain 0.29% of amygdalin, 0.020% of lutin, 0.077% of glycyrrhizic acid and 0.047% of chlorogenic acid. BLM treatment could induce collagen deposition in the lung tissues of rats, indicating that the pulmonary fibrosis rat model had been successfully established. MQZJFD have better effects than the original QZJFD in reducing the pulmonary structure damage and collagen deposition of rat lung fibrosis induced by BLM. MQZJFD could reduce the hydroxyproline content in lung tissues of BLM-treated rats. The biomarkers of fibrosis such as matrix metalloproteinase 9 (MMP9), collagen I and α-smooth muscle actin (α-SMA) were remarkably reduced after treatment with MQZJFD. MQZJFD also have anti-oxidant stress effects by inhibiting the level of malondialdehyde (MDA), but enhancing the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and the level of glutathione (GSH) in the lung tissues of BLM-treated rats. Moreover, the MQZJFD markedly suppressed the over expressions of p-p65/p65 and p-IκBα/IκBα, but upregulated the Nrf2. MQZJFD also suppressed the protein expressions of p-ERK1/2/ERK1/2, p-p38/p38 and p-JNK/JNK in the lung tissues of BLM-treated rats. CONCLUSIONS: MQZJFD could improve the pulmonary fibrosis induced by BLM in rats via inhibiting the fibrosis and oxidative stress via suppressing the activation of NF-κB/Nrf2 and MAPKs pathways.

[Hepatitis B e antigen from chronic hepatitis B patients induces Th1/Th2 cytokine imbalance in vitro].

OBJECTIVE: To study the immunoregulatory effect of hepatitis B virus (HBV) e antigen (HBeAg) on peripheral blood monocytes (PBMCs). METHODS: PBMCs were isolated from patients with chronic hepatitis B (CHB; both HBeAg- and HBeAg+) and healthy controls, and cultured with recombinant HBeAg. The HBeAg-induced changes in expression of PD-1/PD-L1 were measured by flow cytometry of the cells and in secreted cytokines were measured by enzyme-linked immunosorbent assay of the supernatants. Comparisons between two groups were made by the independent-samples t-test; the relationship between PD-1/B7-H1 level and HBV DNA copy number was evaluated by Spearman's correlation analysis. RESULTS: Exposure to HBeAg led to a significant decrease in CD3+CD4+ T lymphocyte-specific expression of IFNa for both the CHB patients' and healthy controls' samples (t = 2.382 and -4.190 respectively, P less than 0.01). For the HBeAg- CHB patients' and healthy controls' samples, the HBeAg exposure led to increased levels of secreted cytokines IL-6, IL-10 and TNFa (t = 2.504, 3.583 and 4.324, P less than 0.01 and t = 3.542, 6.246 and 5.273, P less than 0.01 respectively) and of CD14+ PBMC-specific expression of PD-L1 (t = 4.815 and 3.454, P less than 0.05 respectively). Compared to the HBeAg-negative CHB patients' and healthy controls' samples, the HBeAg+ CHB patients' samples had significantly lower CD3+CD4+ T cell-specific expression of IFNa (t = -3.177 and -4.541, P less than 0.01 respectively), but significantly higher levels of secreted IL-4 (t = 3.382 and 4.393, P less than 0.01 respectively), of CD3+ T cells-specific expression of PD-1/PD-L1 (t = 4.755, 2.942 and 4.518, 4.595, P less than 0.01 respectively), and of CD14+ T cells-specific expression of PD-L1 (t = 5.092 and 5.473, P less than 0.01 respectively). The CD3+ T cells-specific expression of PD-L1 was significantly higher in the samples from HBeAg- CHB patients than from the healthy controls (t = 3.214, P less than 0.01). CONCLUSION: HBeAg was able to down-regulate the production of Th1-type cytokines (IFNgamma), and up-regulate the secretion of Th2-type cytokines (IL-6, IL-10) and the expression of PD-1/PD-L1on monocytes. These changes are conducive to the formation of immune tolerance to HBV. Therefore, HBeAg may play an important role in immune tolerance to chronic HBV infection.

Sulforaphene, a CDK5 Inhibitor, attenuates cognitive deficits in a transgenic mouse model of Alzheimer's disease via reducing Aß Deposition, tau hyperphosphorylation and synaptic dysfunction.

BACKGROUND: Alzheimer's disease (AD) is the most common form of neurodegenerative disorder characterized by progressive loss of memory and cognitive functions. There are two pathological hallmarks, including accumulation of amyloid plaques composed of ß-amyloid peptide (Aß) and deposits of neurofibrillatory tangles (NFT). Cyclin-dependent kinase 5 (CDK5), a serine/threonine kinase, plays an important role in synaptic plasticity and cognitive behavior. Sulforaphene (SF) has been demonstrated to exert anti-AD activity in AD rat model. In this study, we aimed to evaluate the cognitive deficits improving effects of SF on in TgCRND8 mice and to elucidate the underlying molecular mechanisms. METHODS: TgCRND8 mice were intragastrically treated with SF (25 and 50 mg/kg) for 4 months from 3-month-old. The cognitive functions were assessed using Morris Water Maze Test. Cultured primary mouse neurons were pre-treated with SF, followed by co-treatment with Aß1-42 oligomers. CDK5 inhibitor (roscovitine) was used to determine the involvement of CDK5/p25 pathway in the anti-AD effects of SF in primary neurons. RESULTS: Our results showed that SF treatment significantly ameliorated the cognitive deficits in TgCRND8 mice and protected primary mouse neurons against Aß1-42 induced neurotoxicity. SF could modulate the expression of Aß production related markers, and suppress the phosphorylation of tau protein at specific sites in the TgCRND8 mice. In addition, SF enhanced the expressions of synaptic plasticity related markers and CDK5. SF also markedly suppressed the CDK5/p25 activity. CONCLUSIONS: SF is a potent CDK5 inhibitor and a potential therapeutic agent for treatment and prevention of AD. Moreover, SF inhibited the overexpression of CDK5 in primary neurons of mouse.

Primulinapingnanensis, a new species of Gesneriaceae from Guangxi, China.

A new species of Primulina, P.pingnanensis, from the Guangxi Zhuangzu Autonomous Region, China, is described and illustrated here. It is morphologically similar to P.orthandra but has significant differences in the bracts, corolla tube and lobes shape, as well as in the indumentum of the outer surface of the corolla, the filaments, the staminodes and the anthers. Colorful photographs and essential information of this new taxon are also provided, including detailed taxonomic description, distribution, habitat, the comparison table, and the IUCN conservation status. We also discuss a validation of new combination P.crassifolia and Chiritacrassifolia.

Gut dysbiosis aggravates cognitive deficits, amyloid pathology and lipid metabolism dysregulation in a transgenic mouse model of Alzheimer's disease.

Gut dysbiosis, a well-known risk factor to triggers the progression of Alzheimer's disease (AD), is strongly associated with metabolic disturbance. Trimethylamine N-oxide (TMAO), produced in the dietary choline metabolism, has been found to accelerate neurodegeneration in AD pathology. In this study, the cognitive function and gut microbiota of TgCRND8 (Tg) mice of different ages were evaluated by Morris water maze task (MWMT) and 16S rRNA sequencing, respectively. Young pseudo germ-free (PGF) Tg mice that received faecal microbiota transplants from aged Tg mice and wild-type (WT) mice were selected to determine the role of the gut microbiota in the process of neuropathology. Excessive choline treatment for Tg mice was used to investigate the role of abnormal choline metabolism on the cognitive functions. Our results showed that gut dysbiosis, neuroinflammation response, Aß deposition, tau hyperphosphorylation, TMAO overproduction and cyclin-dependent kinase 5 (CDK5)/transcription 3 (STAT3) activation occurred in Tg mice age-dependently. Disordered microbiota of aged Tg mice accelerated AD pathology in young Tg mice, with the activation of CDK5/STAT3 signaling in the brains. On the contrary, faecal microbiota transplantation from WT mice alleviated the cognitive deficits, attenuated neuroinflammation, Aß deposition, tau hyperphosphorylation, TMAO overproduction and suppressed CDK5/STAT3 pathway activation in Tg mice. Moreover, excessive choline treatment was also shown to aggravate the cognitive deficits, Aß deposition, neuroinflammation and CDK5/STAT3 pathway activation. These findings provide a novel insight into the interaction between gut dysbiosis and AD progression, clarifying the important roles of gut microbiota-derived substances such as TMAO in AD neuropathology.

Prognostic value of the immunohistochemical score based on four markers in head and neck squamous cell carcinoma.

Purpose: Head and neck squamous cell carcinoma (HNSCC) ranks sixth among all cancers globally regarding morbidity, and it has a poor prognosis, high mortality, and highly aggressive properties. In this study, we established a model for predicting prognosis based on immunohistochemical (IHC) scores. Methods: Data on 402 HNSCC cases were collected, the glmnet Cox proportional hazards model was used, risk factors were analyzed for predicting the prognosis of survival, and the IHC score was established. We used the IHC score to predict disease-free survival (DFS) using training and independent validation cohorts, including 264 cases in total. Additionally, the accuracy of the IHC score and the TNM system (8th edition) was compared. A DFS prediction nomogram was established by combining the prognostic factors. Results: The IHC scores included CK, Ki-67, p16, and p40 staining intensity. The concordance index and the Kaplan-Meier survival analysis showed that the IHC scores had high predictive power for HNSCC. Our results showed that the IHC score is an independent factor that can predict prognosis in a multivariate Cox regression analysis. When predicting DFS, the IHC score had a significantly higher value for the area under the ROC curve (AUC) than that of the TNM system. A nomogram was established and included the IHC score, age, tumor location, and the TNM stage. The calibration curves exhibited high consistency between the prognosis predicted by our nomogram and the actual prognosis. Conclusions: The IHC score was more accurate than the eighth edition of the TNM system in predicting HNSCC prognosis. Therefore, combining the two methods can facilitate individualized patient consultation and care.

Patchouli alcohol ameliorates the learning and memory impairments in an animal model of Alzheimer's disease via modulating SIRT1.

BACKGROUND: Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases. Patchouli alcohol (PA), a major active ingredient isolated from Pogostemonis Herba, exhibits extensive bioactivity in the central nervous system (CNS) and exerts neuroprotective effects. PURPOSE: This study aimed to investigate the anti-AD effects of PA in an animal model of AD and to elucidate the underlying molecular mechanisms. METHODS: The gas chromatography (GC) was used to determine the ability of PA to pass the blood-brain barrier (BBB) in rats after oral administration. The sporadic AD rat model was established by intracerebroventricularly (ICV) injection with streptozotocin (STZ). PA (25 and 50 mg/kg) was given to rat orally once daily for 42 consecutive days. Morris water maze (MWM) test was performed to determine the learning and memory functions of the STZ-induced AD rats. EX527, a silent information regulator 1 (SIRT1) selective inhibitor, was used to investigate the involvement of SIRT1 in the anti-AD effects of PA in rats. RESULTS: PA could penetrate the BBB. MWM test results showed that PA could significantly ameliorate the learning and memory deficits induced by STZ in rats. Meanwhile, PA enhanced the expression of SIRT1, and markedly alleviated the tau pathology by inhibiting the hyperacetylation (at the site of Lys174) and hyperphosphorylation (at the sites of Thr181, Thr205, Ser396 and Ser404) of tau protein. PA also efficiently suppressed the activation of microglia and astrocytes, and the beta-amyloid (Aß) expression and the deacetylation of nuclear factor-kappa B (NF-κB) at Lys 310 (K310) in the STZ-treated AD rats. EX527, a SIRT1 selective inhibitor, could partially abolish the cognitive deficits improving effect of PA and inhibit the down-regulation of acetylated tau and acetylated NF-κB p65, suggesting that PA exhibited neuroprotective effects against AD via upregulating SIRT1. CONCLUSION: This study reported for the first time that PA could penetrate the BBB to exert its protective effects on the brain after a single-dose oral administration. The current experimental findings also amply demonstrated that PA could improve the cognitive and memory impairments in the STZ-induced AD rat model. The underlying mechanisms involve the alleviations of neuroinflammation, tau pathology and Aß deposition via modulating of SIRT1 and NF-κB pathways. All these findings strongly suggest that PA is a promising naturally occurring compound worthy of further development into an anti-AD pharmaceutical.

Effect of prophylactic gastrostomy on nutritional and clinical outcomes in patients with head and neck cancer.

BACKGROUND: We aimed to identify which enteral feeding method was most beneficial for patients and compare clinical outcomes, quality of life, and complication rates by assessing patients who underwent prophylactic percutaneous endoscopic gastrostomy (pPEG) tube, reactive percutaneous endoscopic gastrostomy (rPEG) tube or reactive nasogastric tube (rNGT) insertion. METHODS: Patients with head and neck cancers (HNCs) were enrolled between April 1, 2013 and April 17, 2019 (n = 335; 296 males, 39 females). Data concerning patient characteristics and treatment modalities were extracted from the medical records. Comparisons between enteral feeding methods were made by univariate and multivariate analysis. Overall survival (OS) outcomes were analyzed by the log rank test using the Kaplan-Meier method. RESULTS: A total of 335 patients were included. The median follow-up time was 29.5 months. There were forty-six patients in the pPEG tube group, 23 patients in the rPEG tube group, and 266 patients in the rNGT group. pPEG, increased body-mass index (BMI), and N0-1 category were significantly associated with less weight loss in the multivariate analysis (all P < 0.05). pPEG decreased the rate of radiotherapy delay compared with that of reactive interventions (23.1% vs. 47.1%, P = 0.007). In terms of quality of life, global health status, role functioning, emotional functioning, cognitive functioning, pain, and dyspnea were significantly improved in the pPEG tube group (all P < 0.05). BMI and weight loss were independent prognostic factors for clinical survival outcomes (all P < 0.05). CONCLUSIONS: pPEG could improve nutrition outcomes, reduce treatment delay, and maintain quality of life.

Nano-Honokiol ameliorates the cognitive deficits in TgCRND8 mice of Alzheimer's disease via inhibiting neuropathology and modulating gut microbiota.

Introduction: Honokiol (HO) exerts neuroprotective effects in several animal models of Alzheimer's disease (AD), but the poor dissolution hampers its bioavailability and therapeutic efficacy. Objectives: A novel honokiol nanoscale drug delivery system (Nano-HO) with smaller size and excellent stability was developed in this study to improve the solubility and bioavailability of HO. The anti-AD effects of Nano-HO was determined. Methods: Male TgCRND8 mice were daily orally administered Nano-HO or HO at the same dosage (20 mg/kg) for 17 consecutive weeks, followed by assessment of the spatial learning and memory functions using the Morris Water Maze test (MWMT). Results: Our pharmacokinetic study indicated that the oral bioavailability was greatly improved by Nano-HO. In addition, Nano-HO significantly improved cognitive deficits and inhibited neuroinflammation via suppressing the levels of TNF-α, IL-6 and IL-1ß in the brain, preventing the activation of microglia (IBA-1) and astrocyte (GFAP), and reducing ß-amyloid (Aß) deposition in the cortex and hippocampus of TgCRND8 mice. Moreover, Nano-HO was more effective than HO in modulating amyloid precursor protein (APP) processing via suppressing ß-secretase, as well as enhancing Aß-degrading enzymes like neprilysin (NEP). Furthermore, Nano-HO more markedly inhibited tau hyperphosphorylation via decreasing the ratio of p-Tau (Thr 205)/tau and regulating tau-related apoptosis proteins (caspase-3 and Bcl-2). In addition, Nano-HO more markedly attenuated the ratios of p-JNK/JNK and p-35/CDK5, while enhancing the ratio of p-GSK-3ß (Ser9)/GSK-3ß. Finally, Nano-HO prevented the gut microflora dysbiosis in TgCRND8 mice in a more potent manner than free HO. Conclusion: Nano-HO was more potent than free HO in improving cognitive impairments in TgCRND8 mice via inhibiting Aß deposition, tau hyperphosphorylation and neuroinflammation through suppressing the activation of JNK/CDK5/GSK-3ß signaling pathway. Nano-HO also more potently modulated the gut microbiota community to protect its stability than free HO. These results suggest that Nano-HO has good potential for further development into therapeutic agent for AD treatment.

Soluble ST2 in serum predicts the prognosis of idiopathic pulmonary fibrosis: a retrospective study.

Background: Idiopathic pulmonary fibrosis (IPF) is a heterogeneous and progressive fibrosing interstitial lung disease with a poor prognosis. However, there are currently no effective biomarker that can reliably predict the prognosis for IPF in clinic. The serum level of soluble suppression of tumorigenicity-2 (sST2), which is involved in the immune response, has proven to be a prognostic predictor for various diseases. Previous studies have confirmed that the immune dysfunction plays an important role in the pathogenesis of IPF and the serum sST2 concentrations in patients with IPF are elevated. However, the relationship between sST2 and the prognosis of IPF remains unknown. Methods: A total of 83 patients with IPF and 20 healthy controls from 2016 to 2021 were enrolled and demographic variables, indices of lung function testing as well as the biomarkers including the sST2 were obtained at baseline. During follow-up, the primary endpoint was defined as all-cause death and clinical deterioration. Cox hazard models and Kaplan-Meier method were used to assess the prognostic value of various indices including sST2. Results: Mean duration of follow-up was 29 months, during which 49 patients had an event, and of them, 35 patients died. The sST2 level was higher in the IPF patients compared with the healthy controls. Although the sST2 level did not directly predict all-cause death in the present study, it was proved to be an independent predictor of event-free survival. Multivariate forward stepwise model which was adjusted by age, sex, and body surface area (BSA) showed that the overexpression of sST2 increased the hazard ratio [1.005, 95% confidence interval (CI): 1.001-1.010]. A higher sST2 serum level heralded more deterioration and the poor outcomes. Moreover, the effect of sST2 on the prognosis of IPF may not necessarily involve the development of IPF-related pulmonary hypertension (PH). Conclusions: In our study, the sST2 serum level was significantly elevated and a higher serum level of sST2 predicted more deterioration and poor outcomes in patients with IPF. Thus, sST2 can serve as a valuable prognostic biomarker for the outcome of IPF. However, further multicenter clinical trials of larger sample size are needed in the future.

Effective Treatment of Small Uncomplicated Skin Abscesses with Fire Needle: A Case Series.

BACKGROUND: Uncomplicated skin abscesses are collections of pus within the skin structure and are usually caused by bacterial infections. Clinically, they are quite common and inevitably affect people of any age. The current management strategies comprise prompt initiation of antibiotics and incision and drainage. However, pain and the long healing process of skin lesions can cause distress to a lot of patients. Fire needling is a characteristic treatment in traditional Chinese medicine (TCM) and has proven effective in treating skin abscesses. Moreover, fire needle therapy has a more desirable cosmetic outcome in contrast to surgical debridement. The purpose of the study is to demonstrate the rapid, effective, minimally invasive, and better cosmetic outcomes of fire needles in the treatment of uncomplicated skin abscesses. METHODS: A total of 10 patients, aged between 1 and 45 years, with skin abscesses, were recruited. All patients who fulfilled the inclusion criteria with lesions less than 4 cm in diameter were topically treated with mupirocin ointment twice a day after fire needle therapy. If the lesion was still purulent after 2 days, it was treated again with fire needle therapy. The efficacy was assessed by a 4-grade scale at 2 days, 1 week, 2 weeks, 4 weeks and 12 weeks post-fire needling. RESULTS: Lesions with a diameter of less than 2 cm achieved significant remission (SR) or partial remission (PR), after 2 days post-treatment and reached complete remission (CR) or significant remission (SR) after 1 week following treatment. Meanwhile, lesions with a diameter of 2-4 cm achieved PR after 2 days and were assessed as CR or SR 1 week after post-fire needle therapy. None of the patients had a recurrence within 12 weeks after treatment. CONCLUSION: Fire needle therapy is a promising treatment method for uncomplicated skin abscesses smaller than 4 cm, which warrants further in-depth and more large-scale studies.

Comparison of the chemical constituents and anti-Alzheimer's disease effects of Uncaria rhynchophylla and Uncaria tomentosa.

BACKGROUND: Uncaria tomentosa, which has similar chemical constituents with Uncaria rhynchophylla, has been reported to alleviate cognitive impairments in Alzheimer's disease (AD) animal models. This study aimed to compare the chemical constituents and anti-AD effect of the ethanol extracts of U. tomentosa (UTE) and U. rhynchophylla (URE). METHODS: The high-performance liquid chromatography (HPLC) was used to compare the chemical constituents of UTE and URE. Streptozotocin (STZ) was intracerebroventricularly (ICV) injected into adult male Sprague-Dawley (SD) rats to establish AD model. UTE (400 mg/kg) or URE (400 mg/kg) was administrated intragastrically once daily to the rats for 6 consecutive weeks. Morris water maze (MWM) test was conducted to assess the neurological functions in the STZ-induced AD rats. The brain tissues of the rats were harvested for further biochemical assay. RESULTS: The MWM test results showed both UTE and URE could significantly improve the learning and memory impairments induced by STZ in rats. Both UTE and URE could significantly inhibit the hyperphosphorylation of tau protein, reduce the elevated levels of pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α), enhance activities of antioxidant enzymes (SOD, CAT and GPx) and increase the protein expression of HO-1. In addition, UTE could decrease the malondialdehyde (MDA) level. Furthermore, both UTE and URE significantly enhanced Akt activation, down regulated the activation of glycogen synthase kinase 3ß (GSK-3ß), and induced the nuclear translocation of Nrf2 in the STZ-induced AD rats. CONCLUSIONS: UTE and URE contained similar chemical constituents. We found for the first time that both of them could ameliorate cognitive deficits in the STZ-induced AD rats. The underlying molecular mechanism involve suppression of tau hyperphosphorylation, anti-oxidant and anti-neuroinflammation via modulating Akt (Ser473)/GSK3ß (Ser9)-mediated Nrf2 activation. These findings amply implicate that both of UTE and URE are worthy of being developed clinically into pharmaceutical treatment for AD.