Anti-Neuroinflammatory Potential of Natural Products in the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is an age-related chronic progressive neurodegenerative disease, which is the main cause of dementia in the elderly. Much evidence shows that the onset and late symptoms of AD are caused by multiple factors. Among them, aging is the main factor in the pathogenesis of AD, and the most important risk factor for AD is neuroinflammation. So far, there is no cure for AD, but the relationship between neuroinflammation and AD may provide a new strategy for the treatment of AD. We herein discussed the main etiology hypothesis of AD and the role of neuroinflammation in AD, as well as anti-inflammatory natural products with the potential to prevent and alleviate AD symptoms, including alkaloids, steroids, terpenoids, flavonoids and polyphenols, which are available with great potential for the development of anti-AD drugs.

Establishing a glutamine metabolism-based model for predicting the prognosis of low-grade glioma.

Background: The natural history of patients with low-grade glioma (LGG) varies widely, but most patients eventually deteriorate, leading to poor prognostic outcomes. We aim to develop biological models that can accurately predict the outcome of LGG prognosis. Methods: Prognostic genes for glutamine metabolism were searched by univariate Cox regression, and molecular typing was constructed. Functional enrichment analysis was done to evaluate potential prognostic-related pathways by analyzing differential genes in different subtypes. Enrichment scores of specific gene sets in different subtypes were measured by gene set enrichment analysis. Different immune infiltration levels among subtypes were calculated using algorithms such as CIBERSORT and ESTIMATE. Gene expression levels of prognostic-related gene signatures of glutamine metabolism phenotypes were used to construct a RiskScore model. Receiver operating characteristic curve, decision curve and calibration curve analyses were used to evaluate the reliability and validity of the risk model. The decision tree model was used to determine the best predictor variable ultimately. Results: We found that C1 had the worst prognosis and the highest level of immune infiltration, among which the highest macrophage infiltration can be found in the M2 stage. Moreover, most of the pathways associated with tumor development, such as MYC_TARGETS_V1 and EPITHELIAL_MESENCHYMAL_TRANSITION, were significantly enriched in C1. The wild-type IDH and MGMT hypermethylation were the most abundant in C1. A five-gene risk model related to glutamine metabolism phenotype was established with good performance in both training and validation datasets. The final decision tree demonstrated the RiskScore model as the most significant predictor of prognostic outcomes in individuals with LGG. Conclusion: The RiskScore model related to glutamine metabolism can be an exceedingly accurate predictor for LGG patients, providing valuable suggestions for personalized treatment.

Enhanced Water Solubility and Anti-Tumor Activity of Oleanolic Acid through Chemical Structure Modification.

Cancer has been a major health problem in the world in the past decades. It is urgent to develop new, effective and safe drugs for the treatment of cancer. There are many pentacyclic triterpenoids with positive anti-tumor activity and safety in nature. Oleanolic acid (OA), as one of the pentacyclic triterpenoids, also has broad biological activities including liver protection, anti-inflammatory, hypoglycemic, antiviral and anti-tumor. Therefore, to investigate its anti-tumor activity and mechanism, many OA derivatives have been developed. Some derivatives are less toxic to normal hepatocytes, which may be due to the strong liver protection ability of OA. However, the poor water solubility of OA is one of the main reasons for the weak anti-tumor activity. It is reported that some OA derivatives could enhance solubility by chemically linking some hydrophilic groups to improve anti-tumor activity. This review not only summarizes the highly water-soluble OA derivatives that can improve anti-tumor activity reported in recent years, but also introduces their possible anti-tumor mechanisms.

Zinc-dependent deacetylases (HDACs) as potential targets for treating Alzheimer's disease.

Alzheimer's disease (AD) as the most prevalent dementia type has become one of the greatest threats to the health and life of the elder people worldwide. Although there has been a great effort in the discovery of anti-AD drugs, those approval drugs only demonstrated the temporarily relieving the symptoms without completely stopping the progression of the neuropathology. It is very urgent and reasonable to develop more effective agents against other therapeutic targets. In the last two decades, zinc-dependent deacetylases (HDACs) have attracted much attention as an important group of epigenetic targets in drug discovery, because five HDAC inhibitors have been approved for clinically treating cancers. This review is to summarize the possible roles of HDACs in AD pathophysiology and their inhibitors used in AD studies. And the future perspectives related to HDACs as epigenetic targets for treating AD by their selective inhibitors, multi-target inhibitors or PROTACs are also discussed.

Clinical outcomes of fetal ovarian masses diagnosed by prenatal ultrasonography and literature review.

With the advancement of prenatal examination technology, more and more fetus with ovarian masses are diagnosed. However, whether such children need intervention measures after delivery, there is no more unified diagnosis and treatment measures in the world. In this study, postnatal data and clinical outcome of fetal diagnosed with ovarian masses were analyzed. We also combined with relevant literature to explore the postpartum intervention measures and timing of such children. A total of 57 cases of abdominal masses from the reproductive system were included in the study. These children were diagnosed with ovarian masses after birth. We collected from 2012 to 2020, the prenatal examination revealed the presence of abdominal masses from the reproductive system, and diagnosis was confirmed by imaging examinations after childbirth. We counted the fetal period data of these children, compared the changes in the postnatal pathology and intervention measures. A total of 57 cases of ovarian masses were diagnosed prenatally, 1 case was lost to follow-up, and 56 cases were finally included in the study. After birth a total of 21 cases of ovarian masses were treated conservatively, of which 18 cases resolved spontaneously during the follow-up process, with an average follow-up period of 30.88 ±â€…18.16 weeks. There were statistically significant differences in the nature and the maximum diameter of the mass between the two groups receiving conservative treatment or surgical treatment after delivery (P < .05).Univariate and multivariate Logistic regression analysis showed that there were significant differences in the nature and diameter of the mass between two groups (P < .05). In addition, we divided the children undergoing postpartum surgery into a laparoscopic surgery group and a conventional open surgery group. Through data analysis, we found that there were statistically significant differences in the age of operation, operation time, and hospitalization days in the two groups of these children (P < .05). Children diagnosed with ovarian masses prenatally generally have a good prognosis. For these children, the treatment plan should be developed according to the child general condition. If child with ovarian mass is treated with surgery, the preservation of ovarian tissue should be emphasized regardless of the size, nature, and torsion of the mass.

Histone Deacetylases as Epigenetic Targets for Treating Parkinson's Disease.

Parkinson's disease (PD) is a chronic progressive neurodegenerative disease that is increasingly becoming a global threat to the health and life of the elderly worldwide. Although there are some drugs clinically available for treating PD, these treatments can only alleviate the symptoms of PD patients but cannot completely cure the disease. Therefore, exploring other potential mechanisms to develop more effective treatments that can modify the course of PD is still highly desirable. Over the last two decades, histone deacetylases, as an important group of epigenetic targets, have attracted much attention in drug discovery. This review focused on the current knowledge about histone deacetylases involved in PD pathophysiology and their inhibitors used in PD studies. Further perspectives related to small molecules that can inhibit or degrade histone deacetylases to treat PD were also discussed.

A solid-supported organocatalyst for asymmetric Mannich reaction to construct C2-quaternary indolin-3-ones.

A simple and novel solid-supported organocatalyst from a 2-chlorotrityl chloride resin-immobilized 4-hydroxyproline was developed, and this organocatalyst has been used for the asymmetric Mannich reaction of 2-aryl-3H-indol-3-ones and aldehydes/ketones. A series of C2-quaternary indolin-3-ones were prepared in good yields (up to 83%) and with excellent diastereoselectivities (up to 20 : 1) and enantioselectivities (up to 99% ee). In addition, the organocatalyst can be recovered by simple filtration and also be reused for the asymmetric Mannich reaction without significant loss of catalytic efficiency.

Bladder cancer-associated transcript 2 contributes to nephroblastoma progression.

BACKGROUND: Nephroblastoma is a common pediatric kidney tumor. Existing evidence has indicated that long non-coding RNAs (lncRNAs) may be associated with tumorigenesis such as nephroblastoma. However, the contribution of lncRNA bladder cancer-associated transcript 2 (BLACAT2) to tumorigenesis and the postoperative nephroblastoma prognosis remains unknown. METHODS: In total, 50 pairs of patient nephroblastoma and corresponding adjacent non-tumorous tissues were analyzed for BLACAT2 expression. The underlying roles of BLACAT2 in nephroblastoma cells were also investigated. The BLACAT2 level was detected in four nephroblastoma cell lines and normal cell line NGC-407 using a quantitative real-time polymerase chain reaction. The potential influence of BLACAT2 on nephroblastoma cells was explored based on RNA interference technology in vitro and in vivo. Moreover, the microRNA targeted by BLACAT2 and its target gene were predicted and verified. RESULTS: BLACAT2 silencing suppressed cell proliferation, colony formation and tumor growth in vivo and promoted cell apoptosis in vitro. Furthermore, BLACAT2 could directly bind to miR-504-3p, thereby decreasing miR-504-3p expression. In addition, the impact of miR-504-3p on proliferation, colony formation and nephroblastoma cell apoptosis was reversed by BLACAT2. Wnt11 was identified as a target of miR-504-3p. CONCLUSIONS: The present study revealed that a novel BLACAT2/miR-504-3p/Wnt11 axis is associated with nephroblastoma, where BLACAT2 is able to sponge miR-504-3p to down-regulate Wnt11.

Attenuation of NLRP3 Inflammasome Activation by Indirubin-Derived PROTAC Targeting HDAC6.

Histone deacetylase 6 (HDAC6) is a potential therapeutic target for treating several diseases. A recent study revealed that HDAC6 is important for NLRP3 inflammasome activation, suggesting that targeting HDAC6 could be useful for treating many inflammatory disorders. Using the proteolysis targeting chimera (PROTAC) strategy, we herein report an HDAC6 degrader with low cytotoxicity by tethering a selective HDAC6 inhibitor derived from a natural product, indirubin, with pomalidomide, a CRBN E3 ligand. Our HDAC6 degrader efficiently and selectively decreased HDAC6 levels in several cell lines, including activated THP-1 cells. Application of this HDAC6 degrader attenuated NLRP3 inflammasome activation in LPS-induced mice, which for the first time demonstrates that HDAC6 PROTAC could be a novel strategy to treat NLRP3 inflammasome-associated diseases.

Neonatal biliary atresia combined with preduodenal portal vein: A case report.

BACKGROUND: Congenital biliary atresia is a type of obstruction of the bile ducts inside and outside the liver, which can lead to cholestatic liver cirrhosis and eventually liver failure. The preduodenal portal vein (PD-PV) is a rare developmental malformation of the PV. The PV courses in front of the duodenum. However, very few cases of neonatal biliary atresia combined with PD-PV have been reported in the scientific literature. CASE SUMMARY: A 1-mo-and-4-d-old child was admitted to the hospital in January because of yellowish skin. After surgical consultation, surgical intervention was recommended. The child underwent Hilar-jejunal anastomosis, duodenal rhomboid anastomosis, and abdominal drainage under general anesthesia. During the operation, the PV was located at the anterior edge of the duodenum. CONCLUSION: Diagnoses: (1) Congenital biliary atresia; (2) PD-PV; and (3) Congenital cardiovascular malformations. Outcomes: Recommendation for liver transplantation. Lessons: The choice of treatment options for neonatal biliary atresia combined with PD-PV.

Indirubin Derivatives as Dual Inhibitors Targeting Cyclin-Dependent Kinase and Histone Deacetylase for Treating Cancer.

To utilize the unique scaffold of a natural product indirubin, we herein adopted the strategy of combined pharmacophores to design and synthesize a series of novel indirubin derivatives as dual inhibitors against cyclin-dependent kinase (CDK) and histone deacetylase (HDAC). Among them, the lead compound 8b with remarkable CDK2/4/6 and HDAC6 inhibitory activity of IC50 = 60.9 ± 2.9, 276 ± 22.3, 27.2 ± 4.2, and 128.6 ± 0.4 nM, respectively, can efficiently induce apoptosis and S-phase arrest in several cancer cell lines. In particular, compound 8b can prevent the proliferation of a non-small-cell lung cancer cell line (A549) through the Mcl-1/XIAP/PARP axis, in agreement with the unique modes of action of the combined agents of HDAC inhibitors and CDK inhibitors. In an A549 xerograph model, compound 8b showed significant antitumor efficacy correlated with its dual inhibition. Our data demonstrated that compound 8b as a single agent could be a promising drug candidate for cancer therapy in combination with CDK and HDAC inhibitors.

Clinical predictors of readmission after surgery for Hirschsprung disease.

ABSTRACT: The reasons for readmission of children with Hirschsprung disease (HD) are multiple. The study aims to predict the relevant factors for the readmission of children with HD by collecting and analyzing the relevant data of the child's admission to the hospital at the time of surgery.A retrospective review was performed including all patients with surgical treatment of HD at our institution between the years of 2011 to 2020. Univariate and multivariate Logistic regression analysis were performed to obtain the independent risk factor for this study. The receiver operating characteristic curve (ROC) were used to assess the performance of derived models.A total of 162 patients were identified. The average presurgery weights were 6.93 ±â€Š1.78 kg in the readmission group and 8.38 ±â€Š3.17 kg in the non-readmission group. Six children were classified as a low-weight in the readmission group, and 11 children classified as low-weight in the non-readmission group. The length of the intestinal tube after resection was 25.25 ±â€Š15.21 cm in the readmission group, and 16.23 ±â€Š4.10 cm in the non-readmission group. The ROC for the prediction model of readmission after HD surgery (AUC = 0.811).In children undergoing the HD surgery, we showed preoperative low body weight and long intra-operative bowel resection significantly increase the probability of readmission due to complications.

Laparoscopic resection of ileocaecal duplication in children (report of 15 cases).

BACKGROUND: Enteric duplication is a congenital anomaly with varied clinical presentation that requires surgical resection for definitive treatment. Ileocaecal (IC) duplications are duplications located at the IC junction, not clearly identified in all the published series. The reported treatment is IC resection and ileocolic anastomosis. The purpose of our study was to present our experience in successfully resection of IC duplication by laparoscope, thus avoiding bowel resection in children. MATERIALS AND METHODS: A retrospective review was conducted of medical records of 15 patients with diagnosis of IC duplication, treated in the Department of Paediatric Surgery of our hospital, within the period from November 2013 to September 2018. RESULTS: Laparoscopic resection of IC duplication was successfully performed in all children without bowel resection. The operation time was 50-90 min (55 ΁ 10 min), and the post-operative hospitalization time was 5-7 days (average, 6 days). The 15 patients were followed up for 6-12 months (average, 10 months). No recurrence was found by abdominal ultrasound examination. The wound had small scars with good appearance of umbilicus. CONCLUSIONS: The laparoscopic approach allows for confirming the diagnosis and accurately defining the exact site of duplication, as well as for effective and safe treatment. Laparoscopic excision of IC duplication without bowel resection is a safe option and is worth promoting.

Neonatal giant hepatic hemangioma: A case report.

RATIONALE: Hepatic hemangioma is the third most common pediatric tumor, and it is rare in the neonatal period. This case study presents a rare case of hepatic hemangioma found in a neonate. PATIENT CONCERNS: A girl who was 18 days of age with the emergence of jaundice and an abdominal mass was admitted for physical examination in the local department. DIAGNOSES: An ultrasound showed that the hepatic left lobe was about 9 cm × 7 cm × 7 cm in size. A CT scan indicated a giant hemangioma in the hepatic left lobe. MRI detected a lesion measuring about 92 mm × 71 mm × 68 mm. INTERVENTIONS: The patient was treated with propranolol 3.5 mg PO bid (body weight 3.8 kg) after 1 week of admission for 4 weeks, but the mass did not appear to regress. Surgery was then performed successfully. OUTCOMES: The patient recovered well without recurrence beyond one year. LESSONS: Imaging strategies and prenatal diagnosis are vital for the diagnosis of infantile hepatic hemangioma. Propranolol is effective in both cutaneous and hepatic multifocal and diffuse hemangioma. Adequate treatment time is necessary to cure the disease. The role of propranolol in massive hepatic hemangioma remains uncertain and needs further investigation.

Diagnostic and prognostic value of microRNAs in cholangiocarcinoma: a systematic review and meta-analysis.

BACKGROUND AND AIM: Several dysregulated microRNAs (miRNAs) have been implicated in the pathogenesis of cholangiocarcinoma (CCA); however, small sample sizes and invariable research designs are limitations, hindering a thorough analysis of miRNAs as diagnostic and prognostic tools for CCA. This study aimed to systematically summarize the clinical value of miRNAs in human CCA both for all available miRNAs and single miRNA with multiple researches. METHODS: Pooled parameters included the area under the curve (AUC), sensitivity, specificity, and hazard ratios (HRs) to separately determine overall diagnostic and prognostic performance. Subgroup and sensitivity analyses were performed only in the event of heterogeneity. Thirty-four studies including 12 diagnostic studies and 22 prognostic studies were eligible for inclusion in this meta-analysis. RESULTS: We observed that miR-21, miR-26, miR-483, miR-106a, miR-150, miR-192, and miR-194 were employed for distinguishing patients with CCA from healthy controls. Pooled sensitivity, specificity, and AUC were 0.82 (95% confidence interval [CI] 0.77-0.86), 0.83 (95% CI 0.75-0.89), and 0.88 (95% CI 0.85-0.91), respectively. Abnormal expression of miR-21, miR-26a, miR-192, miR-200c, miR-221, miR-29a, miR-191, miR-181c, miR-34a, miR-106a, miR-203, and miR-373 in patients was confirmed to associate with poor survival rate. Pooled HRs and 95% CIs were calculated using STATA, resulting in the pooled HR of 1.47 (95% CI 0.91-2.37) for overall survival (OS), 0.67 (95% CI 0.16-2.81) for disease-free survival (DFS), 2.31 (95% CI 1.59-3.36) for progression-free survival (PFS), and 2.68 (95% CI 0.88-8.15) for relapse-free survival (RFS). Thus, CCA patients with dysregulated miRNA expression were confirmed to have shorter OS, DFS, PFS, and RFS. Data regarding the diagnostic and prognostic roles of miR-21 suggested pooled diagnostic results of miR-21 for sensitivity, specificity, and AUC were 0.85 (95% CI 0.76-0.91), 0.92 (95% CI 0.81-0.97), and 0.93 (95% CI 0.91-0.95), respectively, suggesting better diagnostic performance of miR-21 compared with other miRNAs. Meanwhile, pooled prognostic result of miR-21 for HR was 1.88 (95% CI 1.41-2.51), indicating miR-21 could more appropriately predict shorter OS in patients with CCA. CONCLUSION: miRNAs may provide a new approach for clinical application, and miR-21 may be a promising biomarker for diagnosis and prognosis of CCA.

A newborn patient with both annular pancreas and Meckel's diverticulum: A case report of an unusual association.

RATIONALE: Annular pancreas (AP) is recognized as a cause of duodenal obstruction in children, while children with Meckel's diverticulum (MD) are usually asymptomatic. Here we present a rare case with both AP and MD, which was identified by abdominal exploration during diamond-shaped duodenoduodenostomy. PATIENT CONCERNS: A "double-bubble" sign was found by ultrasound at 35 week of pregnancy. After 39 weeks of pregnancy, the male patient was transferred to the Department of General Surgery, Children's Hospital of Soochow University because of a suspected duodenal stenosis. DIAGNOSES: Preoperative abdominal X-ray examination indicated "double-bubble" sign. AP was confirmed by exploratory surgery, with an MD located 30 cm above the ileocecal valve. INTERVENTIONS: Diamond-shaped duodenoduodenostomy and a wedge resection of the intestine with end-to-end anastomosis were performed OUTCOMES:: The patient recovered and his appetite was good without vomiting. LESSONS: Our experience demonstrates that abdominal exploration is essential for children with gastrointestinal malformations.