Resilience to structural and molecular changes in excitatory synapses in the hippocampus contributes to cognitive function recovery in Tg2576 mice

Plaques of amyloid-β(Aβ)and neurofibrillary tangles are the main pathological characteristics of Alzheimer’s disease(AD).However,some older adult people with AD pathological hallmarks can retain cognitive function.Unraveling the factors that lead to this cognitive resilience to AD offers promising prospects for identifying new therapeutic targets.Our hypothesis focuses on the contribution of resilience to changes in excitatory synapses at the structural and molecular levels,which may underlie healthy cognitive performance in aged AD animals.Utilizing the Morris Water Maze test,we selected resilient(asymptomatic)and cognitively impaired aged Tg2576 mice.While the enzyme-linked immunosorbent assay showed similar levels of Aβ42 in both experimental groups,western blot analysis revealed differences in tau pathology in the pre-synaptic supernatant fraction.To further investigate the density of synapses in the hippocampus of 16-18 month-old Tg2576 mice,we employed stereological and electron microscopic methods.Our findings indicated a decrease in the density of excitatory synapses in the stratum radiatum of the hippocampal CA1 in cognitively impaired Tg2576 mice compared with age-matched resilient Tg2576 and non-transgenic controls.Intriguingly,through quantitative immunoelectron microscopy in the hippocampus of impaired and resilient Tg2576 transgenic AD mice,we uncovered differences in the subcellular localization of glutamate receptors.Specifically,the density of GluA1,GluA2/3,and mGlu5 in spines and dendritic shafts of CA1 pyramidal cells in impaired Tg2576 mice was significantly reduced compared with age-matched resilient Tg2576 and non-transgenic controls.Notably,the density of GluA2/3 in resilient Tg2576 mice was significantly increased in spines but not in dendritic shafts compared with impaired Tg2576 and non-transgenic mice.These subcellular findings strongly support the hypothesis that dendritic spine plasticity and synaptic machinery in the hippocampus play crucial roles in the mechanisms of cognitive resilience in Tg2576 mice.

The Role of CK20, p53 and p63 in Differentiation of Some Urothelial Lesions of Urinary Bladder, Immunohistochemical Study

Background: Differentiation of urothelial hyperplasia, dysplasia and carcinoma in situ (CIS) may pose diagnostic difficulties. We aim to evaluate the role of CK20, p53 and p63 in differentiation of such lesions. Methods: we evaluate these markers in 213 cases of bladder lesions (14 hyperplasia, 7 dysplasia, 5 CIS, 25 noninvasive and 162 invasive urothelial carcinoma) in a retrospective study on sections from formalin-fixed, paraffin-embedded blocks. Cytoplasmic staining considered for CK20 and nuclear staining for p53 and p63. Results: CK20 was expressed in 14 out of 14 hyperplasia (4 strong, 7 moderate, 3 weak), in 7 out of 7 dysplasia (4 strong , 3 moderate), in 5 out of 5 CIS, in 19 out of 25 noninvasive carcinoma;strong in 11 (7 low grade, 4 high grade), moderate in 7 (5 low grade, 2 high grade), and weak in 1 case of low grade, in 136 out of 162 invasive carcinoma;strong in 46 (22 grade II, 24 grade III), moderate in 71 (2 grade I, 58 grade II, 11 grade III), and weak in 19 (2 grade I, 15 grade II, 2 grade III), no expression in 2 cases of grade IV. p53 was expressed in 7 out of 14 hyperplasia (weak in all cases), in 7 out of 7 dysplasia (5 strong, 2 moderate), in 5 out of 5 CIS (strong in all cases), in 20 out of 25 noninvasive carcinoma (8 strong, 9 moderate, 3 weak), in 135 out of 162 invasive carcinoma (34 strong, 73 moderate, 28 weak). p63 was expressed in 14 out of 14 hyperplasia, in 7 out of 7 dysplasia, in 4 out of 5 CIS, in 25 out of 25 noninvasive carcinoma, and in 134 out of 162 invasive carcinoma (28 strong, 63 moderate, 43 weak). CK20 was insignificant in noninvasive and significant in invasive carcinoma, while p53 and p63 were significant in noninvasive and invasive carcinoma. Conclusion: CK20, p53 and p63 are useful in differentiation of different bladder lesions.

Therapeutic effect of soluble worm protein acting as immune regulatory on colitis

Objective: To investigate the anti-inflammatory effect of the protein derived from the soluble factor of Heligmosomoides polygyrus(H. polygyrus) excretory-secretory in a colitis model.Methods: Colitis was induced by providing drinking water containing 3% dextran sodium sulfate(DSS) for a week. DSS was administrated in a cycle protocol, each cycle consisted of 7 days of 3% DSS in the drinking water and followed by 7 days of regular water. This study consisted of five treatment groups, including Groups A(control)received untreated water, B(DSS only, without excretory-secretory), and C–E injected(i.p.) with excretory-secretory protein(H. polygyrus excretory-secretory total, excretorysecretory 28 k Da and excretory-secretory 55 k Da, respectively). Mice received injection every week. The injection of excretory-secretory was started from the 6th weeks and continued until 11 weeks. At the end of 11 weeks of the experiment, mice were sacrificed,colon tissue was removed and then subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis, flow cytometry, real-time PCR and histology examination.Results: Mice received H. polygyrus excretory-secretory 55 k Da reduced mono-nuclear cell infiltrations. H. polygyrus excretory-secretory 55 k Da induced the down-regulation of m RNA interferong expression. There were significant differences in the expression of m RNA interferon in the colon of mice after the administration of the excretory-secretory55 k Da protein fraction compared with other groups(P < 0.001), whereas m RNA transforming growth factorb expression up regulated in the colon of mice after the administration of the excretory-secretory 55 k Da protein fraction compared with total excretory-secretory group(P < 0.05). The treatment of colitis in mice with excretorysecretory 55 k Da protein fractions modulated interleukin-10(IL-10) expression,whereas excretory-secretory total and excretory-secretory 28 k Da protein fractions insufficient promoted IL-10 expression. Excretory-secretory 55 k Da proteins fraction promoted IL-10 expression via Foxp3-independent pathways.Conclusions: Excretory-secretory 55 k Da protein could reduce inflammation and have potential therapy. H. polygyrus excretory-secretory 55 k Da was the soluble factor that may help in the development of novel treatments to cure colitis.

Protective effect of Nigella sativa L.to gastric mucous of indomethacin-induced gastric ulcer rats

OBJECTIVE To investigate the effect of Nigella sativa L.as gastric protective on indomethacin-induced rats.METHODS the design of this research is randomized post test control group design.The rats were randomly divided into 5 groups which 5 rats in each.Rats were fasted for 8h before treatment.The first group was a control group(only gave aquadest as vehicle orally).The second group was subjected to induced with indomethacin 30mg·kg-1.The rest groups were subjected to induced by indomethacin and methanolic extract of Nigella sativa L.200,300 and 400mg·kg-1 every 8h for 24 h,respectively,for third,fourth and fifth group.Rats were sacrificed after anesthetized with ketamine and gastric were washed before observed.Macroscopic observation based on a score of lesion and microscopic observation on gastric based by histological HE staining.Whole data were analysis of an ANOVA statistical program.RESULTS The administration of Nigella sativa L.significantly decreased gastric ulcer macroscopically starting at dose 100,200 and 300mg·kg-1(P<0.05).Microscopic observation showed significant decreasing at dose 200 and 300mg·kg-1(P<0.05).Interestingly,there was no significant different between control and dose 300mg·kg-1.Negative correlation between lesion and doses were-0.919,-0.953 for macroscopic and microscopic lesion respectively.It means there was strong correlation between dose and lesion,higher dose lesser lesion.The mechanism of gastric protective of NigellasativaL.may caused by the bioactive compound such as thymoquinone which known as antiinflammation and antioxidant.CONCLUSION Methanolic extract of Nigella sativa L.decreased peptic ulcer both macroscopic and microscopic conditions on indomethacin-induced rats.

Study of the Expression of ALDH1 and CD44 Stem Cell Markers in Male Breast Cancers

Aims: Male breast cancer represents - mor aggressiveness and drug resistance. CSCs are characterized by CD44 and/or ALDH1 expression. In this study, we investigated their expression in male breast cancer. Method: Two in situ ductal carcinoma (DCIS) and 18 invasive duc- tal carcinoma (IDC) male breast cancer cases were studied with Jefferson IRB approval. Membrane staining of CD44 was scored by the percentage of positivity. Cytoplasmic expression of ALDH1 was considered positive. Results: Ten cases had high CD44 expression, which were all IDC. Both DCIS and in situ component of IDC were CD44 low. ALDH1 was only positive in 15 IDCs. ALDH1+ cells were mostly in the invasive component. Both DCIS cases were negative for ALDH1. Among the 15 ALDH1+ IDCs, five with only invasive component had a higher percentage (aver- age 4.4%) of positive cells compared to the other eight with in situ components (average 2.0%). Metastatic cells in sen- tinel lymph nodes had a similar expression pattern of CD44 and ALDH1 as their primary tumor. Conclusion: CD44 and ALDH1 are expressed in male breast cancers and they are overexpressed in invasive cancer compared to carcinoma in situ. These findings suggest that CSCs play an important role in the progression to invasive carcinoma.

Hypoxic Preconditioning Improved Neuroprotective Effect of Bone Marrow-Mesenchymal Stem Cells Transplantation in Acute Glaucoma Models

This study explored the novel strategy of hypoxic preconditioning of Bone Marrow Mesenchymal Stem Cells (BM-MSCs) before intra vitreal transplantation to improve neuroprotective effects of Retinal Ganglion Cells (RGCs) in Acute Glaucoma Models. The methods of this research were isolated mesenchymal stem cells from the bone marrow of adult wild-type Sprague-Dawley (SD) rats. BM-MSCs were cultured under normoxic or hypoxic (1% oxygen for 24 hours) conditions. Normoxic or hypoxic BM-MSCs were transplanted intravitreally 1 week after ocular hypertension induction by acutely increasing IOP to 100 - 120 mmHg for 60 minutes. Rats were killed 4 weeks after transplanted. Apoptosis was examined by tunnel assay and expression Brn3b (Brn3b = RGCs marker) by immunohistochemical analysis of the retina. Results showed that transplantation of hypoxic preconditioning BM-MSCs in acute glaucoma models resulted in a significant apoptosis decreasing (p < 0.05) and an significant increasing in RGCs (p < 0.05), as well as enhanced mor-phologic and functional benefits of stem cell therapy versus normoxic BM-MSCs transplantation. Conclusions: Hypoxic preconditioning enhances the capacity of BM-MSCs transplantation to improve neuroprotective effects of RGCs in Acute Glaucoma Models.

Prediction of hereditary nonpolyposis colorectal cancer using mRNA MSH2 quantitative and the correlation with nonmodifiable factor

BACKGROUND Hereditary non-polyposis colon cancer is a dominantly inherited syndrome of colorectal cancer(CRC),with heightened risk for younger population.Previous studies link its susceptibility to the DNA sequence polymorphism along with Amsterdam and Bethesda criteria.However,those fail in term of applicability.AIM To determine a clear cut-off of MSH2 gene expression for CRC heredity grouping factor.Further,the study also aims to examine the association of risk factors to the CRC heredity.METHODS The cross-sectional study observed 71 respondents from May 2018 to December 2019 in determining the CRC hereditary status through MSH2 mRNA expression using reverse transcription-polymerase chain reaction and the disease’s risk factors.Data were analyzed through Chi-Square,Fischer exact,t-test,Mann-Whitney,and multiple logistics.RESULTS There are significant differences of MSH2 within CRC group among tissue and blood;yet,negative for significance between groups.Through the blood gene expression fifth percentile,the hereditary CRC cut-off is 11059 fc,dividing the 40 CRC respondents to 32.5%with hereditary CRC.Significant risk factors include age,family history,and staging.Nonetheless,after multivariate control,age is just a confounder.Further,the study develops a probability equation with area under the curve 82.2%.CONCLUSION Numerous factors have significant relations to heredity of CRC patients.However,true important factors are staging and family history,while age and others are confounders.The study also established a definite cut-off point for heredity CRC based on mRNA MSH2 expression,11059 fc.These findings shall act as concrete foundations on further risk factors and/or genetical CRC future studies.

MiR-148a inhibits angiogenesis by targeting ERBB3

MicroRNAs （miRNAs） play an important role in carcinogenesis in various solid cancers including breast can-cer. Down-regulation of microRNA-148a （miR-148a） has been reported in certain cancer types. However, the biological role of miR-148a and its related targets in breast cancer are unknown yet. In this study, we showed that the level of miR-148a was lower in MCF7 cells than that in MCF10A cells. V-erb-b2 erythroblastic leukemia viral oncogene homolog 3 （ERBB3） is a direct target of miR-148a in human breast cancer cells through direct binding of miR-148a to ERBB3 3’-UTR region. Overexpression of miR-148a in MCF7 cells inhibited ERBB3 expression, blocked the downstream pathway activation including activation of AKT, ERK1/2, and p70S6K1, and decreased HIF-1α expression. Furthermore, forced expression of miR-148a attenuated tumor angiogenesis in vivo. Our re-sults identify ERBB3 as a direct target of miR-148a, and provide direct evidence that miR-148a inhibits tumor an-giogenesis through ERBB3 and its downstream signaling molecules. This information would be helpful for target-ing the miR-148a/ERBB3 pathway for breast cancer prevention and treatment in the future.

Single-cell systems neuroscience:A growing frontier in mental illness

The development of effective treatments for psychiatric disease has been disappointing in recent decades given the advancements in neuroscience.Moreover,rising rates of mental ilness such as addiction and depression compel scientists and physicians to discover novel and creative solutions.One such approach that has proven effective is systems neuroscience:A focus on networks as opposed to mechanism.Further,investigation at the single-cell and circuit level is likely to be fruitful in such endeavors as this resolution describes the functional psychopathology that allows for intervention.

Managing spondylitis tuberculosis in a patient with underlying diabetes and hypothyroidism:A case report

BACKGROUND Tuberculosis(TB)remains one of the highest Asia’s health problems.Spondylitis TB in diabetes mellitus(DM)and hypothyroidism patients is a rare case of extrapulmonary tuberculosis.However,there is a lack of therapeutic guidelines to treat spondylitis TB,particularly with type 2 DM(T2DM)and hypothyroidism as comorbidities.Here we present a case of spondylitis TB with T2DM and hypothyroidism in a relatively young patient and its therapeutic procedure.CASE SUMMARY We report the case of a 35-year-old male patient from Surabaya,Indonesia.Based on anamnesis,physical examination,and magnetic resonance imaging,the patient has been categorized in stage II of spondylitis TB with grade 1 paraplegia.Surprisingly,the patient also had a high HbA1c level,high thyroid stimulating hormone,and low free T_(4)(FT_(4)),which indicated T2DM and hypothyroidism.A granulomatous process was observed in the histopathological section.The antituberculosis drugs isoniazid and rifampicin were given.In addition,insulin,empagliflozin,and linagliptin were given to control hyperglycemia conditions,and also levothyroxine to control hypothyroidism.CONCLUSION The outcome was satisfactory.The patient was able to do daily activities without pain and maintained normal glycemic and thyroid levels.For such cases,we recommend the treatment of spondylitis TB by spinal surgery,together with T2DM and hypothyroidism therapies,to improve the patients’condition.Prompt early and non-invasive diagnoses and therapy are necessary.

THE HBx PROTEIN EXPRESSION IN LIVER CANCER

The expression of HBx protein in liver tissues from 48 cases of different liver diseases, Including 32 cases of hepatocellular carcinoma (HCC), 10 of chronic hepatitis (CH), 2 of angioma and 4 cases of normal liver was studied. These samples were tested for HBx protein, HBsAg by modified ABC method. Positive rates of HBx in cancer and adjacent Uver tissue were 75. 0% and 62. 5%, and positive rates of HBsAg were 37.5% and 78.1% respectively. The occurence of HBx in the absence of HBsAg was more frequently observed in tissues from HCC (46.9%) man CH (0%). The results showed mat expression of HBx was more active than that of HBsAg, and it Is suggested that HBx might be a useful marker for the diagnosis of liver cancer.

Inhibition of vascular endothelial growth factor expression by Chinese medicine of Hedyotis diffusa Willd herbal compounds

The Hedyotis diffusa Willd herbal compounds(HDWHCs)are commonly used as Chinese medicine to treat cancer patients with established clinical therapeutic efficacy in China.However,the underlying mechanisms remain to be elucidated.In this study,we used freeze-dried powder of the water extracts of HDWHCs to investigate the potential mechanisms of HDWHCs in cancer treatment.HDWHCs treatment significantly inhibited vascular endothelial growth factor(VEGF)mRNA levels and VEGF transcriptional activation in cancer cells.HDWHCs also had a remarkable inhibitory effect on the expression of hypoxia-inducible factor 1alpha(HIF-1alpha).Forced expression of HIF-1αrestored VEGF transcriptional activation inhibited by HDWHCs,indicating that HDWHCs suppressed VEGF expression through decreasing HIF-1alpha expression.Moreover,HDWHCs inhibited cyclooxygenase-2(COX-2)expression,and overexpression of HIF-1alpha restored HDWHCs’inhibitory effect on COX-2 at transcriptional level.These findings may provide better understanding of HDWHCs’anti-cancer mechanism in cancer treatment.

Three primary malignancies in 17 years in a man with chronic hepatitis B

The occurrence of three primary malignancies in a single patient is an infrequent phenomonen with an estimated occurrence at 0.1%.Notably,patients with hepatocellular carcinoma(HCC)are particularly unlikely to develop extrahepatic primary malignancies.In this light,we present a case of patient with chronic hepatitis B who developed HCC,as well as two other primary malignancies.This case exhibits an exceedingly rare combination of cancers,underlining the importance of continued cancer surveillence in those with a history of primary malignancy.