bluuebunny/crossref_metadata_2025 huggingface dataset:
Antioxidant Status in Healthy Humans after Acute Consumption of Juçara Fruits (Euterpe edulis)
Authors: Di Pietro Patricia , Cardoso Alyne , Vieira Francilene , Boaventura Brunna , de Liz Sheyla , Borges Graciele , de Assis Maria Alice , Fett Roseane , da Silva Edson
Published: June 2021

Source of support: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).

This study aimed evaluating the effect of acute consumption of juçara juice (Euterpe edulis) rich in anthocyanin on biomarkers of oxidative stress in healthy subjects. This cross‐over clinical trial used water as control. Eleven volunteers were evaluated 4 times, before consumption and 1h, 2h and 4h after the intake of juice or water. The parameters evaluated were: ferric reducing antioxidant potential (FRAP), uric acid, glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT) and lipid hydroperoxides (LH). Analyses of variance for repeated measures revealed a significant effect of this treatment on FRAP and GPx. A moderate correlation was observed between FRAP and uric acid (r = 0.31). A significant interaction between type of treatment and time on lipid oxidation (HL) was also found. After ingestion of juice, relative average changes showed within the 2nd hour maximum elevation in the enzymatic activities of SOD (34.3%), CAT (18%) and GPx (8.5%), was reached. The juçara juice ingestion showed effect on the for the FRAP and enzymatic activity of GPx and interaction of lipid peroxidation that decreased over time. Further studies that investigate the antioxidant properties of the fruit juçara in the human are needed.
Association between Intake of Fish and Shellfish and Milk and Dairy Products with Cardio Vascular Disease(CVD) Risk Factors in Middle‐Aged Female with Type 2 Diabetes(T2D)
Authors: Kim Hyesook , Park Seokyung , Yang Hyesu , Choi Young Ju , Huh Kap Bum , Chang Namsoo
Published: June 2021

This study was aimed to examine the association between intake of fish and shellfish and milk and dairy products with CVD risk factors in 356 middle‐aged (40‐64 years) female with T2D. Dietary food intake was assessed by semiquantitative food frequency questionnaire method. The average daily intakes of fish and shellfish and milk and dairy products were 63.9 g and 127.5 g, respectively. After adjustment for age, body mass index and energy intake, multiple regression analysis showed that intake of fish and shellfish (p=0.0423) and milk and dairy products (p=0.0094) was negatively associated with serum triglyceride level. These results suggest that intake of fish and shellfish and milk and dairy products is associated with decreased CVD risk in middle‐aged female patients with T2D.

[This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF‐2013R1A1A2011544) and Brain Korea 21 Plus.]
Evaluation of the phenolic compounds and fatty acid profiles of English walnut (J. regia) extract
Authors: Kim Yoo‐Sun , Lee Jae‐Hwan , Choi Sang‐Woon , Kim Yuri
Published: June 2021

The purpose of the present study was to determine various ingredients of English walnut (J. regia), including phenolic acids, flavonoids, essential fatty acids, and tocopherols which are expected to provide health benefits. A high‐performance liquid chromatographic (HPLC) method was used to evaluate the contents of phenolic acids and tocopherols in walnut extracts. HPLC separation was performed on a symmetry C18 column for phenolic components and u‐Porasil column for tocopherols analysis. Saturated and unsaturated fatty acids were also quantified through gas chromatography (GC) using a SP‐2560 column and a flame ionization detector. We found that catechin (137.54 mg/ 100g) was a dominating phenolic acid in walnut extracts followed by chlorogenic acid (13.60 mg/100 g), ellagic acid (12.57 mg/100 g), and gallic acid (10.70 mg/100 g). In lipid extraction, a high content of polyunsaturated fatty acids and a low concentration of saturated fatty acids were observed. The most predominant component of walnut oil was linoleic acid, comprising 64.6 %, followed by 14.6 % of linolenic acid and 12.6 % of oleic acid, which agreed with previous published data. We also found that γ‐tocopherol was the most abundant tocopherol, followed by minor quantities of α‐tocopherol. In conclusion, our data provide each ingredient of walnut extract and indicate walnut contains high concentration of various polyphenolic and antioxidative compounds which are suggested to be the major bioactive compounds for the health benefits.
Capsaicin and Capsiate: Comparison of Effects at a Traditional Meal
Authors: Swint Jenna , Beining Katrina , Bryant Jennifer , Tucker Robin , Ludy Mary‐Jon
Published: June 2021

Spicy foods containing capsaicin, the pungent compound in hot peppers, have been reported to promote negative energy balance. A non‐pungent alternative is capsiate, contained in CH‐19 sweet peppers. This study's purpose was to compare effects of capsaicin and capsiate consumed orally as part of a traditional meal. Subjects (n=11M, 13F; aged 25.2±10.2 y, BMI 21.7±2.4 kg/m2) who consumed spicy foods for 15.4±10.6 y prior to the study (n=3 < monthly, n=8 >3 times weekly, 13 intermediate) participated. In this randomized crossover trial, self‐reported appetitive sensations were recorded at 30‐min intervals for 4.5 hrs after capsaicin (~2 mg), capsiate (~2 mg), or control (no pepper) meals. Blood pressure (BP) was recorded at 15‐min intervals for 1 hr after test meals. Post‐meal energy intake (EI) was measured at an ad libitum challenge meal (4.5 hr after test meals) and self‐reported for the remainder of each test day. While the flavor of the control was better liked than the capsaicin‐containing meal (p=0.022), there were no differences in liking of capsiate and control meals. All meals were well liked (蠅 3.2 on a 5‐pt visual analog scale (VAS)). Likelihood of purchasing a similarly flavored restaurant meal was good for all meals (蠅 2.9 on a 5‐pt VAS), with subjects tending to be more likely to purchase capsiate or control meals (p=0.066). Appetite, BP, or EI did not vary based on meal. These findings suggest that low capsaicin and capsiate doses are well accepted when added to traditional meals and are unlikely to cause adverse effects. Lack of metabolic effects may be related to lack of power to stratify by spicy food use or low capsaicin and capsiate doses.
Protective Effect of HT057 Treatment on Dextran Sulfate Sodium Induced Colitis in Mice
Authors: Lee Donghun , Song Jungbin , Kim Hyun Soo , Lee Hyun Jeong , Kim Young‐Sik , Lee Sung Hyun , Park Juyeon , Kim Hocheol
Published: June 2021

Inflammatory Bowel Disease (IBD) is a chronic and frequently disabling inflammatory disorder of the intestine. Atractylodes macrocephala and Taraxacum mongolicum have been used for various inflammatory diseases in traditional Korean medicine and can be used as food ingredients worldwide. In this study, protective effect of the herbal mixture of A. macrecephala and T. mongolicum (HT057) in dextran sulfate sodium (DSS) induced experimental colitis which mimics the clinical and histological features of IBD. Colitis was induced by 5% DSS with drinking water in balb/c mice. HT057 (30, 100 or 300 mg/kg) was orally administered to mice twice per day for 10 days. Colon length, mouse weight, disease activity index (DAI), myeloperoxidase (MPO) activity, and histological score were measured after administration. HT057 significantly improved the colon length (7.2%, p<0.01 at 100 mg/kg) which reflects the extent of colon damage in IBD as compared to control group. Mice with DSS‐induced colitis showed loss of body weight and DAI score which is a result of IBD along with diarrhea and blood loss compared to normal group, while mice treated with HT057 showed significantly protected the loss of body weight (7.8%, p<0.001 at 100 mg/kg) and DAI score (27.6%, p<0.001 at 300 mg/kg). HT057 also significantly reduced MPO activity, and histological score which reflect the severity and extent of inflammation. In conclusion, HT057 has protective effect in inflammatory intestinal mucosal injury against DSS induced colitis and these findings suggest that HT057 might be a promising functional food ingredient against IBD.
Effect of Yoghurt and its Probiotics on Fecal Probiotic Content; a Randomized Controlled Trial
Authors: Ivey Kerry , Yang Rongchang , Ryan Una , Lin Szu‐Yu , Hodgson Jonathan , Prince Richard
Published: June 2021

Background

Despite a long history of safe use and the incorporation of probiotics into current therapeutic guidelines, the ability of yogurt and its probiotics to colonize the gastrointestinal tract, the appropriate mode of administration in order to maximize probiotic efficacy remain uncertain.

Aim

To determine the effect of daily probiotic supplementation of Lactobacillus acidophilus La5 (La5) and Bifidobacterium animalis subsp lactis BB12 (BB12) from capsules and the whole food (yogurt) form, on faecal counts of La5, BB12, and total Bifidobacteria.

Methods

Following a 3‐week washout period, 156 men and women over 55 y were randomized to a 6‐week double‐blinded parallel study. The four intervention groups were: A) probiotic yogurt plus probiotic capsules; B) probiotic yogurt plus placebo capsules; C) control milk plus probiotic capsules; and D) control milk plus placebo capsules. Results are presented as the median (IQR) number of bacteria per g feces.

Results

When compared to control milk, probiotic yoghurt supplementation increased the fecal content of both BB12 [control milk: 10 (1‐100) BB12/g; probiotic yogurt: 820 (4‐2,815); P<0.001] and to a lesser extent La5 [control milk: 95 (6‐222) La5/g; probiotic yogurt: 107 (23‐634) La5/g; P=0.035]. When compared to placebo capsules, probiotic capsules increased the fecal content of BB12 [control milk: 10 (1‐356) BB12/g; probiotic yogurt: 230 (14‐1,409); P<0.001], but did not alter La5 content (P>0.05).

Conclusion

In relation to probiotic capsules, supplementation with probiotic bacteria from yogurt was more efficacious at increasing the number of beneficial bacteria residing in the gastrointestinal tract.
Dietary D‐psicose in substitution for sucrose influences adipose tissue metabolism in a mouse model of obesity
Authors: Kim Su Jeong , Sung Mi‐Kyung , Kim Sun‐Eun , Lim Wha Sun , Lee Kang‐Pyo , Park Chong‐Jin , Kim Hye‐Jung , Moon Min‐Sun
Published: June 2021

D‐psicose (DP), a C‐3 epimer of D‐fructose, is known to possess anti‐adipogenic effect. We investigated the effect of dietary DP substitution for sucrose on adipose tissue metabolism in ob/ob mice. C57BL/6J ob/ob mice were assigned to either AIN‐93G or 5% w/w DP diet. After sacrifice on week 12, we measured adipose tissue mass, adipocyte size, and fat deposition. We determined the mRNA expression of genes related with inflammation and adipogenesis in white adipose tissue (WAT). Gene expression patterns of WAT and pathway analysis were performed using Illumina MouseRef‐8 and Ingenuity Pathway Analysis, respectively. In mice fed DP supplemented diet, body weight, mass of adipose tissue, adipocyte size, and fat deposition decreased.The mRNA expression of genes related with inflammation (TNF‐α, IL‐6) and adipogenesis (PPAR‐γ, C/EBP‐α) in WAT decreased in mice fed DP supplemented diet. Genomic analysis revealed that 63 up‐regulated and 106 down‐regulated genes were affected by DP supplemented diet. The top networks in response to DP supplementation include inflammatory response, lipid metabolism, molecular transport, and small molecule biochemistry. Specifically, expression of inflammatory response related genes including CD36, CD44, TLR8, and TLR13 was down‐regulated in response to DP supplemented diet, which were in line with the observed decreased mRNA expression of TNF‐α and IL‐6. Our data suggest that DP replacement has beneficial effects on adipose tissue metabolism. [High Value‐added Food Technology Development Program 113035‐3, Food and Rural Affairs]
Novel Drug DCQ Induces Colon Cancer Cell Apoptosis Through HIF‐1α Pathway
Authors: Sougiannis Alexander‐Jacques , Saxena Arpit , Kaur Kamajeet , Depaepe Sarah , Fayad Raja
Published: June 2021

Recent developments in the field of cancer genomics have shown transcription factor HIF‐1α as a major player in the survival and proliferation of colorectal tumors. Presence of hypoxic areas in tumors facilitate the differentiation and nuclear translocation of HIF‐1α which leads to transcription of hypoxic genes causing vascularization and metastasis of tumors. Hypoxia targeted drug engineering has led to significant advancements in cancer treatments as a method of directly utilizing the hypoxic regions against the tumor to cause cell death and inhibition of growth. Novel drug DCQ (2‐benzoyl‐3‐phenyl 6,7‐dichloroquinoxaline 1,4‐dioxide) has shown promising anti‐tumor results in‐vitro and in‐vivo. The purpose of this study was to utilize a tumor xenograft mouse model to investigate the effectiveness and mechanism of action of DCQ. Methods: 10 week old Balb/c mice were injected subcutaneously with 2 million CT‐29 cells and were monitored for tumor growth over 14 days. Then, mice were randomly assigned to two treatment groups: DCQ treatment given at 17mg/kg body weight and 100μL DMSO injection as control. Injections were given bi‐weekly over a four week period. At sacrifice, tumors were obtained and sectioned. Results: DCQ caused significant decrease in tumor weight (p<0.05) and final tumor area (p<0.05) at time of sacrifice than DMSO injected mice. Histological analysis showed increased total apoptotic area (p<0.05) in tumor tissue sections. Western blot analysis showed a decreased nuclear expression of HIF‐1α (p<0.05).

Conclusions

DCQ increases tumor apoptosis through mechanisms involving down regulation of HIF‐1α. Future investigations will observe the effect of DCQ using APCmin/+ mouse model in a supplemental study.
Possible roles of CXCL17 in angiogenesis during tumor progression
Authors: Matsui Aya , Morikawa Shunichi , Ezaki Taichi
Published: June 2021

Recently, chemokines have drawn more attention as important targets in cancer therapy from viewpoints of tumor metastasis and recruitment of immune suppressor cells. Our previous studies showed that CXCL17 expression by tumor cells enhanced the tumor growth in mice, and demonstrated that CXCL17 also induced migration of myeloid‐derived suppressor cells (MDSCs) into the tumors. In the present study, we focused on tumor blood vessels as one of responsible factors in the progression of CXCL17‐expressing tumors to clarify the effects of CXCL17 and neutrophil‐like MDSCs on tumor blood vessels. CXCL17‐expressing colon26

cells (a mouse colon cancer cell line) injected subcutaneously into BALB/c mice, showed an increase in CD31+ endothelial cell areas and well‐maintained blood vessel meshworks compared with CXCL17‐nonexpressing control tumors. Moreover, the number of NG2+ pericytes increased in the tumor vessels of these CXCL17‐expressing tumors. Furthermore, CXCL17 was adopted in the chemotaxis assay to separate the neutrophil‐like MDSCs from mouse splenocytes. Tumor cells transplanted together with the CXCL17‐chemotactic neutrophil‐like MDSCs enhanced their tumor angiogenesis compared with these transplanted with irrelevant splenocytes. These results suggest that CXCL17 may induce the structural and functional changes in tumor blood vessels via controlling neutrophil‐like MDSCs.
Whole Genome Sequence of Multiple Myeloma‐Prone C57BL/KaLwRij Mouse Strain Suggests the Origin of Disease Involves Multiple Cell Types
Authors: Wilson William , Amend Sarah , Chu Liang , Lu Lan , Liu Pengyuan , Serie Daniel , Su Xinming , Xu Yalin , Wang Dingyan , Gramolini Anthony , Hurchla Michelle , Vachon Celine , Colditz Graham , Vij Ravi , Weilbaecher Katherine , Tomasson Michael
Published: June 2021

Monoclonal gammopathy of uncertain significance (MGUS) is the requisite precursor to multiple myeloma (MM), a malignancy of antibody‐producing plasma B‐cells. The genetic basis of MGUS and its progression to MM remains poorly understood. C57BL/KaLwRij (KaLwRij) is a spontaneously derived inbred mouse strain with a high frequency of benign idiopathic paraproteinemia (BIP), a phenotype with similarities to MGUS including progression to MM. Using mouse haplotype analysis, human MM SNP array data, and whole exome and whole genome sequencing of KaLwRij mice, we identified novel KaLwRij gene variants, including deletion of Samsn1 and deleterious point mutations in Tnfrsf22 and Tnfrsf23. These variants significantly affected multiple cell types implicated in MM pathogenesis including B‐cells, macrophages, and bone marrow stromal cells. These data demonstrate that multiple cell types contribute to MM development prior to the acquisition of somatic driver mutations in KaLwRij mice, and suggest that MM may an inherently non‐cell autonomous malignancy.
Sustained Delivery of EGCG and TMQ On Fracture Healing Using Male Rats As A Model
Authors: Benghuzzi Hamed , Tucci Michelle , Cameron Joseph
Published: June 2021

The benefits of natural products as an alternative to conventional treatment of various diseases have begun to emerge. Nigella sativa and green tea, natural herbs have been used for many acute as well as chronic conditions. The objectives of this study were (1) to successfully deliver the active components of black seed, thymoquinone (TMQ), and green tea, epigallocatechin‐3‐gallate, or EGCG at sustained levels using a tricalcium phosphate delivery system (TCPL); (2) to evaluate the effects TMQ and EGCG on bone healing (induced femoral defect) in adult male rats. Thirty animals were randomly divided into five equal groups. Groups I and II animals served as control, and sham, while groups III and IV served as TMQ and EGCG experimental groups (0.2 g of TQM or EGCG loaded TCPL). Group V animals served as TMQ (0.2 gm)+EGCG (0.2gm) treated group. Blood, x‐rays and body weights were collected and recorded weekly. Metabolic biomarkers were also evaluated weekly. At the end of 30 days, animals were sacrificed and vital as well reproductive organs were collected and analyzed morphometrically. The results revealed the following: (i) gross anatomical observation indicated an increase in the healing pattern of animals in all experimental groups compared to the sham operated group, (ii) the ease of osteogenesis was in the following order: TMQ+EGCG>TMQ>EGCG>shams, and (iii) no significant differences where detected in the levels of cholesterol, proteins, maliondialdehyde and alkaline phosphatase in all groups. In conclusion, it appears that sustained delivery of TMQ+EGCG can synergistically enhance bone healing compared to TMQ and EGCG treated animals.
A role for FIZZ1 in a model of scleroderma
Authors: Liu Tianju , Martins Vanessa , Wu Zhe , Gonzalez De los Santos Francina , Phan Sem
Published: June 2021

De novo genesis of the myofibroblast is a key feature of tissue fibrosis, including the dermal fibrosis associated with scleroderma but its origin remains controversial. Since dermal fibrosis is accompanied by loss of subcutaneous fat, the possibility that adipocytes could serve as progenitors for myofibroblasts was evaluated in this study. Based on the ability of FIZZ1 to induce myofibroblast differentiation, its effects on adipocytes derived from 3T3‐L1 cells were evaluated. The results showed that FIZZ1 inhibited expression of the adipocyte differentiation markers, PPAR‐γ, FABP4 and C/EBPα while promoting myofibroblast differentiation as determined by induction of α‐smooth muscle actin (α‐SMA) and type I collagen expression. To evaluate in vivo significance, the effects of FIZZ1 deficiency were evaluated using the mouse bleomycin (BLM)‐induced scleroderma model. In FIZZ1 knockout mice, BLM treatment caused less subcutaneous lipoatrophy and dermal fibrosis compared to that in wild type animals. These in vivo findings were consistent with the in vitro findings showing the ability of FIZZ1 to induce adipocyte to myofibroblast trans‐differentiation. Interestingly, FIZZ1 expression was dramatically induced when 3T3‐L1 cells were fully differentiated into adipocytes, suggesting their role as a source of FIZZ1 in vivo. These findings suggest a potential role for FIZZ1 in regulating the subcutaneous lipoatrophy as a consequence of adipocyte trans‐differentiation into the myofibroblast, which is a key player in the dermal fibrosis associated with scleroderma.
KvLQT1 Function in Lung Physiology
Authors: Girault Alban , Chebli Jasmine , Prive Anik , Maille Emilie , Peloquin Fannie , Robichaud Annette , Brochiero Emmanuelle
Published: June 2021

Acute lung injury and its more severe form, acute respiratory distress syndrome (ARDS), are characterized by extensive alveolar injury and lung edema. It has been established that the resolution of ARDS parameters is highly dependent on alveolar regeneration and edema resorption. Because we previously demonstrated that KvLQT1 potassium channels are involved in alveolar repair processes and in the control of ion and liquid transports in vitro, we now decided to investigate their role in lung function and in the resolution of ARDS parameters in vivo, using a KvLQT1 knockout (KO) mice model.

We first noted an absence of morphological difference in airway structures (trachea, bronchus and alveolus) between control (wild type, WT) and KvLQT1 KO mice. We then evaluated the impact of KvLQT1 extinction on the mechanical properties of the respiratory system using the flexiVent system (SCIREQ Inc.). Our results showed a significant increase of tissue damping and dynamic resistance of the respiratory system in KvLQT1 KO mice compared to WT.

The role of KvLQT1 was then evaluated in a model of lung edema induced by thiourea, disrupting the integrity of endothelial/alveolar barrier. We observed a significant increase in the wet/dry ratio (W/D, index of lung edema) in both WT and KO mice. Interestingly, the thiourea‐induced W/D increase was partially prevented by a treatment with R‐L3, a KvLQT1 activator, in WT mice. However, this beneficial effect of R‐L3 was lost in KO mice.

Our results show that the activation of KvLQT1 K+ channels could play a role in the resolution of ARDS parameters, especially pulmonary edema resorption.

Funded by CIHR, NSERC, FRQS.
Medical and Social Aspects of Termination of Pregnancy in Semey city in Kazakhstan
Authors: Yesbolatova Gulya , Kozhanova Saule , Sagimova Gulzira , Mekebaeva Alma , Temirtassova Zhanna , Musina Alya
Published: June 2021

Formation of risk groups of abortion is an important part of the mother and child health program which is possible with a detailed analysis of epidemiological data.

Objectives

To identify risk groups and critical periods for miscarriage based on the analysis of medical and social aspects of abortion in Semey, Eastern Kazakhstan.

Methods

Study was performed on 507 cases of miscarriage during 2011‐2012. Women were at age of 15‐45 years.

Results

20% of miscarriage cases were in age 21‐23 years, 28.8% were unmarried. With increasing age group the proportion of cases of miscarriage decreased from 16.8% in 24‐26 years to 3.7% for 42‐45 years. The proportion of unmarried women also reduced from 20.0% to 5.3% respectively. Miscarriage among girls of 15‐17 years was in 3.9% and girls of 18‐20 years in 13.0% of all cases, 80‐90% were unmarried. More than 65% of miscarriage occur in the first period of mature from 21 to 35 years. Among the medical and social aspects of abortion 65.8% are spontaneous abortion, 24.6% abortion for social and 9.6 % for medical reasons. These data did not differ in 2011 and 2012. Spontaneous abortion in 2011 occurred in 66.0% of cases, and in 2012 in 65.7 % of cases, for social reasons in in 25.1% and 23.9% respectively, for medical indications were at 9.6% and 10.3 % of cases respectively. The greatest number of cases of spontaneous abortion accounted on 16 and 20 weeks. On 16 weeks spontaneous abortion occurred in 16.9 % and on 20 weeks in 20.3% of all cases.

Conclusion

Among the medico‐social aspects of miscarriage more than 65 % are spontaneous abortion. The risk group for miscarriage is the age group of 21‐23 years with the high percentage of unmarried women.
Long Term Probiotic Use Increases Bone Density in Female Mice
Authors: Collins Fraser , Quach Darin , Irwin Regina , Schaefer Laura , Britton Robert , Parameswaran Narayanan , McCabe Laura
Published: June 2021

Probiotic bacteria are micro‐organisms that when taken in adequate amounts have beneficial effects on the host. A previously published study from our laboratory demonstrated that short term (4 week) treatment of male but not female mice, with Lactobacillus reuteri (ATCC 6475) lead to increased bone density. In the present study we investigate the long term (8 weeks) effects of L. reuteri treatment in female mice.

Female Balb/c mice were treated by gavaging with L. reuteri (1x109cfu/ml) or vehicle control (MRS broth) three times per week. In addition, L. reuteri (1.5x108cfu/ml) or vehicle was added to the drinking water for the duration of the study. At 4 and 8 weeks femoral trabecular bone parameters were measured by µCT. Bone marrow (BM) cellular phenotype was analyzed by flow cytometry and RANKL, OPG and TGFβ gene expression evaluated by qPCR.

Similar to our earlier studies in fertile female mice, we did not observe any effect of LR on bone parameters at 4 week treatment. Interestingly however, at 8 weeks a significant 30.3% increase in femoral trabecular bone volume fraction was identified in L. reuteri treated mice. Examination of BM cellular phenotype and gene expression demonstrated that L. reuteri increased numbers of CD4+ T cells and significantly reduced RANKL expression at 4 weeks but not at 8 weeks. OPG and TGFβ expression were found to be elevated at 4 weeks, with TGFβ expression significantly increased at 8 weeks in the L. reuteri cohort.

Together our data indicates that long term L. reuteri treatment increases femoral trabecular bone in female mice via the regulation of immune cells and expression of key genes involved in osteoclastogenesis
Second Year Medical Students' Perceptions of Self‐directed versus Cued Learning of Pharmacotherapeutics in a High Fidelity Medical Simulation (HFMS)
Authors: Gorman Laurel , Hernandez Caridad , Castiglioni Analia
Published: June 2021

Evidence suggests that teaching pharmacology in second year high HFMS promotes learning, but no data exists on ideal methods to teach pharmacology in HFMS. The aim of this study was to compare medical students' perceptions of two methods, student‐directed non‐cued vs. cued drug selection for teaching pharmacology during a pulmonary insufficiency and shock physiology HFMS using SimMan 3G®. We employed a cross‐over design where 50% of the students, working in groups of 3, were asked to select treatment choices based on recall during a shock HFMS but were cued to drug choices during a pulmonary insufficiency HFMS. The other half completed the task in the opposite order. All groups participated in a multidisciplinary debrief immediately after the HFMS. Following HFMS, students completed a voluntary survey assessing perceptions. Results are reported as mean rating on a 1‐5 Likehart scale where 5=strongly agree. Forty‐three (43%) percent of learners preferred the cued method, 33% preferred the non‐cued method, and 25% reported no preference. Students using the non‐cued method for the shock HFMS rated promotion of critical thinking higher in comparison with cued learning (4.8 vs 4.5, respectively), although the difference was not significant (p=0.08). Students using either method equally perceived that learning pharmacology in HFMS was clinically relevant (4.8), improved autonomic pharmacology understanding (4.5), provided clerkship preparation (4.7), and that feedback in the debriefing enhanced learning (4.75). In conclusion, learners in these simulations perceived that both non‐cued and cued teaching methods enhanced their learning.
Influence of Hormones on Social Rank and Vulnerability to Cocaine Reinforcement in Female Cynomolgus Monkeys
Authors: Kromrey Sarah , Czoty Paul , Nader Michael
Published: June 2021

Nonhuman primate (NHP) social groups, which represent a continuum from environmental enrichment in dominant (DOM) monkeys to chronic social stress in subordinates (SUB), have been used to study susceptibility and resilience to human diseases, including drug abuse. We have shown that social rank influences sensitivity to cocaine (COC) in NHPs, although it is not clear how hormone fluctuations may influence rank or how hormones are modified after rank is established. This study used female NHPs and examined whether estrogen (E2), progesterone (P4) or testosterone (T) predicted eventual rank, changed following hierarchy establishment, or was associated with susceptibility to COC self‐administration (SA). Prior to social housing, E2 exposure across the menstrual cycle was greater in eventual SUB compared to eventual DOM; there were no differences in P4. After hierarchies were formed (4 monkeys/pen), E2 exposure across the cycle decreased in SUB and differences between ranks were no longer observed. DOM had decreases in P4 after hierarchies stabilized, whereas SUB showed increases in P4 following rank formation. T concentrations did not predict or differ between ranks; decreases in T concentrations were observed across all ranks following hierarchy formation. When given access to COC (0.0003‐0.1 mg/kg/inj), SUB acquired COC SA at lower doses than DOM. This effect could be driven by higher circulating E2 since an inverse relation between E2 and dose of COC at which SA occurred was observed. These results enhance our understanding of an individual's response to factors related to social environment and their relationship to COC SA. Such information will aid in the development of pharmacological treatment strategies for drug addiction. DA017763, DA036973
The Effects of a Humanized Anti‐Cocaine Monoclonal Antibody on Cocaine Metabolism and Urinary Excretion in Mice
Authors: Wetzel Hanna , Tabet Michael , Norman Andrew
Published: June 2021

The humanized recombinant anti‐cocaine monoclonal antibody h2E2 is a potential immunotherapy for cocaine abuse. h2E2 may be expected to inhibit the metabolism of cocaine, yet over one hour it had no effect on cocaine's elimination rate. It was hypothesized that this apparent elimination represents a slowed distribution. The effects of h2E2 on cocaine metabolism and excretion over 6 hours were investigated. Mice were injected with h2E2 or vehicle, then one hour later with an equimolar dose of cocaine. At times ranging from 45 s to 6 h, mice were sacrificed and blood was collected. Urine was collected from the time of cocaine injection until animals were sacrificed. GC/MS was used to quantify cocaine and its major metabolite in mice, ecgonine methyl ester (EME). In vehicle and h2E2 treated mice, after the initial one‐hour decline plasma cocaine concentrations were steady, though at levels 2.8‐fold higher in h2E2 treated mice. In vehicle treated mice, EME formation was complete within the first hour, then declined with a 57 min half‐life. EME plasma concentrations were lower in the presence of h2E2 over the first hour, and undetectable thereafter. This indicates that the metabolism of cocaine was inhibited by h2E2. Cocaine and EME concentrations were 89 and 50% lower in the urine of mice treated with h2E2, indicating that h2E2 also inhibited urinary excretion of cocaine. As there is no evidence that cocaine is being metabolized or excreted, it is likely that the disappearance of cocaine from the plasma represents distribution into a non‐plasma compartment, or a change in the metabolic pathway. Despite these dramatic effects, how cocaine is eliminated from the body in the presence of h2E2 remains to be elucidated. Supported by NIH DP1DA031386.
Serotonin Transporter‐Independent Actions of the Antidepressant Vortioxetine as Revealed Using the SERT M172 Mouse
Authors: Nackenoff Alex , Simmler Linda , Baganz Nicole , Paffenroth Krista , Stanwood Gregg , Pehrson Alan , Sánchez Connie , Blakely Randy
Published: June 2021

The most common antidepressants are serotonin (5‐HT) selective reuptake inhibitors (SSRIs), believed to provide benefit by antagonizing the 5‐HT transporter (SERT). To improve efficacy, drugs have been developed that target additional sites, which questions whether one (e.g. SERT) or more of the anticipated targets accounts for therapeutic efficacy. For example, the novel antidepressant vortioxetine (VORT) antagonizes SERT, but also interacts with 5‐HT1A, 3, and 7 receptors at clinically relevant doses. We assessed the SERT‐dependent actions of VORT using a novel transgenic mouse model (SERT Met172) that prior studies demonstrate limited high‐affinity interactions of many antidepressants, with normal 5‐HT transport function. Consistent with these findings, we documented a ~20x loss in potency for VORT at SERT in synaptosomal preparations compared to WT, consistent with evidence of reduced CNS SERT occupancy. Importantly, a loss of SERT interactions in the SERT M172 model could also be demonstrated in vivo following acute (10mg/kg i.p.) VORT injections, as monitored in chronoamperometry and microdialysis studies. Despite loss of VORT interactions with SERT in the M172 model, we found that, unlike citalopram and fluoxetine, VORT maintained its ability to reduce immobility in Tail Suspension and Forced Swim Tests. These findings indicate that the acute behavioral actions of VORT in these preclinical tests of antidepressant efficacy are independent of SERT antagonism, consistent with the potential for a novel mechanism of action in the treatment of depression
Immunohistofluorescence Localization of Histamine and Histamine Receptors in Ganglia and Tissues of the Bivalve Mollusc, Crassostrea virginica
Authors: McLeod Ayana , Semple Danellie , Carroll Margaret , Catapane Edward
Published: June 2021

Histamine (HIS), a biogenic amine is a neurotransmitter in nervous systems and in sensory receptors in a variety of invertebrates rarely has been reported in bivalves. We showed it is involved in sensory reception in sensory‐motor integration of gill lateral cell cilia beating in the bivalve, Crassostrea virginica and used HPLC to show it present in ganglia and tissues. We hypothesize HIS neurons and HIS receptors are present in ganglia and innervated tissue of C. virginica. We tested this with immunohistofluorescence using 1̊ antibodies to HIS and HIS receptors, and fluorescently labeled 2̊ antibodies. Tissues were dissected, snap frozen, cryostat sectioned, fixed with EDAC (N‐Ethyl‐N'‐(3‐dimethylaminopropyl) carbodiimide hydrochloride) or paraformaldehyde, treated with blockers, and incubated with 1̊ then 2̊ antibodies. Whole mounts of gill and mantle also were similarly treated visualized. Results show HIS and HIS H2 receptors in visceral ganglia, gill, mantle body and sensory tentacles of mantle rim. Of particular significance is their presence in sensory tentacles as that correlates well with our previous sensory physiology studies, and their presence in gill interfilamental junctions, the physiology of which has not been well described. The project confirms the identity of HIS and H2 receptors in the nervous system and innervated organs, and coupled with our other work shows HIS to be an important endogenous biogenic amine in the bivalve C. virginica.
Uroguanylin Increases Frequency and Amplitude of Guinea‐pig Bladder Spontaneous Contractility
Authors: Fonteles Manassés , Pereira Eduardo , Santos Claudia , Nascimento Nilberto
Published: June 2021

Uroguanylin (UGN) is a diuretic and natriuretic peptide synthesized mainly in the gut and kidney and stored as proUGN. Uroguanylin is excreted intact in the urine derived from both enteric and renal proUGN. Nevertheless, its effects on the ureter or bladder contractility are not known. We have probed the effect of cumulative concentrations of uroguanylin (10‐9M to 3x10‐6M) in electrically driven ureter or in the spontaneous contractions of the guinea‐pig bladder. Tissues were mounted vertically as strips in 5 ml organ baths for isometric recordings.UGN, a GC‐c agonist, increased bladder motility in a concentration‐related fashion and achieved a maximal effect of 130.3%. The atrial natriuretic peptide (GC‐A agonist), C‐type natriuretic peptide (GC‐B agonist) or sodium nitroprusside (sGC activator) only marginally increased bladder motility by 15.6%, 19.8% and 16.6%, respectively. The unspecific GC antagonist, isatin, completely blocked the effects of UGN (130.5% UGN vs. 6.5% UGN+isatin; p<0.05). This effect was also blocked by tetrodotoxin (TTX), a neuronal sodium channel blocker and by atropine. UGN also increased the frequency of the spontaneous contractions by 52.4% (p<0.01 vs. control). Similarly, neither ANP, CNP nor SNP were able to affect the frequency of bladder contractions. Isatin also completely blocked the effects of UGN on the frequency of contractions (52.4% vs. 4.3%; p<0.001). UGN did not affect the muscle contractions induced by electrical field stimulation (80V;5ms, 10Hz) in both ureter or bladder. Therefore, the effects of UGN are pre‐synaptic, cGMP‐independent and probably dependent on increased release of acetylcholine. A depolarizing effect of UGN was previously shown.
Evaluation of Individual ErbB Receptor Contributions to Cellular Responses Initiated by GGF2
Authors: Sarmiere Patrick , Stricker Jason , Cao Jing , Cain Evan , Srinivas Maya , Vecchione Andrea , Caggiano Tony , Button Donald
Published: June 2021

Neuregulins control processes of both tissue development and homeostasis. Glial growth factor 2 (GGF2; Cimaglermin alfa [USAN]), a Type II isoform of the neuregulin 1 (Nrg1) gene, is a ligand selective for the ErbB3 and ErbB4 members of the EGFR‐family of receptor tyrosine kinases. GGF2 has been shown to be cardioprotective in both in vitro and in vivo injury models and is undergoing clinical testing for the treatment of chronic heart failure. The goal of this work was to define the roles of ErbB3 and ErbB4 receptors in GGF2‐mediated responses in a variety of cell types. Cell lines representing cardiac (HL1), liver (HepG2) and breast (MCF7) tissues were evaluated for ErbB receptor expression via qPCR and then specific receptor subtypes were targeted for knockdown of expression using siRNA. At times corresponding to maximal reduction of ErbB receptor protein levels, cells were stimulated with a range of GGF2 concentrations and evaluated for early Akt phosphorylation (pAkt) responses as well as longer term responses related to cell phenotype. Results from these studies indicate ErbB2, 3 and 4 all contribute to GGF2‐mediated pAkt formation in MCF7 and HL1 cells. However, in HepG2 cells, knockdown of ErbB3, but not ErbB2, attenuated GGF2‐dependent pAkt formation. Interestingly, reduction of ErbB4, but not ErbB3, reduced the cytoprotective effect of GGF2 in doxorubicin treated HL1 cells. Additional studies assessing other ErbB‐mediated signaling responses such as proliferation, maintenance of mitochondrial membrane potential and liver‐specific endpoints are being performed. Our results provide insight on the roles that ErbB receptors play in mediating GGF2 actions across a range of target cell types.
Carvacrol Reduces Cancer Pain by GABAergic System
Authors: Guimaraes Adriana , Scotti Luciana , Scotti Marcus , Mendonça Júnior Francisco , Melo Nayara , Alves Rafael , De Lucca Júnior Waldecy , Quintans Júnior Lucindo
Published: June 2021

The aim of this study was to evaluate the effect of carvacrol (CARV), a monoterpene present in oregano oil, on nociception induced by Sarcoma 180 (S180) in mice. Mice were treated (s.c.) after tumor induction (106 cells/25 mL, s.c.) with vehicle, CARV (12.5‐50 mg/kg, s.c.) or morphine (15 mg/kg) daily for 15 days. Mechanical hyperalgesia was evaluated by von Frey and marcation for Fos protein in lumbar spinal cord by imunofluorescence. All protocols were approved for the UFS Ethic Committee (CEPA: 71/10). Molecular docking studies also were performed to evaluate possible intermolecular interactions of the CARV and muscimol, as ligands of GABAA receptors. CARV (50 mg/kg) was able to increase (p < 0.05) the paw withdrawal threshold in 9 (0.37 ± 0.50 g), 11 (0.85 ± 0.65 g), 13 (1.48 ± 0.65 g) and 15 (1.63 ± 0.62 g) days compared to vehicle (2.50 ± 0.34 g, 3.87 ± 0.46 g, 3.82 ± 0.69 g, 4.24 ± 0.60 g, respectively). CARV also decrease number of positively marked neurons in spinal cord (p < 0.001). Docking studies showed favorable interaction overlay of the CARV with GABAA. These results demonstrate that CARV may be an interesting candidate for the development of new analgesic drugs for the management of cancer pain.
Efficacy of a Novel Fenugreek Seed Extract (Furocyst) in Polycystic Ovary Syndrome in Female Subjects
Authors: BAGCHI DEBASIS , Swaroop Anand , Kumar Pawan , Bagchi Manashi
Published: June 2021

Polycystic ovary syndrome (PCOS) is the most prevalent hormonal disorder among women of reproductive age causing irregular menstrual cycles, excessive body or facial hair, miscarriage and infertility. Infertility is one of most common PCOS symptoms. Because the symptoms of PCOS are seemingly unrelated to one another, the condition is often overlooked and undiagnosed. We conducted an open label, one‐arm, non‐randomized, post‐marketing surveillance study in 50 premenopausal women (18‐45 years, BMI<42) diagnosed with PCOS using a novel fenugreek seed extract (Furocyst, 2 capsules of 500 mg each/day) over a period of 90 consecutive days to determine its efficacy on the reduction of ovarian volume and the number of ovarian cysts. Ethical committee approval was obtained for this study. Furocyst caused significant reduction in ovary volume. Approximately 46% of study population showed reduction in cyst size, while 36% of subjects showed complete dissolution of cyst. It is important to mention that 71% of subjects reported regular menstrual cycle on completion of the treatment and 12% of subjects got pregnant. Overall, 94% of patients were benefitted from this study. Significant increases in luteinizing hormone (LH) and follicular stimulating hormone (FSH) levels were observed compared to the baseline values. Extensive blood chemistry, hematological and biochemical assays demonstrated the broad spectrum safety. Furocyst caused significant decrease in both ovarian volume and the number of ovarian cysts. In summary, Furocyst was efficacious in ameliorating PCOS.
Role of Bone Marrow Derived Macrophages in Acetaminophen‐induced Injury
Authors: Sun C , Francis M , Mandal M , Gardner C , Laskin J , Laskin D
Published: June 2021

Acetaminophen (APAP) is a widely used analgesic that causes centrilobular hepatic necrosis in toxic doses. Macrophages (MP) are known to contribute to APAP toxicity, participating in both proinflammatory and antiinflammatory/wound repair processes. Herein, we analyzed the origin of the cells. Bone marrow chimeric mice were generated using green fluorescent protein (GFP+) mice as donors. Flow cytometric analysis revealed that the bone marrow cells from chimeric mice were more than 80% GFP+. Following APAP administration we observed an increase in GFP+CD11b+ in the liver beginning at 24 h, and persisting for 96 h. These cells were found to consist of immature (F4/80‐) and mature (F4/80+) Ly6Chi proinflammatory and Ly6Clo anti‐inflammatory MP; the majority of Ly6Chi MP were F4/80‐, while Ly6Clo MP consisted of mature and immature cells. Ly6Clo MP were found to increase in the liver 72‐96 h after APAP, a time coordinate with tissue repair. Analysis of liver sections confirmed the accumulation of mature F4/80+GFP+ MP in the livers of APAP treated mice. Findings that these cells did not express mannose receptor, a marker of anti‐inflammatory MP, support the idea that bone marrow derived pro‐ and anti‐inflammatory MP subpopulations accumulating in the liver are distinct. Grant support: NIH AR055073; ES005022.
An Exploration of the Mechanisms Underlying Proximal Tubular Vacuolization in Mice with Low Expression of the NADPH‐Cytochrome P450 Reductase
Authors: Li Lei , Liu Senyan , Dickman Kathleen , Sells Stewart , Ding Xinxin , Mei Changlin , Zhang Qing‐Yu , Gu Jun
Published: June 2021

Cytochrome P450 reductase (CPR or POR) is an obligatory redox partner for all microsomal P450 enzymes. A large, global decrease in POR expression, in a Cpr‐low mouse model, was previously found to lead to altered sex steroid hormone homeostasis, female infertility, and decreased capacity for xenobiotic metabolism. The aim of this study was to further characterize the Cpr‐low mouse model, in order to identify additional phenotypes that may reveal vulnerability in people with low POR expression. Here we report age‐dependent appearance of marked vacuolization in the proximal tubules of 4‐9 month old male (but not female) Cpr‐low mice. The vacuoles, which were negative for fat (Oil‐red O) and glycogen (PAS) staining, were localized in S1/S2, but not S3, segment of the proximal tubules. Proximal tubule vacuolization was also observed in an extrahepatic Cpr‐low mouse model, in which POR expression was normal in the liver, but low elsewhere. Thus, the renal vacuolization in the Cpr‐low mice was not due to a metabolic dysfunction in the liver. Furthermore, the renal vacuolization was associated with an elevation in serum levels of blood urea nitrogen (BUN), a biomarker for deficits in kidney function. These findings suggest that chronic suppression of POR expression may lead to increased susceptibility to renal injuries or diseases.
Cardiotonic Steroids Inhibit NHE3 in Renal Proximal Tubules by a Src Kinase Dependent Pathway
Authors: Nascimento Nilberto , Godinho Alana , Cortez Lôrrainy , Santos Claudia , Fonteles Manassés , Lessa Lucília
Published: June 2021

Cardiotonic steroids (CE) are known as sodium‐pump inhibitors. The natriuretic property of these compounds is related to the inhibition of the α1 isoform of Na+/K+ATPase (NKA) in renal tubules. NHE3, the main route for Na+ and bicarbonate reabsorption in proximal tubules, depends on the Na+ gradient generated by the NKA. The present study aimed to investigate and compare the effects and mechanisms of 50 nM bufalin (BUF), telocinobufagenin (TBG), marinobufagenin (MBG) and ouabain (OUA) on NHE3 activity by the stationary renal microperfusion technique. By this method we are able to measure the H+ secretion in nephron segments through H+ sensitive microelectrodes. We observed that all compounds studied promoted a inhibition of proximal H+ secretion / bicarbonate reabsorption when compared to the control, being BUF the most potent compound (JHCO3‐,nmol.cm‐2.s‐1–control ethanol ‐2,11±0,16(10); BUF 1.04 ± 0.07 (8)*; TBG 0.077 ± 1.36(10)*; OUA 1.48 ± 0.10 (11)* and MBG 1.63 ± 0.08 (10)*. Our data also showed that this effect involved the inhibition of NHE3, since in the presence of NHE3 inhibitor (S3226), BUF did not promote additional inhibition. Furthermore, we demonstrated the involvement of NKA‐Src kinase pathway in the action signaling mechanism of these steroids on NHE3 activity, since in the presence of Src kinase specific inhibitor (SU6656), the inhibitory effect promoted by the CE was abolished.