bluuebunny/crossref_metadata_2025 huggingface dataset:
A GLP‐1R Positive Allosteric Modulator Acts through Covalent Modification
Authors: Nolte Whitney
Published: June 2021

The glucagon‐like peptide‐1 receptor (GLP‐1R) is an important target for the treatment of type 2 diabetes. Recent studies have identified several small molecule potentiators of the GLP‐1R. The focus of these studies is to investigate the mechanism of action of one of the most studied GLP‐1R potentiators, 4‐(3‐benzyloxyphenyl)‐2‐ethylsulfinyl‐6‐(trifluoromethyl)pyrimidine (BETP), which potentiates the signaling of weak agonists at the receptor. BETP is a reactive electrophile, making covalent modification of the receptor a potential mechanism for its action. The potentiation of weak agonists by BETP is resistant to washout, providing evidence that it acts by covalently modifying the GLP‐1R. Clickable analogs of BETP modify active, membrane‐bound GLP‐1R in living cells. Studies using mass spectrometry‐based proteomics identified Cys347 and Cys438 as sites at which BETP modifies the GLP‐1R. The functional relevance of the modification at Cys347 and not Cys438 was established through site‐directed mutagenesis. Full agonists retained activity at the Cys347Ala mutant of GLP‐1R; however, BETP no longer potentiated the function of the weak agonist, GLP‐1(9‐36)NH2. These results illustrate that BETP covalently modifies Cys347 in intracellular loop 3 (ICL3) of GLP‐1R and that this modification is necessary for its potentiation of GLP‐1R activity. We further show that introduction of a cysteine residue in ICL3 of two other GPCRs, the glucagon receptor and the gastric inhibitory polypeptide receptor, sensitizes them to ligand potentiation by BETP and GLP‐1R ago‐allosteric modulator, compound 2. These results highlight the potential relevance of this site in ICL3 to enhancing the activity of class B GPCRs and may facilitate the discovery of new small molecule modulators
Neuropeptide‐interactions in Gastric Mucosal Defense Initiated Centrally in the Rat.
Authors: Gyires Klara , Németh József , Zádori Zoltán
Published: June 2021

Background

Several neuropeptides were shown to elicit gastric mucosal protective effect given centrally (intracerebroventricularly /i.c.v./, intracisternally or into discrete brain areas), e.g. TRH, opioid peptides, ghrelin, nociceptin, agmatine, substance P (SP), angiotensin II (Ang II) etc. However, numerous data suggest interactions between neuropeptides or with other endogenous mediators. Aim: To analyse if additional neuropeptides are involved in the gastroprotective effect of Ang II or agmatine (endogenous ligand of imidazoline receptors). Methods: Gastric mucosal lesion was elicited by oral administration of acidified ethanol. The compounds were given i.c.v. 10 min prior to ethanol and the lesions were determined 60 min later. The mucosal somatostatin and CGRP contents were determined by RIA. Results: 1. Both Ang II (0.012‐0.191 nmol) and agmatine (0.88‐4.4.nmol) induced significant reduction of the gastric lesions. 2. Parallel, the dramatic decrease of mucosal CGRP and somatostatin levels of gastric mucosa following ethanol administration was restored by both compounds. 3. The gastroprotective effect of Ang II was inhibited both by candesartan and L 733 060, selective NK1 receptor antagonist. Moreover, the protective effect of agmatine was inhibited both by alpha2/imidazoline I1 receptor antagonists idazoxan/efaroxan and the selective I1 receptor ligand, AGN 192403 as well as the opioid receptor antagonist, naloxone.

Conclusion

SP and opioid peptides might be involved in the gastroprotive effect of Ang II and agmatine, respectively.

Supported by OTKA 75965
Kolaviron‐Induced Inhibition of H1299 Lung Cancer Cells Growth and Survival via PKA/P13K Pathways
Authors: Blake Courtney , Adetokunbo Oyagbemi , Adedapo Adeolu , Omobowale Tayo , Yakubu Momoh
Published: June 2021

Kolaviron (KV), a natural biflavonoid obtained from the seeds of Garcinia kola, has been noted for its diverse pharmacological actions such as its antioxidative, antiproliferative, and anti‐inflammatory properties. We have evaluated the antiproliferative and cytotoxic effects of KV on H1299 lung cancer cell line. H1299 Cell was cultured in modified medium fortified with 10% FBS using 96 well plates and MTT assay was performed to determine effects of KV (0.025‐100 mg/ml) on cell proliferation 24 hrs. or 48 hrs. (cytotoxic/apoptosis) after plating. MTT assay indicates that KV dose‐and time ‐dependently inhibited H1299 cell proliferation as well as causing cell death in the cytotoxic studies. These effects were significantly different from the control. The cytotoxic effects of KV were only partially reversed at 24 and 48 hrs. following treatment with cell division/ cell growth promoter, 8‐bromoadenosine 3':5'‐cyclic monophosphate (1mM) analog of cAMP. This observation indicates that KV is probably mediating its cytotoxic effects via inhibition of pro‐survival and pro‐apoptotic signals mediated by cAMP modulated downstream effectors through PKA/PI3K, pathways. These preliminary results suggest that KV has therapeutic potential against lung cancer and the mechanisms of actions need further investigation.
Enhanced SpO2s in response to Intermittent Hypoxia (IH) in a Patient with COPD. Progress Report II
Authors: Cardoso Sergio , Samillan Victor , Werneck M , Pereira P , Horowitz Michal , Feuers R
Published: June 2021

Hypoxic interventions restore functions in human conditions, including COPD. Cardoso et al (The Faseb Journal,Suppl. April 2014,28,1,LB 787) have reported normalization of SpO2s when associating Exercise with @ Rest periods, while off supplemental O2, to the management of a 75 yrs old patient with stage IV COPD on LTOT. The use of Exercise while off O2 was not pursued. Too stressful for the patient. We now report that enhancements of SpO2s (recorded at 1' intervals with pulse oximeters) were obtained and sustained with weekly applications of IH alone (O2 off, 13:00 to 14:00 hrs/day, for 60' @ rest) from 9/17 to 11/5/2014. Periodic hematocrits, hemoglobin and total RBC were done to monitor the pt's responses to hypoxia. The Mean of Means for SpO2s (9/17 to 11/5,2014) during the initial 22 minutes off O2 was 91.96, SD=1.29 , while for the total 60' off O2 the Mean was 89.01,SD=1.51 (P=0.0067). Hematocrit (42.7%), hemoglobin and total RBC on 9/12/2014 were unchanged from those obtained prior to the initiation of our studies (3/7/2012). Our results (improved Quality Of Life, reduction in frequency and dosage of medications) support the use of IH in pts c/ COPD. Efforts are being made to minimize possible/probable LTOT associated oxidative damage with reductions of her 24/7 supplemental O2 rates and or frequency.
Combined aliskiren and L‐arginine treatment prevents vascular dysfunction in renovascular hypertension.
Authors: Santuzzi Cintia , Tiradentes Renata , Gouvea Sonia , Abreu Glaucia
Published: June 2021

We investigate aliskiren, L‐arginine and both treatments on vascular reactivity in aortic rings. Hypertension was induced by clipping renal artery and animals were divided: Sham, 2‐kidney, 1‐clip (2K1C), 2K1C+aliskiren (ALSK), 2K1C+L‐arginine (L‐arg), and 2K1C+aliskiren and L‐arginine (ALSK+L‐arg) treatment for 4 weeks. Blood pressure was monitored and endothelium‐dependent and independent vasoconstriction and relaxation were assessed. ALSK+L‐arg decreased blood pressure, contractile response to phenylephrine and improved the acetylcholine relaxation. Endothelium removal and incubation with L‐NAME increased the response to phenylephrine in all groups, but magnitude was higher in ALSK+L‐arg group. Enalapril reduced phenylephrine response in 2K1C and ALSK groups and Losartan reduced in all of the groups. Apocynin reduced contractile response in 2K1C, ALSK and ALSK+L‐arg groups and incubation with superoxide dismutase reduced the response in 2K1C and ALSK groups. eNOS expression increase in 2K1C and L‐arg groups and iNOS increased only in 2K1C group compared with other groups. AT1 expression increase in 2K1C compared to Sham, ALSK and ALSK+L‐arg groups, AT2 expression increase in ALSK+L‐arg group compared to Sham and L‐arg groups, SOD2 increased in ALSK+L‐arg group compared to 2R1C, ALSK and L‐arg group, on the other hand, gp91phox decreased in ALSK+L‐arg compared with 2K1C and ALSK. In conclusion, combined ALSK+L‐arg was effective in preventing endothelial dysfunction of 2K1C hypertensive rats and the mechanisms responsible appear to be related to the modulation of local renin‐angiotensin system, which is associated with the reduction in endothelial oxidative stress.
Lung Progenitor Cells Expressing PW1 Gene Participate in Vascular Remodeling During Pulmonary Arterial Hypertension
Authors: NADAUD Sophie , DIERICK France , HERY Tiphaine , MONCEAU Virginie , MOUGENOT Nathalie , CRISAN Mihaela , DORFMULLER Peter , MARODON Gilles , BESSON Vanessa , MARAZZI Giovanna , SASSOON David , HULOT Jean‐Sébastien , SOUBRIER Florent
Published: June 2021

AIM

PW1+ progenitors were identified in adult tissues and can differentiate in smooth muscle cells (SMC) in vitro. Our hypothesis is that PW1+ progenitors are recruited to participate in the vascular remodeling during pulmonary hypertension (PAH).

METHODS

PW1IRESnLacZ+/‐ mice express the β‐galactosidase as a reporter gene for PW1 expression allowing to follow the lineage of PW1+ cells. These mice were exposed to chronic hypoxia (CH) to induce PAH and lung vessels neomuscularisation.

RESULTS

In rodent and human lung, PW1+ cells were adjacent to small vessels. They express c‐Kit, PDGFRα and pericyte markers and differentiate in vitro into SMC. After 4 days of CH, proliferating lung PW1+ cells were increased (x3, p<0.01) as well as PDGFR‐α+/PW1+ and c‐Kit+/PW1+ cells (x2 and x8, p<0.001). In small pulmonary vessels, the proportion of β‐Gal+ vascular SMC derived from PW1+ cells was increased (64% vs 35%, p<0.05) suggesting a recruitment and differentiation of PW1+ cells into lung vascular SMC. Moreover, WT mice irradiated and engrafted with GFP+/β‐Gal+ bone marrow cells did not show any increase in GFP+ or β‐gal+ SMC in lung vessels after 4 days of CH indicating that the lung PW1+ progenitors are not derived from bone marrow. In the human PAH lung, PW1+ cells were also observed in the media of remodeled vessels.

CONCLUSION

These results suggest that lung resident PW1+ progenitors are recruited to participate in the vascular remodeling of small pulmonary vessels in experimental and human PAH.
Targeted delivery of microRNAs by microparticles to inflamed endothelium ameliorates endothelial inflammation and atherosclerosis
Authors: Ma Shuangtao , Tian Xiao Yu , Mu Chaofeng , Shen Haifa , Bismuth Jean , Wong Wing Tak
Published: June 2021

Rationale

The E‐selectin in endothelium promotes the growth of atherosclerotic plaques. We identified an E‐selectin‐targeting thioaptamer (ESTA) and conjugated it onto a multistage vector (MSV) to form an ESTA‐MSV microparticle. We tested E‐selectin‐targeted delivery of microRNAs (miRs) for the treatment of atherosclerosis.

Methods and Results

The E‐selectin was up‐regulated, while the miR‐146a and miR‐181b were down‐regulated, in TNF‐α‐treated human microvascular endothelial cells (HMVECs). MiR‐146a and miR‐181b mimics were packaged into the ESTA‐MSV. Both miR‐146a and miR‐181b attenuated TNF‐α‐induced endothelial inflammation. Moreover, the monocyte adhesion to HMVECs was also attenuated by miR‐146a or miR‐181b. The ApoE‐/‐ mice were injected with ESTA‐MSV‐packaged miR‐146a or miR‐181b biweekly through tail vein for 12 weeks. Injection of miR mimics resulted in a 4.7‐ and 5.7‐fold overexpression of miRs in mouse aortas. The immunofluorescence staining showed the co‐localization of E‐selectin and miRs in aortic endothelium. MiR‐146a and miR‐181b significantly inhibited atherosclerotic lesion size, lipids deposition, macrophage and lymphocyte infiltration in plaques, and expression of adhesion molecules in aortas.

Conclusions

E‐selectin‐targeting delivery of miR‐146a and miR‐181b to inflamed endothelium inhibits atherosclerosis. These findings provide a novel delivery system for miR‐based therapy of atherosclerosis.
SRF Involvement in Egr‐1‐dependent Signaling in Acrolein‐mediated Inflammatory Responses
Authors: Yousefipour Zivar , Newaz Mohammad
Published: June 2021

Acrolein, a major environmental pollutant has been linked to impaired vascular reactivity but the precise mechanism is not clear. Involvement of inflammatory pathways has been proposed as one of the mechanisms involved. Serum response factor (SRF), a transcription factor, regulates cell development, differentiation and proliferation. Early growth response‐1 (Egr‐1), a nuclear protein, functions as a transcriptional regulator and activates the transcription of several hundred genes. This study explored regulatory influence of SRF on Egr‐1‐dependent signaling in acrolein‐mediated inflammatory responses. Male sprague‐dawley rats (8 weeks old) were exposed to 2 mg/kg/day of acrolein (gavage, 1 week) alone or in combination with rosiglitazone (ROZ, 10 mg/kg/day, gavages, 1 week) or clofibrate (CLO, 250 mg/kg/day, i.p. 1 week). At the end of the treatment period isoprostane level was measured in urine. Changes in the expression of SRF and Egr‐1 proteins in kidney homogenate were determined by western blot. Our results indicated increased generation of ROS in rats treated with acrolein with a reduction after treatment with ROZ andCLO. There was a significant increase in SRF, and Egr‐1 protein expression (~2‐fold and 1.8 fold) in acrolein treated rats compared to the control which was attenuated in presence of CLO and ROZ (52% and 45%; p<0.05). Acrolein treatment significantly reduced TAS expression and only ROZ treatment improved TAS expression. Treatment with CCG‐1423 (SRF inhibitor, 0.03 mg/kg/day, i.p. 1 week) improved TAS expression and reduced SRF and Egr‐1 protein expression. Our results indicate that acrolein up‐regulation of Egr‐1 might be SRF dependent.
Perivascular Adipose Does Not Affect Endothelium‐Dependent Relaxation or Contractionin Spontaneously Hypertensive and Wistar Kyoto Rat Aorta
Authors: Wood Laura , Denniss Steven , Holder Peter , Rush James
Published: June 2021

This study examined the effect of the presence or absence of naturally adhering perivascular adipose tissue (PVAT+ or PVAT‐, respectively) on acetylcholine (Ach)‐stimulated endothelium‐dependent vasorelaxation inisolated phenylephrine‐precontractedaortic rings, and onAch‐stimulated endothelium‐dependent vasocontraction in isolated quiescent (non‐precontracted) L‐NG‐Nitroarginine methyl ester‐preincubated aortic rings from 25‐30 wk old Spontaneously Hypertensive rats (SHR; n=4‐8) and Wistar Kyoto rats (WKY; n=6‐8). Ach from ‐10.0 to ‐5.0 LogM resulted in a dose‐dependent relaxation response in PVAT‐ rings from both WKY (Maximum Amplitude (Max Amp): 85.6±5.8%; EC50: ‐7.72±0.08LogM; Area Under the Curve (AUC): 236±18) and SHR (Max Amp: 87.3±6.1%; EC50: ‐7.90±0.07LogM; AUC: 255±23), with no statistically significant differences found between strains in any dose‐response curve‐fit parameter (p<0.05). In both WKY and SHR, the curve‐fit parameters of the Ach‐stimulated relaxation response in PVAT+ rings were found not to be statistically different from thoseof the PVAT‐ rings.Inquiescent rings, Ach resulted in a dose‐dependent vasocontractile response in PVAT‐ rings from both WKY (Max Amp: 16.5±1.6%; EC50: ‐6.32±0.10LogM; AUC: 28±4) and SHR (Max Amp: 43.7±7.0%; EC50: ‐6.25±0.11LogM; AUC: 59±10), with a greater Max Amp and AUC in SHR (p<0.01). In both WKY and SHR, the curve‐fit parameters of the Ach‐stimulated contractile response in PVAT+ rings were found not to be statistically different from those of the PVAT‐ rings. These preliminary data suggest that, under the conditions examined, the presence of PVAT does not affect endothelium‐dependent relaxation or contraction.

Funded by NSERC Canada.
Examining the Effect of Doxorubicin on Apoptotic Signaling in Skeletal Muscle of ARC KO Mice
Authors: Mitchell Andrew , Merkel Leah , Quadrilatero Joe
Published: June 2021

Apoptosis repressor with caspase recruitment domain (ARC) is an anti‐apoptotic protein that inhibits both the intrinsic and extrinsic apoptotic pathways. Along with its potent anti‐apoptotic actions, ARC has a unique tissue expression with high levels found in skeletal muscle, cardiac muscle, neurons, as well as some cancers. Within skeletal muscle, ARC content is fiber‐type specific with highest expression in slow‐twitch fibers. Despite its high expression, ARC's anti‐apoptotic role in skeletal muscle is not fully understood. To determine whether ARC contributes to apoptotic resistance, wild‐type (WT) and ARC knockout (KO) mice were given intraperitoneal injections of doxorubicin (DOX) (20 mg/kg) or saline. 24 hrs post injection, mice were sacrificed, the gastrocnemius was removed, and separated into red (RG) and white (WG) portions. DOX treated mice lost significantly more weight than saline controls (p<0.0001); however, whole gastrocnemius weights did not change. In RG, DOX increased ROS (p<0.01), with post hoc analysis revealing a significant increase between KO saline and KO DOX mice (p<0.05). DOX treatment significantly increased caspase‐9 (p<0.01) and calpain (p<0.05) activity; however, caspase‐8 and ‐3 activity remained unchanged. There was also a significant increase in calpain activity between KO saline and KO DOX treated mice (p<0.05). In WG, DOX had no influence on ROS levels. Interestingly, there was an increase in caspase‐3 activity in KO DOX and KO saline treated mice (p<0.05) despite no change in upstream initiator caspases. Taken together, 24 hr DOX treatment affected apoptotic signaling in RG to a greater extent than in WG. Furthermore, a lack of ARC led to higher ROS, as well as increased calpain activity in RG following DOX treatment.
Effect of Altered Endogenous Melatonin Regulated by Conditional Light Exposure on Neural Reorganization by Regulation of ER Stress Response and Autophagy after Spinal Cord Injury
Authors: Kim Joo‐Heon , Jin Yunho , Park Sookyoung , Hong Yonggeun
Published: June 2021

Spinal cord injury causes unfolded protein response (UPR) to recover from endoplasmic reticulum (ER) stress. Melatonin is known to delay ER stress‐induced apoptosis. Furthermore, it has been suggested that melatonin‐mediated autophagy can induce neuroprotection.

The purpose of this study was to elucidate the effect of endogenous melatonin on neural reorganization and locomotor recovery after spinal cord injury. To diversify the concentration of endogenous melatonin, differentiated light exposure time was needed. Thus, experimental animals were divided into 5 groups; group1 (12‐hr light/12‐hr dark), group2 (6‐hr light/18‐hr dark), group3 (24‐hr dark), group4 (18‐hr light/6‐hr dark), group5 (24‐hr light). 7 days after injury, animals were engaged in locomotor assessment.

The BBB score of experimental animals was increased inversely proportional to light exposure time. Similarly, the more the rats were blocked from light, the more neural cells were reorganized. Furthermore, axonal sprouting showed a tendency to relatively increase in accordance with light blockade.

In conclusion, UPR and autophagy might interact to play a neuroprotective role and, this effect is intensified by endogenous melatonin.

Funding : 2012R1A1A2005089, 2013R1A2A2A01067169, KGM4611512, 2014R1A1A3051724
Synthesis of type I collagen in an animal model of skin injury via TGF‐β1 and IGF‐1R upregulation
Authors: Choi Jeonghyun , Hong Yonggeun
Published: June 2021

Many approaches that accelerate the wound healing process have been developed. However, improving the speed and quality of healing remain a challenging task faced by clinicians. Collagens are an important component in all phage of wound healing. They impart integrity and strength to all tissue. Transforming growth factor‐beta1 (TGF‐β1) is important in inflammation, angiogenesis, reepithelialization, and connective tissue regeneration. This play a role in wound contraction by facilitating fibroblast contraction of the collagen matrix. Insulin‐like growth factor‐1 (IGF‐1) is a cytokine that participates in the cellular granulation process during wound healing. IGF‐1 has also described as an agent that acts anabolically and anti‐catabolically in a wide variety of cell type. The aim of this study was to evaluate whether upregulation of TGF‐β1 and IGF‐1R related to tissue repair process of wound in an animal model. Skin injury were created 1.5㎠ on dorsal right and left. Animal were housed in ad libitum and controlled with a photoperiod of 12h. On postoperative 3h, 15h, 2d, 7d, and 10d the complete wound with a 0.5 ㎝ margin was carefully removed. TGF‐β1 gene expression was increased in 2d, 7d, and 10d. IGF‐1R gene expression was showed in the same manner. Synthesis of type I collagen was growing as time dependent. These finding suggest that typeIcollagen synthesize was influenced by TGF‐β1 and IGF‐1R.

Funding: 2012R1A1A2005089, 2013R1A2A2A01067169, KGM4611512
Effectiveness of a Structured Educational Program for Type 2 Diabetic Patients in Outpatient Care
Authors: Li V. , Dalenov E.
Published: June 2021

The objective of this study was to evaluate the effectiveness of structured education of patients with type 2 diabetes in the disease management within the scopeof endocrinological outpatient care. The study was performed among the adult cohort of patients with type 2 diabetes, that were monitored in outpatient servicein Astana.

According to the study results 70% of patients with type 2 diabetes, who were observed in outpatient setting, were in a state of poor compensation. Intermediate HbA1clevel was 9,25±0,15%, average BMI was 29,3±0,5 kg/m2, average systolic blood pressure of 154±3,1mm.rt.art., averagediastolic blood pressure 88±1,4 mm.rt.art., total cholesterol 6,94±0,8 mmol/l, triglycerides 1,78±0,1 mmol/l. The study showed significant improvement in compensation of diabetes in patients that attended educational program in comparison with the control group: HbA1c decreased from 9,33±0,18% to 8,21±0,12%. One‐time training course does not lead to long‐term metabolic compensation: after 12 months there was an increase NbA1s with 8,21±0,12% to 8,5±0,12%. In the absence of post‐training self‐monitoring of the blood glucose level, the effectiveness of trainingdecreased: the indicator HbA1cin trained patients but without further self‐monitoring rose again up to 9,3±0,31%, and in patients without any training ‐ 9,33±0,18 p>0.05. According to the test results using a SpielbergerState‐Trait Anxiety questionnaire there was a high level of personal anxiety in 73.3% of patients, which indicatedthat patients were in a state of constant stress. After undergoing the educational program a positive correction of psychological condition of the patients was observed, through decreased level of anxiety: high level of situational anxiety during the training decreased from 24.5% to 8.9%, p<0.05.
Regulation of pancreatic β cell function by GLP‐1 released from α cells in response to activation of TGR5 by bile acids
Authors: Kumar Divya , Asgharpour Amon , Mirshahi Fariddodin , Grider John , Murthy Karnam , Sanyal Arun
Published: June 2021

We previously showed that activation of Gs‐coupled TGR5 in pancreatic β cells by bile acids induces insulin secretion. Glucagon released from pancreatic α cells and glucagon‐like peptide 1 (GLP‐1) released from intestinal L cells regulate insulin secretion. Both glucagon and GLP‐1 are processed from the same precursor, proglucagon by cell‐specific expression of proconvertases 1 (PC1) and PC2.

AIM

To test the hypothesis that TGR5 activation upregulates PC1 expression and GLP‐1 release from α cells and promotes insulin release in a paracrine fashion.

RESULTS

Expression of TGR5 was demonstrated in αTC1‐6 cells and islets from mouse and human. Treatment of αTC1‐6 cells, and islets from mice or human with 25 mM glucose for 7 days induced PC1 expression and GLP‐1 release; the effect of glucose was augmented by lithocholic acid and the TGR5 specific ligand, INT‐777. Insulin secretion by INT‐777 in human islets cultured under 25 mM glucose was inhibited by the GLP‐1 receptor antagonist, exendin (9‐39), suggesting augmentation of β cell function by GLP‐1 released from α cells. Treatment of islets from db/db mice, but not control mice with INT‐777 induced GLP‐1 release. Intraperitoneal treatment with INT‐777 for 7 weeks significantly attenuated the increase in body weight, and improved glucose tolerance and insulin sensitivity in db/db mice compared to control mice. CONCLUSION. Activation of TGR5 by bile acids augments hyperglycemia‐induced PC1 expression and GLP‐1 release in pancreatic α cells, which in turn, acts in a paracrine manner to promote insulin secretion from β cells. Thus, in diabetes, secretions of α and β cells act in concert to regulate blood glucose levels.
The Efficacy of a Minimal Dose of Aerobic Exercise or Soluble Fiber for Lowering Postprandial Blood Glucose Response
Authors: Elder Anna , Rohrer Christina , Ganther Gretchen , Hunt Brian
Published: June 2021

Background

The global prevalence of diabetes is increasing. Thus, strategies to manage blood glucose are of great importance. Previous studies have shown a single dose of exercise or soluble fiber can lower the postprandial glycemic response. These studies, however, typically used large doses of exercise or fiber. Our study aimed to determine if the current minimum dose of aerobic exercise or the minimal recommended serving of soluble fiber is sufficient to significantly reduce postprandial blood glucose response.

Methods

12 subjects (7 female) between the ages of 18 and 25 yr. participated in the study. After an overnight fast, participants consumed 75g of an oral glucose beverage for each condition: 1) control (glucose drink only), 2) exercise (30 min at 70% of heart rate max), and 3) fiber: 7g of Prima Yerba fiber (3.5g soluble). Order of conditions was balanced across participants. Blood was drawn at 0, 10, 20, 30, 60, 90, and 120 min. after consuming the drink and the plasma was analyzed for glucose concentration. Glucose was plotted over time and the incremental area under the curve (iAUC) was calculated.

Results

The iAUC under the control condition (202+/‐136 mmol/L.min) was not different from either exercise (229+/‐163 mmol/L.min) or fiber (300+/‐210 mmol/L.min).

Conclusion

These data suggest that the current recommended minimal dosage of daily exercise and fiber are not sufficient to acutely manage blood glucose levels.
Effect of Acute Bouts of High Intensity Exercise in Hot and Cold Environments on Autophagy, Oxidative, and Inflammatory Proteins in Neutrophils
Authors: Lewis James , Greska Eric , Cosio‐Lima Ludmilla , Lee Youngil
Published: June 2021

Moderate exercise has been shown to increase the body's immune cells and their activity. Circulating blood neutrophils (NEUTs) play an important role in being the first respondents of the innate immune system. Understanding neutrophil's response to varying body temperatures during exercise by examining changes in stress proteins, may reveal novel information as to how the human body adapts to stressful environments, continues normal cellular function and initiates the immune system response. The purpose of this study was to determine whether intense bouts of exercise in different environmental conditions induces autophagy and cytokine responses in neutrophils. Male human subjects (n=9), (22+2 years old) cycled at 70% VO2max for 30 minutes during two separate exercise sessions in an environmental chamber set at 15 °C on the first session and 32°C in the second session. Blood samples were taken before (PRE), immediately after (POST), and one hour after (1H POST) each session. NEUTs were isolated and examined using Western Blot analysis to determine changes in specific protein expression. Heat shock protein (HSP72), cytokine (TNF‐a), autophagy proteins (LC3‐II) and ubiquitinated proteins were quantified. No significant changes in proteins were observed between treatments. These findings may suggest that 30 minutes of intense cycling is not strenuous enough to produce significant changes in autophagy and inflammatory activation. Our results indicate that short bouts of intense exercise in stressful environments (hot vs. cold) may be safe and not cause unnecessary inflammatory responses.
Analysis and morbidity prognosis for stomach and esophageal cancers in the regions of Kazakhstan
Authors: Orazova Galiya , Karp Leonid , Dossakhanov A.
Published: June 2021

Introduction

Esophageal cancer and stomach cancer occupy the leading places in the structure of morbidity and mortality not only in Kazakhstan but also around the world.

Methods

Morbidity prognosis for esophageal and stomach cancers within the regions of Kazakhstan was conducted on the basis of on the level of morbidity from 1999 to 2013. Correlation analysis was used for estimation. Morbidity prognosis was conducted by fitting time‐series models, constructed on the basis of dynamic series for the observation period and its extrapolation to 2015‐2016. The length of the prognosis period was determined by the quantity of data.

Results

A strong association was found between the level of morbidity with cancer of esophagus and stomach (r=0.76‐0.78), predominantly in southern regions of the country. A moderate positive association was found in western regions; in other regions there was weak/no association of the level of morbidity with cancer of stomach and esophagus (r<0.33). In general the trend of reduction of morbidity with cancer of esophagus and stomach has been noted in in Kazakhstan; however, the nature of reduction of oncological morbidity is different. In the coming years, comparatively high levels of morbidity are expected in northern and eastern regions of the country (with a downward trend), and also in the central region.

Conclusions

The pattern in the level of morbidity of cancer of the esophagus and stomach in general is subject to common social processes law of development – reduction of morbidity level with decrease of reduction rate. The most common function for reflection of dynamics law of oncological morbidity is a logarithmic function.
Skeletal Muscle Wasting during Cancer Progression: Exploring the Therapeutic Role of Enhanced Aerobic Capacity
Authors: Alves Christiano , das Neves Willian , de Almeida Ney , Voltarelli Vanessa , Lancha Antonio , Brum Patricia
Published: June 2021

The aim of this study was to test whether enhanced aerobic capacity would counteract cancer cachexia by attenuating skeletal muscle wasting. For doing that, we have standardized a new rat model of cancer cachexia by injecting Walker 256 tumor cells in bone marrow. Importantly, this model displayed anorexia, exacerbated oxidative stress, inflammation and skeletal muscle atrophy restricted to glycolytic fibers. Twelve days post tumor cells injection, rats showed severe aerobic exercise intolerance when compared to health control rats (~2 fold, p < 0.001). Importantly, we observed a correlation between changes in exercise tolerance and the survival rate (p = 0.01, r = 0.74), suggesting that aerobic exercise capacity is a strong predictor of early death. In order to improve oxidative metabolism, we then submitted tumor‐bearing rats to two different exercise training protocols: moderated‐intensity training (MIT) and high‐intensity interval training (HIIT). MIT and HIIT have increased exercise capacity toward control rat levels and improved survival (+21% and +31%, respectively). Importantly, both protocols have not changed tumor size or prevented glycolytic muscle fiber atrophy (p > 0.05). However, MIT and HIIT have enhanced oxidative metabolism evaluated by citrate synthase activity (+71% and +60%, respectively) and total glutathione levels (+44% and +30%, respectively) in plantaris skeletal muscle. Collectively, our results suggest that aerobic exercise training does not counteract cancer‐induced skeletal muscle atrophy, but mitigate oxidative metabolism impairment, increasing survival.

Financial support: FAPESP (2014/03016‐8).
Ameloblastoma of the mandible
Authors: Sagyndyk H.L. , Kozhakov B.B. , Batyrov T.W.
Published: June 2021

Under current conditions, patients began to turn in the early stages of the disease, and the emergence of large technical capabilities in most tumors are diagnosed in the early stages, when education is small. But sometimes, currently, there are cases when the tumor reaches a large size.

Introduction

In oral and maxillofacial surgery and a single common treatment ameloblastom is now a radical removal of education with jaw resection within healthy tissue. However, given the relatively favorable course of this disease, we believe that radicalism should be on the principle of reasonable sufficiency, not to disability patient.

Research and Results: In our experience of 15 operated patients intraoral approach was performed to remove the tumor. Here is an example of a patient operated by us: the patient J. 25 years, turned over 1year after the accidental discovery of the tumor. Diagnosis: ameloblastoma in angle and body of the mandible right. Histological diagnosis is the same. Bone cavity after the above all procedures filled autobone taken from the iliac and kera‐oss in combination with a 1: 1 ratio. Bone defect restored the newly formed bone.

Discussion

When the above sparing surgical interventions when patients suffered sparing surgery by oral, medical rehabilitation is relatively simple and does not require social adaptation.

To control the possible recurrence of the tumor must be an annual survey with X‐rays for 10 years.
SERCA1 overexpression in skeletal muscle preserves motor function and delays disease onset in a mouse model of ALS
Authors: Chen Dapeng , Mazala Davi , Chin Eva
Published: June 2021

We previously showed that disruption of intracellular Ca2+ homeostasis in skeletal muscle is one of the pathophysiological features of amyotrophic lateral sclerosis (ALS). The purpose of this study was to investigate whether SERCA1 overexpression would improve motor function and disease progression in ALS mice. B6SJL‐Tg(SOD1*G93A)1Gur/J (ALS) mice were bred with skeletal muscle α‐actinin SERCA1 overexpressing mice to generate: i) wild type (WT; n=11); ii) SERCA1 overexpression (WT/+SERCA1; n=14); iii) SOD1*G93A ALS (ALS; n=7); iv) SERCA1 overexpressing SOD1*G93A ALS mice (ALS/+SERCA1; n=11). Mice were evaluated weekly (9 ‐16 wks) for motor function (grip test) and time of symptom onset and at 16 wks for muscle mass and SERCA1 activity. SERCA1 overexpressing mice had decreased gastrocnemius muscle mass in WT (125.4 ± 5.9 vs. 71.9 ± 13.1 mg; p<0.05 for WT vs. WT/+SERCA1) but increased mass in ALS (59.6 ± 0.1 vs. 73.1 ± 0.1 mg; p<0.05 for ALS vs. ALS/+SERCA1). SERCA1 overexpression resulted in a 1.8‐fold increase in SR Ca2+ ATPase activity in ALS mice (39.9 ± 2.1 vs. 70.4 ± 12.4 umol/g tissue mass/min; p<0.05 for ALS vs. ALS/+SERCA1). This was associated with improved motor function in ALS mice at 14 wks (111.4 ± 16.2 vs. 67.7 ± 13.1 sec; p<0.05) and 16 wks (53.1 ± 11.8 vs. 8.9 ± 3.4 sec; p<0.05) for ALS/+SERCA1 vs. ALS mice and a delay in disease onset (101.9 ± 2.6 vs. 91.1 ± 4.7 days in ALS/+SERCA1 vs. ALS). These data indicate that SERCA1 overexpression in skeletal muscle improves motor function and slows disease progression in a mouse model of ALS. We hypothesize that this is due to improved muscle health and stability of the neuromuscular junction. Increasing SERCA1 expression and/or activity in skeletal muscle may be a new therapeutic strategy to treat ALS.
Superoxide Dismutase: Free Radical Degradation in Health and Disease
Authors: Kessler Eric , Cross Delaney , Olson Sarah , Person Andrew , Smith Hunter , Kaja Simon
Published: June 2021

Oxygen is necessary for sustaining human life; however, toxic and reactive superoxide free radicals spontaneously form during cellular metabolism. These free radicals are highly reactive and harmful to the body if not degraded by superoxide dismutase (SOD). The eukaryotic, cytoplasmic isoform, CuZn SOD, converts toxic superoxide into hydrogen peroxide or oxygen. Subsequently, the enzymes catalase and glutathione peroxidase aid the conversion of hydrogen peroxide into oxygen and water. The CAPS (Center for Advanced Professional Studies) SMART (Students Modeling A Research Topic) Team modeled CuZn SOD using 3D printing technology to understand its molecular structure and function. CuZn SOD is a homodimer with each subunit composed of an eight flattened beta‐barrel fold. The funnel‐shaped active site containing copper and zinc cations attract negatively charged superoxide radicals. Cu is coordinated by His46, His48, His63, and His120, while Zn is coordinated by His63, His71, His80, and Asp83. The dismutation reaction begins when Cu2+ removes an electron from one superoxide. Then, as Cu+ it donates this added electron to a second superoxide, which is rapidly neutralized by two hydrogen ions, forming hydrogen peroxide. Mutations in the SOD1 gene greatly decrease enzyme activity. 15‐20% of familial amyotrophic lateral sclerosis (ALS) cases are caused by such mutations. Excess SOD is also harmful: in Down's Syndrome, trisomy of the SOD1 locus on chr 21 leads to increased CuZn SOD levels which indirectly contribute to the neurological symptoms of this disease. It is anticipated that future study of CuZn SOD may bring relief to patients with these debilitating conditions.
The opioid system of the medial amygdaloid nucleus modulates autonomic and hormonal responses caused by restraint stress in rats
Authors: Fassini Aline , Scopinho América , Fortaleza Eduardo , Resstel Leonardo , Correa Fernando
Published: June 2021

The medial amydaloid nucleus (MeA) modulates several physiological and behavioral processes, including autonomic changes during aversive situations. The restraint stress (RS) causes significant increase in neuronal activity of the MeA when compared to other amygdaloid nuclei. In addition, the opioid system participates of the mediating cardiovascular responses, including those associated with aversive situations. Based on the facts mentioned above, the hypothesis of this study is that the MeA opioid neurotransmission is involved in the modulation of cardiovascular and endocrine responses evoked by RS. Male Wistar rats (240‐280g) were used. Guide cannulae were implanted bilaterally in the MeA for drug injection and a polyethylene catheter was implanted in the femoral artery for mean arterial pressure (MAP) and heart rate (HR) record. 10 minutes before microinjection of drugs or vehicle into the MeA, rats were subjected to RS. EDTA plasma were used to measured the corticosterone level by ELISA.Increasing doses of the naloxone into the MeA, at dose‐dependent manner, potentiated the increase of MAP (r2=0.2096, df=18, P<0.05) and tachycardia (r2=0.1704, df=18, P<0.05) and the decrease of tail temperature (r2=0.2462, df=18, P<0.05) caused by RS. Also, MeA treatment with naloxone potentiated the increase in corticosterone levels (F4,22= 3.49; P=0.24) at 0.03 and 3nmol/100nL of opioid antagonist. In conclusion, opioid neurotransmission mediates the MeA inhibitory influence on restraint‐evoked cardiovascular and endocrine changes. Financial Support: FAPESP, CAPES and FAEPA.
Activation of Brainstem and Hypothalamic Areas Related to Increased Tail Skin Temperature in Ovariectomized Rats
Authors: Fonseca Cristina , Gonçalves Gleisy , Szawka Raphael , Reis Adelina
Published: June 2021

Hot flushes are usually treated with estrogen replacement in postmenopausal women but the neural pathways involved are poorly understood. We investigated the activation of brain areas associated with the increase in tail skin temperature in an animal model of menopause. Female Wistar rats were ovariectomized (OVX) and implanted with subcutaneous capsules containing 17ß‐estradiol (E2) (OVX+E2) or corn oil (OVX). Tail skin temperature (TST) was recorded during two hours at ambient temperature at 3, 7 and 14 days after surgery. On day 15th, rats were perfused and the brains were processed for immunohistochemistry. Neuronal activity was evaluated by counting the number of Fos‐immunoreactive (ir) cells. On day 14 after ovariectomy, the TST in OVX rats was higher than in OVX+E2 rats. All the brain areas examined exhibited significantly more Fos‐ir cells in OVX than OVX E2 rats. In the brainstem, OVX rats displayed more Fos/tyrosine hydroxylase doubled‐labeled neurons in the A1, A2 and locus coeruleus compared with OVX+E2 rats. OVX rats exhibited more Fos‐ir neurons than OVX+E2 rats in the rostral preoptic area (POA), anteroventral periventricular nucleus (AVPV), and median preoptic nucleus (MnPO) in the preoptic area and in the paraventricular nucleus (PVN) and arcuate nucleus (ARC) of the hypothalamus. Moreover, there was a high correlation between the TST and Fos expression in the A1, A2, AVPV and POA. Thus, ovariectomy gradually increases TST and induces neuronal activation in the brainstem, preoptic area and hypothalamus. Fos expression in neurons of the A1, A2, AVPV, and POA is directly correlated with TST, suggesting these brain areas are associated with the thermoregulatory effects of estrogen.
Financial support: CNPQ, FAPEMIG, CAPES
Comprehensive Proteomics in Vasopressin‐Sensitive mpkCCD Cells: Virtual Western Blotting
Authors: Emamian M.S. , Yang C‐R , Tongyoo P. , Sandoval P.C. , Raghuram V. , Knepper M.A.
Published: June 2021

Vasopressin regulates the water channel aquaporin‐2 in collecting duct cells. Identification of the mechanisms involved depends on knowledge of the genes expressed. To obtain a comprehensive proteome list for vasopressin‐sensitive mpkCCD cells, we used protein mass spectrometry to identify proteins after two levels of fractionation: differential centrifugation followed by SDS‐PAGE. After slicing the resulting gels into 43 consecutive blocks, the gel blocks were subjected to in‐gel trypsinization followed by LC‐MS/MS. After filtering out poor spectra (target‐decoy analysis), 6766 unique proteins were identified. All peptides for each protein were mapped back to the gel‐block of origin to create a 'virtual western blot' for each protein. A histogram of apparent/calculated MW (ρ) for all proteins in the 17,000 Xg fraction revealed a mode of 1.05 and a median of 1.08, indicating that most proteins run at an apparent MW consistent with values calculated by summing the residue masses for all amino acids. However, a moderate fraction of proteins had either a high ρ (>1.45, n=475) or low ρ (<0.65, n=309). Bioinformatic analysis of the high ρ group indicated that a large fraction of these proteins are annotated as “N‐linked glycosylated” or “DNA binding”. The latter have positively‐charged DNA‐binding regions. The low ρ group had significantly lower pI values and shorter half‐lives than the total population. Many of the proteins in the low ρ group are known to undergo physiological cleavage (e.g. presenilin‐1, syndecan‐1) or are resident lysosomal proteins. Interestingly, aquaporin‐2 showed an aberrant band at ~17 kD (detected both by MS and western blotting) that could be a cleaved or alternatively spliced isoform of aquaporin‐2. The data provide a resource for future studies of vasopressin action.
Exocytotic Release of ATP from preBötzinger Complex Astrocytes Contributes to the Hypoxic Ventilatory Response via a P2Y1 Receptor, PLC, PKC‐Dependent Mechanism
Authors: Rajani Vishaal , Sheikhbahaei Shahriar , Zhang Yong , Chu Nathan , Zwicker Jennifer , Posse de Chaves Elena , Pagliardini Silvia , Smith Jeffrey , Kasparov Sergey , Gourine Alexander , Funk Gregory
Published: June 2021

The hypoxic ventilatory response (HVR) comprises an initial increase in ventilation followed by a secondary depression. We tested the hypothesis that the exocytotic release of ATP by astrocytes in the preBötC attenuates this secondary depression via a P2Y1 receptor (R)‐mediated increase in ventilation. The preBötC of adult rats was injected with an adenovirus expressing tetanus toxin light chain (TeLC) and GFP under the control of the GFAP promoter. 7 days later rats were anesthetized and the HVR (10% O2, 5 min) measured via the phrenic nerve. Ventilation increased initially in the control group to 1.7±0.21 of baseline and then fell to 1.4±0.14. In the TeLC group, the HVR was significantly reduced during the initial (1.5± 0.08) and the secondary (1.2±0.05) phases. Unilateral injection of P2Y1R antagonist MRS2279 (500 µM) into the preBötC revealed that endogenous activation of P2Y1Rs significantly attenuated the secondary depression. Multiple second messenger blockers attenuated the frequency increase evoked by injection of a P2Y1R agonist MRS2365 (10μM) into the preBötC of rhythmic medullary slices of neonatal rats. These data suggest that during hypoxia, preBötC astrocytes release ATP, which binds to P2Y1Rs that act through PLC‐IP3‐gated Ca2+ release and PKC to increase ventilation. Supported by CIHR, AIHS, CFI, WCHRI, Wellcome Trust.
Health of Elderly People in the Context of Their Profession
Authors: Doszhanova G. , Tardzhibayeva S. , Sholikbayeva M.
Published: June 2021

Professional activities of the respondents should be considered as one of the leading factors that affect the health of the elderly.

A total of 512 people, representative by gender and age of the general population ‐ 48,000 people. Out of them the elderly are 337 and 175 old patients.

Among the professional activities of elderly men 22.8% belong to technical professions, 15.5% to personnel of service ‐ economic management, builders and unskilled workers, whose share is 11.4%. Women make up a core group of employees of medicine (15.4%), education (14.7%) and unskilled workers (15.4%).

The results of the social opinion poll showed that the prevalence of cardiovascular diseases among pensioners is (78.3%), personnel of service ‐ economic management is (75.4%), economists is (70.4%), law enforcement and defense (62.5%), technical workers is (60.3%) and agricultural workers is (58.3%). While the distribution of respiratory pathology officers is associated with the profession of lawyers (75%), law enforcement officers and workers in agriculture (50%). Analysis of the incidence of bone ‐ muscular system showed that this pathology is more susceptible to agricultural workers (66.7%). As a leading place in the structure of morbidity of elderly contingent belongs to the Ivory Coast, it should be noted that the high percentage of hypertension and coronary heart disease are among law enforcement and defense officers (71.4%, 42.9%) among employees of service ‐ management (64.6%, 16.7%).

Thus, employees of service ‐ law enforcement and defense officials, agriculture workers and economists were less adaptable and more susceptible to pathological processes that accompanied by unstable, course, increasing of the number of chronic diseases, the presence of associated diseases and decreased reactivity.