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Journal of Applied Biomedicine Jun 2024Myo-inositol (MI), present in a variety of foods, is essential in several important processes of cell physiology. In this study, we explored the protective effects of MI...
Myo-inositol (MI), present in a variety of foods, is essential in several important processes of cell physiology. In this study, we explored the protective effects of MI against hyperglycemia and dyslipidemia in db/db mice, a typical animal model of type 2 diabetes mellitus (T2DM). MI supplement effectively suppressed the high plasma glucose and insulin levels and markedly relieved the insulin resistance (IR) in the db/db mice, comparable to metformin's effects. In MIN6 pancreatic β cells, MI also restrained the upsurge of insulin secretion stimulated by high-concentration glucose but had no impact on the promoted cell proliferation. Moreover, MI abated the enhanced plasma triglyceride and total cholesterol levels in the db/db mice. Notably, the lipid droplet formation of mesenchymal stem cells (MSCs) from db/db mice was significantly diminished after the treatment of MI, indicating that MI could effectively inhibit the differentiation of db/db mouse MSCs into adipocytes. However, MI regretfully failed to control obesity in db/db mice. This work proved that MI significantly helped db/db mice's metabolic disorders, indicating that MI has potential as an effective adjunctive treatment for hyperglycemia and dyslipidemia in T2DM patients.
Topics: Animals; Insulin Resistance; Dyslipidemias; Inositol; Mice; Diabetes Mellitus, Type 2; Male; Insulin; Mesenchymal Stem Cells; Blood Glucose; Insulin-Secreting Cells; Adipocytes; Hyperglycemia
PubMed: 38912862
DOI: 10.32725/jab.2024.009 -
Annals of Surgery Open : Perspectives... Jun 2024Our aim was to assess whether complications after pancreatoduodenectomy (PD) impact long-term quality of life (QoL) and functional outcomes.
OBJECTIVE
Our aim was to assess whether complications after pancreatoduodenectomy (PD) impact long-term quality of life (QoL) and functional outcomes.
BACKGROUND
There is an increasing number of long-term post-PD survivors, but few studies have evaluated long-term QoL outcomes.
METHODS
The EORTC QLQ-C30 and QLQ-PAN26 questionnaires were administered to patients who survived >5 years post-PD. Clinical relevance (CR) was scored as small (5-10), moderate (10-20), or large (>20). Patients were stratified based on whether they experienced a complication during the index hospitalization.
RESULTS
Of 305 patients >5 years post-PD survivors, with valid contact information, 248 completed the questionnaires, and 231 had complication data available. Twenty-nine percent of patients experienced a complication, of which 17 (7.4%) were grade 1, 27 (11.7%) were grade 2, and 25 (10.8%) were grade 3. Global health status and functional domain scores were similar between both groups. Patients experiencing complications reported lower fatigue (21.4 vs 28.1, < 0.05, CR small) and diarrhea (15.9 vs 23.1, < 0.05, CR small) symptom scores when compared to patients without complications. Patients experiencing complications also reported lower pancreatic pain (38.2 vs 43.4, < 0.05, CR small) and altered bowel habits (30.1 vs 40.7, < 0.01, CR moderate) symptom scores. There was a lower prevalence of worrying (36.2% vs 60.5%, < 0.05) and bloating (42.0% vs 56.2%, < 0.05) among PD survivors with complications.
CONCLUSIONS
Post-PD complication rates were not associated with long-term global QoL or functionality, and may be associated with less severe pancreas-specific symptoms.
PubMed: 38911654
DOI: 10.1097/AS9.0000000000000400 -
Hepatobiliary Surgery and Nutrition Jun 2024The establishment of preoperative chemotherapy (PCT) with FOLFIRINOX and gemcitabine/nab-paclitaxel in recent years has enabled resectability in many patients with...
BACKGROUND
The establishment of preoperative chemotherapy (PCT) with FOLFIRINOX and gemcitabine/nab-paclitaxel in recent years has enabled resectability in many patients with initially locally advanced pancreatic cancer (LAPC). Nevertheless, information about the impact of PCT on surgical results is scarce.
METHODS
All patients with initial LAPC who received surgery after chemotherapy at the high-volume centre for pancreatic surgery of St. Josef-Hospital Bochum between 2015 and 2022 were included in this retrospective cohort analysis.
RESULTS
A total of 139 patients underwent surgery after pre-treatment with FOLFIRINOX (76.3%), gemcitabine/nab-paclitaxel (11.5%), both (5.8%) and other regimens (6.5%). Eighty-five tumors (61.2%) were resectable after PCT. R0 resection was achieved in 92.9%, R1 in 7.1% and R2 in 0% of cases. Fifty-four tumors were still not resectable at the time of surgery. Surgical results of the patients did not show increased postoperative mortality and morbidity compared to the literature data. Postoperative 30-day mortality was 1.4%. Rates for pancreas-specific complications [postoperative pancreatic fistula (POPF), delayed gastric emptying (DGE), postpancreatectomy hemorrhage (PPH), and others] were not increased. POPF occurred in 10.5% and DGE in 26.3% after pancreaticoduodenectomy. After distal pancreatectomy, POPF was detected in 37.5% and DGE in 12.5%. Median postoperative survival (31 13 months) and overall survival after initial diagnosis (40 20 months) were significantly longer in resected patients (P<0.001). Postoperative recurrence-free survival in resected patients amounted to 12 months.
CONCLUSIONS
This study underlines that PCT allows resectability of primarily unresectable patients with LAPC without increasing perioperative mortality and morbidity. It may lead to a significant prolongation of recurrence-free and overall survival in resected patients after PCT.
PubMed: 38911210
DOI: 10.21037/hbsn-23-426 -
Hepatobiliary Surgery and Nutrition Jun 2024
PubMed: 38911206
DOI: 10.21037/hbsn-24-92 -
Frontiers in Pharmacology 2024Acute pancreatitis (AP) is an inflammatory condition that resolves spontaneously, but occasionally, develops into systemic inflammation, organ failure and mortality....
BACKGROUND
Acute pancreatitis (AP) is an inflammatory condition that resolves spontaneously, but occasionally, develops into systemic inflammation, organ failure and mortality. Oxidative stress and activation of inflammatory pathways represent major players in AP pathogenesis. Current management of AP relies on attenuating injuries to the pancreas and putting the inflammatory process under control. In this study, we investigated the role of sitagliptin in modulating L-arginine-induced AP in rats.
METHODS
Swiss rats were subdivided into a healthy control group, AP group (a single dose of L-arginine 250 mg/100 g, intraperitoneal), and sitagliptin + L-arginine-treated group (10 mg sitagliptin/kg body weight/day, orally). Sitagliptin treatment started 1 hour after L-arginine injection and continued for 3days. Biochemical and histopathological investigations were performed on serum and tissue samples collected from test animals.
RESULTS
L-arginine increased pancreatic meyloperoxidase and serum amylase- and lipase activities and serum levels of TNF-α, LT-α, IFN-γ, IL-1α/β, IL-6, IL-10, IL-12, and IL-15. AP animals showed elevated MDA and NO and decreased GSH and serum calcium levels. Histopathological changes were observed by H&E staining. Sitagliptin treatment significantly ameliorated these biochemical and histological changes diminishing the signs of AP.
CONCLUSION
Sitagliptin treatment was effective in ameliorating L-arginine-induced AP which can be regarded to its anti-inflammatory and antioxidant effect.
PubMed: 38910880
DOI: 10.3389/fphar.2024.1389670 -
Magnetic Resonance in Medical Sciences... Jun 2024To compare the utility of thin-slice fat-suppressed single-shot T2-weighted imaging (T2WI) with deep learning image reconstruction (DLIR) and conventional fast spin-echo...
PURPOSE
To compare the utility of thin-slice fat-suppressed single-shot T2-weighted imaging (T2WI) with deep learning image reconstruction (DLIR) and conventional fast spin-echo T2WI with DLIR for evaluating pancreatic protocol.
METHODS
This retrospective study included 42 patients (mean age, 70.2 years) with pancreatic cancer who underwent gadoxetic acid-enhanced MRI. Three fat-suppressed T2WI, including conventional fast-spin echo with 6 mm thickness (FSE 6 mm), single-shot fast-spin echo with 6 mm and 3 mm thickness (SSFSE 6 mm and SSFSE 3 mm), were acquired for each patient. For quantitative analysis, the SNRs of the upper abdominal organs were calculated between images with and without DLIR. The pancreas-to-lesion contrast on DLIR images was also calculated. For qualitative analysis, two abdominal radiologists independently scored the image quality on a 5-point scale in the FSE 6 mm, SSFSE 6 mm, and SSFSE 3 mm with DLIR.
RESULTS
The SNRs significantly improved among the three T2-weighted images with DLIR compared to those without DLIR in all patients (P < 0.001). The pancreas-to-lesion contrast of SSFSE 3 mm was higher than those of the FSE 6 mm (P < 0.001) and tended to be higher than SSFSE 6 mm (P = 0.07). SSFSE 3 mm had the highest image qualities regarding pancreas edge sharpness, pancreatic duct clarity, and overall image quality, followed by SSFSE 6 mm and FSE 6 mm (P < 0.0001).
CONCLUSION
SSFSE 3 mm with DLIR demonstrated significant improvements in SNRs of the pancreas, pancreas-to-lesion contrast, and image quality more efficiently than did SSFSE 6 mm and FSE 6 mm. Thin-slice fat-suppressed single-shot T2WI with DLIR can be easily implemented for pancreatic MR protocol.
PubMed: 38910138
DOI: 10.2463/mrms.mp.2024-0017 -
Nature Communications Jun 2024HNF4A and HNF1A encode transcription factors that are important for the development and function of the pancreas and liver. Mutations in both genes have been directly...
HNF4A and HNF1A encode transcription factors that are important for the development and function of the pancreas and liver. Mutations in both genes have been directly linked to Maturity Onset Diabetes of the Young (MODY) and type 2 diabetes (T2D) risk. To better define the pleiotropic gene regulatory roles of HNF4A and HNF1A, we generated a comprehensive genome-wide map of their binding targets in pancreatic and hepatic cells using ChIP-Seq. HNF4A was found to bind and regulate known (ACY3, HAAO, HNF1A, MAP3K11) and previously unidentified (ABCD3, CDKN2AIP, USH1C, VIL1) loci in a tissue-dependent manner. Functional follow-up highlighted a potential role for HAAO and USH1C as regulators of beta cell function. Unlike the loss-of-function HNF4A/MODY1 variant I271fs, the T2D-associated HNF4A variant (rs1800961) was found to activate AKAP1, GAD2 and HOPX gene expression, potentially due to changes in DNA-binding affinity. We also found HNF1A to bind to and regulate GPR39 expression in beta cells. Overall, our studies provide a rich resource for uncovering downstream molecular targets of HNF4A and HNF1A that may contribute to beta cell or hepatic cell (dys)function, and set up a framework for gene discovery and functional validation.
Topics: Hepatocyte Nuclear Factor 4; Hepatocyte Nuclear Factor 1-alpha; Insulin-Secreting Cells; Diabetes Mellitus, Type 2; Hepatocytes; Humans; Animals; Gene Expression Regulation; Mice; A Kinase Anchor Proteins; Organ Specificity
PubMed: 38909044
DOI: 10.1038/s41467-024-48647-w -
Biochimie Jun 2024Amyloidosis forms a large family of pathologies associated with amyloid deposit generated by the formation of amyloid fibrils or plaques. The amyloidogenic proteins and...
Amyloidosis forms a large family of pathologies associated with amyloid deposit generated by the formation of amyloid fibrils or plaques. The amyloidogenic proteins and peptides involved in these processes are targeted against almost all organs. In brain they are associated with neurodegenerative disease, and the Translocator Protein (TSPO), overexpressed in these inflammatory conditions, is one of the target for the diagnostic. Moreover, TSPO ligands have been described as promising therapeutic drugs for neurodegenerative diseases. Type 2 diabetes, another amyloidosis, is due to a beta cell mass decrease that has been linked to hIAPP (human islet amyloid polypeptide) fibril formation, leading to the reduction of insulin production. In the present study, in a first approach, we link overexpression of TSPO and inflammation in potentially prediabetic patients. In a second approach, we observed that TSPO deficient rats have higher level of insulin secretion in basal conditions and more IAPP fibrils formation compared with wild type animals. In a third approach, we show that diabetogenic conditions also increase TSPO overexpression and IAPP fibril formation in rat beta pancreatic cell line (INS-1E). These data open the way for further studies in the field of type 2 diabetes treatment or prevention.
PubMed: 38908539
DOI: 10.1016/j.biochi.2024.06.007 -
Biomedicine & Pharmacotherapy =... Jun 2024Pancreatic cancer (PC) shows a high fatality rate that can only be faced with a combination of surgery and chemotherapy or palliative treatment in the case of advanced...
Pancreatic cancer (PC) shows a high fatality rate that can only be faced with a combination of surgery and chemotherapy or palliative treatment in the case of advanced patients. Besides, PC tumors are enriched with subpopulations of cancer stem cells (CSCs) that are resistant to the existing chemotherapeutic agents, which raises an important need for the identification of new drugs. To fill this gap, we have tested the anti-tumoral activity of microbial extracts, which chemical diversity offers a broad spectrum of potential new bioactive compounds. Extracts derived from the fungus Onychocola sp. CF-107644 were assayed via high throughput screening followed by bioassay-guided fractionation and resulted in the identification and isolation of six benzophenone derivatives with antitumoral activity: onychocolones A-F (#1-6). The structures of the compounds were established by spectroscopic methods, including ESI-TOF MS, 1D and 2D NMR analyses and X-ray diffraction. Compounds #1-4 significantly inhibited the growth of the pancreas tumoral cell lines, with low-micromolar Median Effective Doses (EDs). Compound #1 (onychocolone A) was prioritized for further profiling due to its pro-apoptotic effect, which was further validated on 3D spheroids and pancreatic CSCs. Protein expression assays showed that the effect was mechanistically linked to the inhibition of MEK onco-signaling pathway. The efficacy of onychocolone A was also demonstrated in vivo by the reduction of tumor growth in a pancreatic xenograft mouse model generated by CSCs. Altogether, the data support that onychocolone A is a promising new small molecule for hit-to-lead development of a new treatment for PC.
PubMed: 38908208
DOI: 10.1016/j.biopha.2024.117018 -
Clinics (Sao Paulo, Brazil) 2024This study explored the correlation between pancreatic islet α cell function, as reflected by the plasma glucagon levels, and Diabetic Peripheral Neuropathy (DPN) in...
BACKGROUND
This study explored the correlation between pancreatic islet α cell function, as reflected by the plasma glucagon levels, and Diabetic Peripheral Neuropathy (DPN) in patients with Type 2 Diabetes Mellitus (T2DM).
METHODS
A total of 358 patients with T2DM were retrospectively enrolled in this study and divided into the Non-DPN (NDPN) group (n = 220) and the DPN group (n = 138). All patients underwent an oral glucose tolerance test to detect levels of blood glucose, insulin and glucagon, and the Area Under the Curve (AUC) for Glucagon (AUCglu) was used to estimate the overall glucagon level. The Peripheral Nerve Conduction Velocity (PNCV), Amplitude (PNCA) and Latency (PNCL) were obtained with electromyography, and their Z scores were calculated.
RESULTS
There were significant differences regarding the age, disease duration, serum levels of alanine aminotransferase, aspartate aminotransferase, urea nitrogen, high-density lipoprotein, and 2h-C peptide between these two groups (p < 0.05). The NDPN group had higher glucagon levels at 30, 60 and 120 min and AUCglu (p < 0.05). The Z-scores of PNCV and PNCA showed an increasing trend (p < 0.05), while the Z-score of PNCL showed a decreasing trend (p < 0.05). The glucagon levels were positively correlated with PNCV and PNCA, but negatively correlated with PNCL, with Gluca30min having the strongest correlation (p < 0.05). Gluca30min was independently related to PNCV, PNCL, PNCA and DPN, respectively (p < 0.05). The function of pancreatic α islet cells, as reflected by the plasma glucagon level, is closely related to the occurrence of DPN in T2DM patients.
CONCLUSION
Gluca30min may be a potentially valuable independent predictor for the occurrence of DPN.
Topics: Humans; Diabetes Mellitus, Type 2; Male; Middle Aged; Female; Diabetic Neuropathies; Glucagon; Retrospective Studies; Blood Glucose; Neural Conduction; Glucose Tolerance Test; Aged; Adult; Electromyography; Glucagon-Secreting Cells; Insulin; Area Under Curve; Time Factors; Reference Values
PubMed: 38908048
DOI: 10.1016/j.clinsp.2024.100392