Cells Of Pancreas Research Articles

Deletion of BMP6 Worsens the Phenotype of Hemojuvelin-Deficient Mice and Attenuates Hepcidin Levels Reached after LPS Stimulation

Liver sinusoidal endothelial cells (LSEC) produce bone morphogenetic protein BMP6 which acts on the hepatocyte co-receptor hemojuvelin (HJV) to regulate hepcidin production. Both are required to ensure optimal maintenance of iron homeostasis. In the mouse, deletion of either Bmp6 or Hjv leads to a similar phenotype characterized by hepcidin insufficiency, severe iron loading and extrahepatic iron accumulation in males, which is consistent with the current views that HJV is a coreceptor for BMP6.Whether BMP6 and HJV may also signal to hepcidin independently of each other is still a topic of discussion. To provide evidence that BMP6 and HJV can separately stimulate hepcidin, we intercrossed Hjv and Bmp6 knockout mice and looked whether deletion of both Bmp6 and Hjv in mice of the F2 progeny was aggravating the phenotype of single knockout animals. Whether BMP6 and HJV are both required for the upregulation of hepcidin by inflammatory stimuli is another unresolved issue. We took the opportunity of having genetically comparable single and double knockout animals to challenge them with LPS and examine the impact of Bmp6 and/or Hjv deletion on Smad signaling and hepcidin expression after stimulation.Interestingly, deletion of Bmp6 more dramatically repressed the already reduced hepcidin expression of Hjv-/- mice, regardless of sex. These observations were confirmed at the protein level and Western-blot analyses showed that deletion of Bmp6 further altered Smad1/5/8 signaling in the liver of Hjv-/-mice. Whereas Bmp6-/- or Hjv-/- males have iron depositsin acinar cells of the exocrine pancreas and in the heart, females do not accumulate iron in these extrahepatic tissues, which reflects the fact that, in the absence of testosterone, their hepcidin is less strongly repressed than in males. Nevertheless, the concomitant loss of Bmp6 suppresses this hepcidin advantage over males. As a consequence, and in contrast to single Bmp6-/- or Hjv-/- females, double knockout females have massive iron loading in all extrahepatic tissues examined.Notably, while LPS significantly induces hepcidin mRNA and protein not only in wild-type males and females, but also in single and double knockout animals, the level reached after stimulation depends on basal expression of hepcidin. It is highest in wild-type mice, intermediate in Bmp6-/- and in Hjv-/- mice, and lowest in double knockout animals. This is compatible with the proposed synergy between IL6/STAT3 and BMP/SMAD signaling in regulating hepcidin during inflammation. Smad5 signaling was previously shown to be activated by activin B as a consequence of LPS stimulation but to have no impact on hepcidin induction. Here, although activation of Smad5 by LPS was similar in wild-type and in Bmp6-/- mice, the level of hepcidin reached after stimulation was much lower in Bmp6-/- mice. In contrast, Hjv-/- mice present with reduced Smad5 activation compared with Bmp6-/- mice but have similar induction of hepcidin. These data definitely confirm the lack of relationship between activation of Smad1/5/8 signaling by inflammatory stimuli and elevation of hepcidin expression.In conclusion, analysis of this Bmp6-/- x Hjv-/- intercross clearly shows that deletion of both Bmp6 and Hjv further represses hepcidin and aggravates the phenotype of single knockout animals. This indicates that, when one actor of the major hepcidin signaling pathway is lacking, alternative pathways, although less efficient to activate Smad1/5/8, succeed in maintaining hepcidin to a level avoiding extrahepatic iron accumulation in females. The suppression of these alternative pathways, as here in Bmp6/Hjv double knockout animals, leads to a greater repression of hepcidin in mice of both genders and a substantial exacerbation of the extrahepatic iron overload phenotype in females. Our data also show that induction of hepcidin by LPS in vivo is linked to BMP/Smad signaling before but not after stimulation. Notably, the less severely affected Bmp6-/- or Hjv-/- females produce, when challenged with LPS, more hepcidin than unchallenged wild-type mice. Thus, in females, treatments targeting BMP type I receptors will be more effective against anemia of inflammation than treatments that would target only hemojuvelin, as the latter would not prevent BMP6 to signal to hepcidin independently of HJV. DisclosuresNo relevant conflicts of interest to declare.

Thymoquinone Preserves Pancreatic Islets Structure Through Upregulation of Pancreatic β-Catenin in Hypothyroid Rats.

BackgroundAltered status of thyroid hormones, which have a key role in regulating metabolism, was reported to affect glucose homeostasis and insulin secretion.ObjectiveThis study was designed to assess the impact of propylthiouracil (PTU)-induced hypothyroidism on the pancreatic islet cells and the efficacy of thymoquinone (TQ) in alleviating this impact and explore the mechanism behind it alleviating oxidative stress and affecting β-catenin expression.Materials and MethodsPTU (6 mg/kg/body weight) was used to induce hypothyroidism in Wistar rats. Four groups of rats (n=6 each) were utilized in this study. Untreated hypothyroid and TQ-treated hypothyroid groups (50 mg/kg/body weight for 4 weeks) were included. Thyroid functions, antioxidant profile and pancreatic β-catenin and IL-10 mRNA were measured. Histopathological and immunohistochemical assessment of the pancreas was performed.ResultsPTU administration induced a hypothyroid status that was associated with a marked disturbed oxidant/antioxidant status and a significant hyperglycemia (p<0:001), hypoinsulinemia (p=0.01) and decreased HOMA-β-cell (p<0.001). Islet cells of hypothyroid pancreas showed many degenerative changes with increased apoptosis, reduced insulin β-catenin immunoexpression. Administration of TQ alleviated these effects on the thyroid function, antioxidants, structure of pancreatic islet cells. Up-regulation of β-catenin, IL-10 and CAT gene expression in pancreatic islets after treatment with TQ supported its antioxidant and preserving β-cell function and viability mechanistic action.ConclusionTQ alleviated PTU-induced hypothyroidism changes in insulin homeostasis and pancreatic β cells mostly through its antioxidant effect as well as up-regulation of pancreatic β-catenin expression.

A Transcriptionally Distinct Subpopulation of Healthy Acinar Cells Exhibit Features of Pancreatic Progenitors and PDAC.

Pancreatic ductal adenocarcinoma (PDAC) tumors can originate either from acinar or ductal cells in the adult pancreas. We re-analyze multiple pancreas and PDAC single-cell RNA-seq datasets and find a subset of nonmalignant acinar cells, which we refer to as acinar edge (AE) cells, whose transcriptomes highly diverge from a typical acinar cell in each dataset. Genes upregulated among AE cells are enriched for transcriptomic signatures of pancreatic progenitors, acinar dedifferentiation, and several oncogenic programs. AE-upregulated genes are upregulated in human PDAC tumors, and consistently, their promoters are hypomethylated. High expression of these genes is associated with poor patient survival. The fraction of AE-like cells increases with age in healthy pancreatic tissue, which is not explained by clonal mutations, thus pointing to a nongenetic source of variation. The fraction of AE-like cells is also significantly higher in human pancreatitis samples. Finally, we find edge-like states in lung, liver, prostate, and colon tissues, suggesting that subpopulations of healthy cells across tissues can exist in pre-neoplastic states. SIGNIFICANCE: These findings show "edge" epithelial cell states with oncogenic transcriptional activity in human organs without oncogenic mutations. In the pancreas, the fraction of acinar cells increases with age.

Imaging Beta-Cell Function in the Pancreas of Non-Human Primates Using a Zinc-Sensitive MRI Contrast Agent.

Non-invasive beta cell function measurements may provide valuable information for improving diabetes diagnostics and disease management as the integrity and function of pancreatic beta cells have been found to be compromised in Type-1 and Type-2 diabetes. Currently, available diabetes assays either lack functional information or spatial identification of beta cells. In this work, we introduce a method to assess the function of beta cells in the non-human primate pancreas non-invasively with MRI using a Gd-based zinc(II) sensor as a contrast agent, Gd-CP027. Additionally, we highlight the role of zinc(II) ions in the paracrine signaling of the endocrine pancreas via serological measurements of insulin and c-peptide. Non-human primates underwent MRI exams with simultaneous blood sampling during a Graded Glucose Infusion (GGI) with Gd-CP027 or with a non-zinc(II) sensitive contrast agent, gadofosveset. Contrast enhancement of the pancreas resulting from co-release of zinc(II) ion with insulin was observed focally when using the zinc(II)-specific agent, Gd-CP027, whereas little enhancement was detected when using gadofosveset. The contrast enhancement detected by Gd-CP027 increased in parallel with an increased dose of infused glucose. Serological measurements of C-peptide and insulin indicate that Gd-CP027, a high affinity zinc(II) contrast agent, potentiates their secretion only as a function of glucose stimulation. Taken in concert, this assay offers the possibility of detecting beta cell function in vivo non-invasively with MRI and underscores the role of zinc(II) in endocrine glucose metabolism.

Interpreting type 1 diabetes risk with genetics and single-cell epigenomics.

Genetic risk variants that have been identified in genome-wide association studies of complex diseases are primarily non-coding1. Translating these risk variants into mechanistic insights requires detailed maps of gene regulation in disease-relevant cell types2. Here we combined two approaches: a genome-wide association study of type 1 diabetes (T1D) using 520,580 samples, and the identification of candidate cis-regulatory elements (cCREs) in pancreas and peripheral blood mononuclear cells using single-nucleus assay for transposase-accessible chromatin with sequencing (snATAC-seq) of 131,554 nuclei. Risk variants for T1D were enriched in cCREs that were active in T cells and other cell types, including acinar and ductal cells of the exocrine pancreas. Risk variants at multiple T1D signals overlapped with exocrine-specific cCREs that were linked to genes with exocrine-specific expression. At the CFTR locus, theT1D risk variant rs7795896 mapped to a ductal-specific cCRE that regulated CFTR; the risk allele reduced transcription factor binding, enhancer activity and CFTR expression in ductal cells. These findings support a role for the exocrine pancreas in the pathogenesis of T1D and highlight the power of large-scale genome-wide association studies and single-cell epigenomics for understanding the cellular origins of complex disease.

Histology of hematoxylin–eosin and immunohistochemical diabetes rat pancreas after giving combination of moringa leaves (Moringa oleifera) and clove flower (Syzygium aromaticum) extracts

The purpose of this study was to determine the regeneration activity of pancreatic beta cells by a combination of the ethanol extracts of Moringa leaves and Clove flower. These extracts prepared by maceration with ethanol as solvent . This is an experimental laboratory research by using post test only group design . The subject of this research is 40 white male rats of Wistar strain ( Rattus norvegicus ) and were conditioned DM by streptozotozine-nicotinamide induction . The rats randomly divided into 8 groups , and each group consisted of 5 rats . Combination dose of Moringa leaves and Clove flowers extracts used are 150 : 40 mg / kg body weight of mice , 100 : 80 mg / kg body weight of mice and 50 : 120 mg / kg body weight of mice . The rats were sacrificed and the pancreas taken to be made preparations histopathology , staining and observation tissues with HE and IHC methods. The results showed that the staining and observation tissues of heart with HE method acquired the positive control group , the single test group and the combination group were showing the islet on the Langerhans island of the pancreas is bigger than in the negative control group. The morphology of the island of Langerhans increasingly large indicates increasing the regeneration of the cells of the islet beta pancreas; whereas the method of IHC acquired the negative control group seen lack of display intensity of positive reaction Ag &amp; Ab beta cells with are marked with brown cells . In the positive control group , the single test group and the combination group , seen a positive reaction of Ag &amp; Ab insulin-producing beta cells characterized by brown cells and insulin expression dominating pancreatic island of Langerhans.

Stabilized Longitudinal In Vivo Cellular-Level Visualization of the Pancreas in a Murine Model with a Pancreatic Intravital Imaging Window.

Direct in vivo cellular-resolution imaging of the pancreas in a live small animal model has been technically challenging. A recent intravital imaging study, with an abdominal imaging window, enabled visualization of the cellular dynamics in abdominal organs in vivo. However, due to the soft sheet-like architecture of the mouse pancreas that can be easily influenced by physiologic movement (e.g., peristalsis and respiration), it was difficult to perform stabilized longitudinal in vivo imaging over several weeks at the cellular level to identify, track, and quantify islets or cancer cells in the mouse pancreas. Herein, we describe a method for implanting a novel supporting base, an integrated pancreatic intravital imaging window, that can spatially separate the pancreas from the bowel for longitudinal time-lapse intravital imaging of the pancreas microstructure. Longitudinal in vivo imaging with the imaging window enables stable visualization, allowing for the tracking of islets over a period of 3 weeks and high-resolution three-dimensional imaging of the microstructure, as evidenced here in an orthotopic pancreatic cancer model. With our method, further intravital imaging studies can elucidate the pathophysiology of various diseases involving the pancreas at the cellular level.

Diabetes mellitus accelerates the progression of osteoarthritis in streptozotocin-induced diabetic mice by deteriorating bone microarchitecture, bone mineral composition, and bone strength of subchondral bone.

BackgroundThe purpose of this study was to develop an optimal diabetes-osteoarthritis (DM-OA) mouse model to validate that diabetes aggravates osteoarthritis (OA) and to evaluate the microarchitecture, chemical composition, and biomechanical properties of subchondral bone (SB) as a consequence of the DM-OA-induced damage induced.MethodsMice were randomly divided into three groups: DM-OA group, OA group, and sham group. Blood glucose levels, body weight, and food intake of all animals were recorded. Serum calcium (Ca) and osteocalcin (OCN) levels were compared in the three groups. The messenger ribonucleic acid (mRNA) and protein expression of key regulators for bone metabolism were detected. A semi-quantitative grading system [Osteoarthritis Research Society International (OARSI)] was used to evaluate cartilage and SB degeneration. Microspectroscopy, microindentations, micro-computed tomography (CT) imaging, and fracture load of compression testing were also used to evaluate trabecular SB properties.ResultsGlycemic monitoring and pancreas pathological results indicated stable high blood glucose and massive destruction of pancreas and islet cells in the DM-OA group. Serum levels of bone specific alkaline phosphatase (ALP-B) and tartrate-resistant acid phosphatase 5b (TRACP-5b) in the DM-group were higher than those of the other two groups while levels of serum Ca and OCN were lower. Meanwhile, the protein and mRNA expression of osteoblast-specific biomarkers [osteoprotegerin/receptor activator of nuclear factor kappa-B ligand (OPG/RANKL) ratio, collagen type I (COL-I), Runt-related transcription factor 2 (RUNX-2), OCN] were suppressed, and osteoclast-specific biomarkers [sclerostin (SOST)] was elevated in the DM-OA group. The mineral-to-collagen ratio, microindentation elastic modulus, hardness, micro-architectural parameters, bone mineral density, and fracture load of SB trabecular bone of the DM-OA group joint were lower than those of the other two groups. On the other hand, The OARSI score, trabecular spacing, and structural model index of the DM-OA group joint were higher than those of the other two groups.ConclusionsThe glycemic and pancreatic pathological results indicated that the DM-OA model was a simple and reliable model induced by streptozotocin (STZ) and surgery. The results revealed the mechanisms through which diabetes accelerates OA; that is, by damaging and deteriorating the functions of SB, including its microarchitecture, chemical composition, and biomechanical properties.

Cadmium induces endoplasmic reticulum stress-mediated apoptosis in pig pancreas via the increase of Th1 cells

Cadmium (Cd), an environmental pollutant, causes several adverse reactions in animals. High dose of Cd has serious cytotoxicities, including the induction of programmed cell necrosis, autophagy and apoptosis, which has aroused wide public concern. The balance of cytokine network is affected by Th1/Th2 balance which is closely related to immune response and the occurrence, development, treatment and outcome of various diseases. Cd can induce severe apoptosis, but the relationship between Cd induced apoptosis and Th1/Th2 balance has not been clarified. In this study, we established a pig Cd poisoning model, exposing to CdCl2 for 40 days (20 mg Cd/kg diet). Firstly, deviation of Th1/Th2 balance was observed by fluorescence staining, and apoptosis was observed by TUNEL staining. Then, real-time fluorescence quantitative analysis and Western blot were used to detect the expression of related proteins. The results show that Cd can interfere with the balance of Th1/Th2 and shift the balance towards Th1. In addition, through the experiments, we found that Cd exposure can increase the expression of glucose-regulated protein 94 (GRP94) and glucose-regulated protein 78 (GRP78), marker proteins of unfolded protein response (UPR). Cd exposure can increase the expression of pancreatic endoplasmic reticulum kinase (PERK), CCAAT-enhancer-binding protein homologous protein (CHOP), inositol-requiring enzyme 1 (IRE-1), activating transcription factor 6 (ATF-6), cysteinyl aspartate specific proteinase (Caspase12), indicating the three branches (ATF6, PERK and IRE-1) of endoplasmic reticulum stress (ER-stress) were activated. Moreover, we found that the expression of pro-apoptosis genes in the downstream pathway of ER-stress increased. In summary, our results indicated that Cd exposure upregulated the expression of pro-apoptosis related genes and caused apoptosis via the activation of the ER-stress signaling pathways in pancreas cells. And these negative effects were correlated with the equilibrium drift of Th1/Th2, increase in the expression and secretion of Th1 cytokines.

Biological role of phlorotannis extracted from brown algae and its activity in the diabetic treatment: Thesis Abstract

Thesis Abstract Diabetes mellitus characterized by hyperglycemia which associated with failure of various organs. Therefore, this study aims to investigate biological activity including the antioxidant, antibacterial and antidiabetic activities of polyphenolic compound derived from Egyptian brown seaweed Cystoseira compressa and Sargassum linifolium. Phlorotannis has been extracted and confirmed by different chemical and physical tests. The seaweed extracts exhibited higher antioxidant properties. Phlorotannis extracts showed antibacterial activity evaluated against species [Staphylococcus aureus, Escherichia coli, and Bacillus cereus]. In vivo study fifty white male albino rats were divided into six equal groups. The first three groups of rats are control normal, control C. compressa extract and control S. linifolium extract groups, the last three groups which are diabetic by intraperitoneal injection of streptozotocin (STZ) had one diabetic control and diabetic that got 60 mg/kg of C. compressa phlorotannis extract and diabetic that got 60 mg/kg of S. linifolium after four weeks of diabetes induction. Phlorotannis extracts decrease serum glucose, α-amylase, glucosidase activity and liver malondialdehyde (MDA). However serum insulin, hepatic glutathione and total antioxidant capacityTAC were significantly increased compared with diabetic non-treated groups. Also phlorotannis make activation of AMPKα2 expression in skeletal muscle in treated group as compared to diabetic group. The histopathological results supported that phlorotannis extracts markedly reduce damage in β cells of pancreas. Finally this study confirmed that phlorotannis extract from C. compressa and S. linifolium algae have the capacity to act as antioxidant and antidiabetic agents. These results point phlorotannins extracts as potential pharmaceutical resources for human health.

CBA: Cluster-Guided Batch Alignment for Single Cell RNA-seq

The power of single-cell RNA sequencing (scRNA-seq) in detecting cell heterogeneity or developmental process is becoming more and more evident every day. The granularity of this knowledge is further propelled when combining two batches of scRNA-seq into a single large dataset. This strategy is however hampered by technical differences between these batches. Typically, these batch effects are resolved by matching similar cells across the different batches. Current approaches, however, do not take into account that we can constrain this matching further as cells can also be matched on their cell type identity. We use an auto-encoder to embed two batches in the same space such that cells are matched. To accomplish this, we use a loss function that preserves: (1) cell-cell distances within each of the two batches, as well as (2) cell-cell distances between two batches when the cells are of the same cell-type. The cell-type guidance is unsupervised, i.e., a cell-type is defined as a cluster in the original batch. We evaluated the performance of our cluster-guided batch alignment (CBA) using pancreas and mouse cell atlas datasets, against six state-of-the-art single cell alignment methods: Seurat v3, BBKNN, Scanorama, Harmony, LIGER, and BERMUDA. Compared to other approaches, CBA preserves the cluster separation in the original datasets while still being able to align the two datasets. We confirm that this separation is biologically meaningful by identifying relevant differential expression of genes for these preserved clusters.

EXTENUATING EFFECTS OF Terminalia catappa LEAVES AND Persea americana SEED EXTRACTS ON STREPTOZOTOCIN-INDUCED LIPIDS PERTURBATION AND PANCREATIC DAMAGE IN DIABETIC RATS

Diabetes mellitus develops either due to insufficient insulin secretion or lack of insulin resulting from damaged pancreas beta cells. Dyslipidaemia is an acute complication in diabetes mellitus. The aim of this study was to investigate the extenuating effects of T. cattapa leaves and P. americana seed aqueous extracts on streptozotocin-induced lipids profile perturbation and pancreatic damage in experimental rats. Thirty male albino rats were randomly divided into six groups (n = 5). Group 1: (negative control), group 2: 80 mg/kgbwt streptozotocin (positive control), group 3: (80 mg/kgbwt streptozotocin + 200 mg/kgbwt T. catappa leave extract), group 4: (80 mg/kgbwt streptozotocin + 200 mg/kgbwt Persea americana seed extract), group 5: (80 mg/kgbwt streptozotocin + 200 mg/kgbwt extracts-mixture), group 6: (80 mg/kgbwt streptozotocin + 5 mg/kgbwt glibenclamide (standard drug). A single dose of streptozotocin was administered to the rats intraperitoneally; the extracts and glibenclamide were administered orally for 21 days, after which their pancreas was excised for histology. Thereafter, extracts of T. catappa leaves and P. americana seed on serum lipid levels imbalance in streptozotocin-induced diabetic rats were investigated. Histological studies showed a degenerative effect of the pancreatic islet cells of strotozotocin-induced groups. Results showed improvement in the regulation of lipid metabolism as well as the regeneration of the beta cells of pancreas on treatment with T. catappa leaves and P. americana seed. The extracts both equally exert significant antidyslipidemic effects in diabetic rats, in view of the extenuating effects of the extracts on pancreatic islet cells.

In pancreatic β-cells myosin 1b regulates glucose-stimulated insulin secretion by modulating an early step in insulin granule trafficking from the Golgi.

Pancreatic β-cells secrete insulin, which controls blood glucose levels, and defects in insulin secretion are responsible for diabetes mellitus. The actin cytoskeleton and some myosins support insulin granule trafficking and release, although a role for the class I myosin Myo1b, an actin- and membrane-associated load-sensitive motor, in insulin biology is unknown. We found by immunohistochemistry that Myo1b is expressed in islet cells of the rat pancreas. In cultured rat insulinoma 832/13 cells, Myo1b localized near actin patches, the trans-Golgi network (TGN) marker TGN38, and insulin granules in the perinuclear region. Myo1b depletion by small interfering RNA in 832/13 cells reduced intracellular proinsulin and insulin content and glucose-stimulated insulin secretion (GSIS) and led to the accumulation of (pro)insulin secretory granules (SGs) at the TGN. Using an in situ fluorescent pulse-chase strategy to track nascent proinsulin, Myo1b depletion in insulinoma cells reduced the number of (pro)insulin-containing SGs budding from the TGN. The studies indicate for the first time that in pancreatic β-cells Myo1b controls GSIS at least in part by mediating an early stage in insulin granule trafficking from the TGN.

MFG-E8 Plays an Important Role in Attenuating Cerulein-Induced Acute Pancreatitis in Mice.

Milk fat globule-EGF factor 8 (MFG-E8) is a secreted glycoprotein that regulates tissue homeostasis, possesses potent anti-inflammatory properties, and protects against tissue injury. The human pancreas expresses MFG-E8; however, the role of MFG-E8 in the pancreas remains unclear. We examined the expression of MFG-E8 in the pancreas at baseline and during cerulein-induced acute pancreatitis in mice and determined whether MFG-E8 attenuates the progression of pancreatitis, a serious inflammatory condition that can be life-threatening. We administered cerulein to wild-type (WT) and Mfge8 knockout (KO) mice to induce pancreatitis. Immunoblot analysis showed that MFG-E8 is constitutively expressed in the murine pancreas and is increased in mice with cerulein-induced acute pancreatitis. In situ hybridization revealed that ductal epithelial cells in the mouse pancreas express Mfge8 transcripts at baseline. During pancreatitis, Mfge8 transcripts were abundantly expressed in acinar cells and endothelial cells in addition to ductal epithelial cells. Knocking out Mfge8 in mice exacerbated the severity of cerulein-induced acute pancreatitis and delayed its resolution. In contrast, administration of recombinant MFG-E8 attenuated cerulein-induced acute pancreatitis and promoted repair of pancreatic injury in Mfge8 KO mice. Taken together, our study suggests that MFG-E8 protects the pancreas against inflammatory injury and promotes pancreatic tissue repair. MFG-E8 may represent a novel therapeutic target in acute pancreatitis.

Antidiabetic effect of Nigella sativa compared with metformin on blood glucose levels in streptozotocin induced diabetic albino wistar rats

Background: Antidiabetic drugs are many but all of them have adverse effects ranging from simple side effects to serious side effects like hypoglycemic coma. We need alternative drugs which will not only lower blood sugar level but have fewer side effects. One such daily use ingredient in our food is Nigella sativa (kalonji) which has many properties.Methods: This was an objective study in an experimental animal. We divided albino wistar rats into six groups each group with six rats. Diabetes was induced using drug streptozotocin. Three doses of Nigella sativa 0.5 ml, 1 ml, 1.5 ml orally per rat were used. Metformin (100 mg/kg body weight) was used as standard drug. Blood sugar was estimated using glucometer on day 0 (starting day of treatment), day 5, day 10, day 20, day 40. The effect of Nigella sativa was compared with metformin group using the Anova test. Statistical analysis was done using SPSS software version 20.Results: Nigella sativa (NS) produced significant hypoglycemic effect. NS in the dose of 0.5 ml, 1 ml and 1.5 ml produced significant reduction in blood glucose in comparison to day 0. Metformin also (100 mg/kg body weight) produced significant reduction in blood glucose on day 20 and day 40. Comparison of hypoglycemic effect of Nigella sativa is not significantly different on day 10 (1 ml) and day 20 (1.5 ml) in comparison to Metformin (100 mg/kg body weight). Histopathological examination showed that there was partial regeneration of beta islet cells of pancreas by 1.5 ml of Nigella sativa which were damaged due to streptozotocin treatment.Conclusions: Alternative method of treatment for diabetes is very much needed and the study shows the use of the spice (Nigella sativa) daily can lower the blood sugar levels and can serve as an alternative treatment of diabetes mellitus.

Eicosapentaenoic Acid Inhibits KRAS Mutant Pancreatic Cancer Cell Growth by Suppressing Hepassocin Expression and STAT3 Phosphorylation.

Background: The oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation was reported to be the signature genetic event in most cases of pancreatic ductal adenocarcinoma (PDAC). Hepassocin (HPS/FGL1) is involved in regulating lipid metabolism and the progression of several cancer types; however, the underlying mechanism of HPS/FGL1 in the KRAS mutant PDAC cells undergoing eicosapentaenoic acid (EPA) treatment remains unclear. Methods: We measured HPS/FGL1 protein expressions in a human pancreatic ductal epithelial (HPNE) normal pancreas cell line, a KRAS-wild-type PDAC cell line (BxPC-3), and KRAS-mutant PDAC cell lines (PANC-1, MIA PaCa-2, and SUIT-2) by Western blot methods. HEK293T cells were transiently transfected with corresponding KRAS-expressing plasmids to examine the level of HPS expression with KRAS activation. We knocked-down HPS/FGL1 using lentiviral vectors in SUIT-2 cells and measured the cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and clonogenicity assays. Furthermore, a lipidomic analysis was performed to profile changes in lipid metabolism after HPS/FGL1 knockdown. Results: We found that the HPS/FGL1 level was significantly upregulated in KRAS-mutated PDAC cells and was involved in KRAS/phosphorylated (p)-signal transduction and activator of transcription 3 (STAT3) signaling, and the knockdown of HPS/FGL1 in SUIT-2 cells decreased cell proliferation through increasing G2/M cell cycle arrest and cyclin B1 expression. In addition, the knockdown of HPS/FGL1 in SUIT-2 cells significantly increased omega-3 polyunsaturated fatty acids (PUFAs) and EPA production but not docosahexaenoic acid (DHA). Moreover, EPA treatment in SUIT-2 cells reduced the expression of de novo lipogenic protein, acetyl coenzyme A carboxylase (ACC)-1, and decreased p-STAT3 and HPS/FGL1 expressions, resulting in the suppression of cell viability. Conclusions: Results of this study indicate that HPS is highly expressed by KRAS-mutated PDAC cells, and HPS/FGL1 plays a crucial role in altering lipid metabolism and increasing cell growth in pancreatic cancer. EPA supplements could potentially inhibit or reduce ACC-1-involved lipogenesis and HPS/FGL1-mediated cell survival in KRAS-mutated pancreatic cancer cells.

Pre-existing beta cells but not progenitors contribute to new beta cells in the adult pancreas.

It has been suggested that new beta cells can arise from specific populations of adult pancreatic progenitors or facultative stem cells. However, their existence remains controversial, and the conditions under which they would contribute to new beta-cell formation are not clear. Here, we use a suite of mouse models enabling dual-recombinase-mediated genetic tracing to simultaneously fate map insulin-positive and insulin-negative cells in the adult pancreas. We find that the insulin-negative cells, of both endocrine and exocrine origin, do not generate new beta cells in the adult pancreas during homeostasis, pregnancy or injury, including partial pancreatectomy, pancreatic duct ligation or beta-cell ablation with streptozotocin. However, non-beta cells can give rise to insulin-positive cells after extreme genetic ablation of beta cells, consistent with transdifferentiation. Together, our data indicate that pancreatic endocrine and exocrine progenitor cells do not contribute to new beta-cell formation in the adult mouse pancreas under physiological conditions.

From friend to foe: Pro-apoptotic action of nuclear ARC in diabetes.

Apoptosis repressor with caspase recruitment domain (ARC) is an established cytoplasmic anti-apoptotic factor relevant for cancer and metabolic disease. In this issue of Developmental Cell, McKimpson etal. show that ARC can assume potent pro-apoptotic effects in β cells of the endocrine pancreas via translocation to the nucleus.

Diabetic kidney disease and transplantation options

AbstractDiabetes is the leading cause of chronic kidney disease worldwide and associated with significant morbidity and mortality. Despite advances in treatment options for diabetic kidney disease, a substantial proportion of patients still progress to end‐stage renal disease. While not without its own risk and complications, transplantation remains the best modality of renal replacement therapy in terms of patient outcome and cost‐effectiveness when compared to dialysis.This article reviews diabetic kidney disease with a focus on options for transplantation including kidney, pancreas and islet cell transplantation. Copyright © 2021 John Wiley &amp; Sons.

Antenatal Thymosin β4: a New Tool for Accelerating Fetal Development in Preterms? Thymosin Beta-4: a Breakthrough in the “Physiological” Regenerative Medicine in Preterm Newborns

To prevent the health risks related to prematurity, multiple drugs have been introduced in clinical practice in recent years. This paper focuses on a new "physiological" regenerative approach to be started in the perinatal period, particularly on very low birth weight preterm infants. This new preventive approach underlined the necessity to start regenerative medicine very early after birth, a period in which kidney, brain, pancreas, and lung stem cells maintain their proliferative and differentiating abilities. Among the multiple factors proposed in the literature as potential growth promoters for preterm neonates, thymosin beta-4 (Tβ4) has been indicated as one of the most important candidates for regenerative medicine.