Hepatocellular carcinoma (HCC) is on the rise worldwide, and its incidence in diabetic patients is two to three times that of non-diabetics. Current therapeutic options fail to provide considerable ...survival benefits to patients with HCC. There is a strong possibility that the FDA-approved antidiabetic combination of empagliflozin and metformin could show complementary effects to control HCC progression. However, their multitarget effects have not yet been studied on HCC development. Therefore, the present study aims to evaluate the antitumorigenic activity of this combination in non-diabetic mice with diethylnitrosamine-induced HCC. Empagliflozin/metformin combination prolonged survival and improved histological features of mice livers. Additionally, Empagliflozin/metformin showed anti-inflammatory potential and relieved oxidative stress. On the one hand these effects are likely attributed to the ability of metformin to inactivate NF-κB in an AMPK-dependent mechanism and on the other hand to the ability of the empagliflozin to inhibit the MAPKs, p38 and ERK1/2. Empagliflozin also showed a less robust effect on AMPK than that of metformin. Moreover, empagliflozin enhanced the autophagy inducing activity of metformin. Furthermore, empagliflozin/metformin exhibited increased apoptotic potential. Consequently, empagliflozin augmented the antitumorigenic function of metformin by exerting better control of angiogenesis, and metastasis. To conclude, our findings suggest empagliflozin as an ideal adjunct to metformin for the inhibition of HCC progression. In addition, since the incidence of hypoglycemia is minimal due to insulin-independent mechanism of action of both treatments, empagliflozin/metformin could be a promising therapeutic modality for the management of diabetic patients with HCC; and even non diabetic ones.
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•Empagliflozin/metformin combination prolonged the survival of mice with HCC.•Empagliflozin/metformin showed apoptotic and anti-inflammatory potential.•Metformin inhibited NF-κB signals in an AMPK-dependent mechanism in murine HCC.•Empagliflozin inhibited the MAPKs, p38 and ERK1/2 in mice livers with HCC.•Empagliflozin is as an ideal adjunct to metformin for the inhibition of HCC progression.
Empagliflozin and metformin are widely used for the treatment of type 2 diabetes. These drugs showed marked anti-inflammatory effects in different animal models
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enhancing AMPK activity. Yet, the ...protective anti-inflammatory effects of their combination against ulcerative colitis have not been previously investigated. The current study aimed to explore the potential of empagliflozin/metformin combination to mitigate the DSS-induced rat colitis model. The modulating effects of empagliflozin and metformin on the AMPK/mTOR/NLRP3 axis and T cell polarization were delineated. In this study, distal colons were examined for macroscopic and microscopic pathological alterations. ELISA, qRT-PCR, and immunohistochemistry techniques were applied to detect proteins and cytokines involved in AMPK/mTOR/NLRP3 axis and T Cell polarization. Oral administration of empagliflozin (10 mg/kg/day) and metformin (200 mg/kg/day) combination alleviated colitis as revealed by the reduced disease activity index, macroscopic damage index, colon weight/length ratio, and histopathologic scoring values. Interestingly, empagliflozin/metformin combination significantly enhanced AMPK phosphorylation and depressed mTOR and NLRP3 expression leading to a subsequent reduction in caspase-1 cleavage and inhibition of several inflammatory cytokines, including IL-1β, and IL-18. Reduced mTOR expression and reduced IL-6 levels led to a reduction in Th17 cell polarization and maintenance. Together, the current study reveals that the protective effects of empagliflozin and metformin against DSS-induced colitis are fundamentally mediated
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enhancing AMPK phosphorylation. Since adult humans with diabetes mellitus are at greater risk for developing inflammatory bowel diseases, clinical application of empagliflozin/metformin combination represents a novel therapeutic approach for treating diabetic patients with ulcerative colitis.
Ulcerative colitis (UC) is a prevalent type of inflammatory bowel diseases that may predispose patients to acquire colitis-related cancer if treatment was not effective. Despite the presence of an ...array of established treatment options, current modalities are not successful for a substanial number of patients. The activation of the NLRP3 inflammasome is critical in the development of inflammatory processes in the colon. Additionally, the regulation of NLRP3 via HSP90 inhibition is a potential target to treat UC. Moreover, during inflammation, autophagy allows the turnover of malfunctioning proteins and therefore stands as a viable strategy for inactivating NLRP3 inflammasomes and halting hyperinflammation. Herein, we evaluated the effect of autophagy induction using metformin in the context of HSP90 inhibition by TAS-116 in the dextran sodium sulfate (DSS)-induced UC in rats. We revealed that TAS-116-induced interruption of the protein complex containing HSP90 and NLRP3 might hamper and delay the start of the inflammatory cascade ensued by the NLRP3 inflammasome oligomerization. In such circumstances, the unprotected NLRP3 is subjected to autophagic degradation in an environment of metformin-promoted autophagic signaling. As a result, such dynamic synergy was efficient in combating colon damage and immune-cell infiltration. This was confirmed by the macroscopic and microscopic investigations. Further, biochemical analysis revealed subdued inflammation cascade and oxidative injury. Therefore, simultaneous administration of TAS-116 and metformin is a new management paradigm aimed at inducing malfunction in the NLRP3 followed by augmenting its autophagic degradation, respectively. However, further studies should be conducted to assess the reliability and consistency of this novel approach.
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•TAS-116-induced unprotection of NLRP3 hampered the start of the inflammatory cascade.•Unprotected NLRP3 is degraded by a metformin-promoted autophagic signaling.•This dynamic synergy was efficient in combating DSS-induced colon damage in rats.•TAS-116/metformin subdued oxidative stress, immune-cell infiltration and inflammation.•TAS-116/metformin simultaneous administration is a new management paradigm in colitis.
A schematic representation of the mechanisms of type II diabetes mellitus (DM) induced by Streptozotocin (STZ) with High fat diet (HFD) for 4 weeks and the role of stevia extract by oral gavage in ...alleviating these changes. We reported the antioxidant, antihyperglycemic, insulinotropic effects of stevia extract reflected on the hyperactive autophagy and sympathetic neuropathy that usually noted in diabetes mellitus. FBG: Fasting blood glucose, CAT: catalase, MDA: malondialdehyde, LC3 (microtubule associated protein-1 light chain-3) & LAMP2 (lysosomal associated membrane protein2),TH: tyrosine hydroxylase, NE: Norepinephrine.
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•Protective role of aqueous extract of stevia on pancreatic β cells of type 2 diabetic rats.•Fasting blood glucose, fasting insulin, pancreatic Malondialdehyde and Catalase.•Western blot for measuring microtubule associated protein-1 light chain-3 and lysosomal associated membrane protein 2; histopathological, histomorphometric studies and tyrosine hydroxylase and norepinephrine expression by immunostaing in pancreatic tissues.•Stevia extract has protective effects on type 2 DM pancreas by its hypoglycemic and antioxidant actions in addition to its ability to attenuate hyperactive autophagy and sympathetic nerve density.
Diabetes mellitus (DM) is a common metabolic disorder affecting more than 400 million people worldwide. Pancreatic islet cell failure due to partial loss or dysfunction of islet cells is a common feature in type 2 DM. The aim of this study to assess the possible protective role of aqueous extract of stevia on pancreatic β cells of type 2 diabetic rats.
Thirty-two male Sprague Dawley rats were divided into four groups; control, control received stevia, type 2 DM and type 2 DM treated with stevia. For all groups; fasting blood glucose, fasting insulin, pancreatic Malondialdehyde (MDA) and Catalase (CAT) were measured. Western blot analysis for measuring LC3 (microtubule associated protein-1 light chain-3) and LAMP2 (lysosomal associated membrane protein 2) was done. Also, histopathological, histomorphometric studies and tyrosine hydroxylase (TH) and norepinephrine (NE) expression by immunostaing in pancreatic tissues were detected.
Type 2 DM resulted in a significant increase in fasting blood glucose, pancreatic MDA, LC3 and LAMP2 expression, TH and NE density with a significant decrease in fasting insulin, pancreatic CAT, pancreatic islet area, the number of islets per unit area and the number of β cell per islet. Also, treatment with stevia extract significantly improved the laboratory and histopathological features of pancreas
Stevia extract has protective effects on type 2 DM pancreas by its hypoglycemic and antioxidant actions in addition to its ability to attenuate hyperactive autophagy and sympathetic nerve density.
HIF-1α is a key factor promoting the development of hepatocellular carcinoma (HCC). As well, AKT-AMPKα-mTOR signaling is a promising target for cancer therapy. Yet, the AKT-AMPKα-mTOR-dependent ...activation of HIF-1α has not been studied in livers with HCC. In addition, the mechanisms underlying the potential antineoplastic effects of sitagliptin (STGPT), an antidiabetic agent, have not yet been elucidated. For that purpose, the N-nitrosodiethylamine (NDEA)-induced HCC mouse model was used in the present study using a dose of 100 mg/kg/week, i.p., for 8 weeks. NDEA-induced HCC mice received STGPT 20, 40, or 80 mg/kg starting on day 61 up to day 120. The present study revealed that STGPT inhibited HIF-1α activation via the interference with the AKT-AMPKα-mTOR axis and the interruption of IKKβ, P38α, and ERK1/2 signals as well. Accordingly, STGPT prolonged the survival, restored the histological features and improved liver function. Additionally, STGPT inhibited angiogenesis, as revealed by a significant downregulation in the VEGF and mRNA expression of CD309 with concomitant inhibition of tissue invasion was evident by an increased ratio of TIMP-1/MMP-2. STGPT exhibited apoptotic stimulatory effect as indicated upon calculating the BCL-2/Bax ratio and by the gene expression of p53. The decrease in AFP and liver index calculation, gene expression of Ki-67 confirmed the antiproliferative activity of STGPT. The anti-inflammatory potential was revealed by the decreased TNF-α level and the downregulation of MCP-1 gene expression. Moreover, an antifibrotic potential was supported by lower levels of TGF-β. These effects appear to be GLP1R-independent. The present study provides a potential basis for repurposing STGPT for the inhibition of HCC progression. Since STGPT is unlikely to cause hypoglycemia, it may be promising as monotherapy or adjuvant therapy to treat diabetic or even normoglycemic patients with HCC.
Introduction: There is a growing interest in studying natural products for the identification of novel lead compounds for drug development for treating inflammatory diseases. Although some studies ...have focused anti-inflammatory activity of benzophenones and xanthones, exploring additional targets such as enzymes and cytokines, involved in their inflammatory response could provide more comprehensive understanding of the compounds’ anti-inflammatory effects. In this study, four xanthones ananixanthone ( 1 ), smeathxanthone A ( 2 ), smeathxanthone B ( 3 ), and 1,3,5,8-tetrahydroxy-2-(3-methybut-2-enyl)-4-(3,7-dimethyloct-2,6-dienyl) xanthone ( 4 ); and three benzophenones guttiferone O ( 5 ), guttiferone M ( 6 ), and aristophenone A ( 7 ) from Garcinia smeathmannii (Planch. & Triana) Oliv. were investigated for their effect on nitric oxide production, cyclooxygenase, lipoxygenase inhibition, and Th1/Th2 cytokines production in activated RAW 264.7 macrophages. Methods: The Griess reagent method and the ferrous oxidation-xylenol orange assay were used to evaluate the inhibition of NO production and the 15-lipoxygenase activity respectively. Cyclooxygenase activity was assessed using the fluorometric COX activity assay kit and measurement of Th1/Th2 cytokines was performed using a flow cytometer. Results: All the tested compounds exhibited a dose-dependent inhibition of NO production with varying degrees of inhibitory effects on 15-LOX activity. Compound ( 6 ), displays the best inhibitory effect on COX-1/COX-2 activity. A general trend of the tested compounds on cytokines profiles revealed that compound ( 5 ) showed a pronounced enhancement of anti-inflammatory cytokines (IL-4 and IL-10). Conclusion: This observation supports future exploration of ananixanthone ( 1 ), guttiferone O ( 5 ), and guttiferone ( 6 ) as potential candidates for the development of anti-inflammatory drugs.
Wound healing comprises organized events involving tissue repair and regeneration. The discovery of toll-like receptors (TLRs) sheds recent light on the mechanisms involved in initiating inflammatory ...responses throughout the healing cascades. Hibiscus sabdariffa (HS) components may exhibit a wound healing action, owing to their antioxidant and anti-inflammatory activities. This study was designed to investigate the early effects of HS loaded in an ointment base on wound healing, antioxidant, antimicrobial effects, burning intensity, and histopathological features on the rat burn model in comparison to the standard treatment, Iruxol® ointment. A burn injury model was used to evaluate the wound healing potency of the preparation. Rats were treated with ointments three times on the day of the induction of the burn. Findings revealed that the strong antioxidant properties of the HS-loaded ointment augmented the skin healing potential by stimulating biomarkers required for skin regeneration. HS repressed the burning-induced inflammation by the effective reduction in the levels of tumor necrosis factor α (TNF-α) and IL-6 through TLR4 protein inhibition. Topical HS downregulates transforming growth factor-beta (TGF-β) levels. HS extract possesses a potential bactericidal activity against highly resistant clinical isolates of Pseudomonas aeruginosa. Overall, this study proclaims that HS-loaded topical preparations could be a valuable product that serves as adjuvants to accelerate burn wound healing through inactivating the TLR4 pathway.
Background
The study was done to compare the value of contrast-enhanced mammography and diffusion-weighted breast MRI in dense breast screening and accurate detection of the breast cancer with ...correlation of the findings to the histopathological results.
The study included 32 female patients having suspicious breast lesions and underwent digital mammography then scheduled for CESM and MRI DW imaging technique. The imaging findings were correlated to the histopathological findings.
Results
The study was conducted on 40 breast lesions in 32 female patients having dense breasts; they were classified by the digital mammography into ACR C (59.4%) and ACR D (40.6%). By CESM, there were twenty three lesions (57.5%) as mass lesions and thirteen lesions (32.5%) as non-mass lesions. Four lesions (10%) showed no contrast enhancement. According to the lesion characteristics in diffusion-weighted imaging, the breast lesions were classified into thirty three lesions (82.5%) with restricted diffusion and seven lesions (17.5%) with non-restricted diffusion. The study showed a cutoff ADC value to detect the malignant lesions in the dense breasts ≤ 1.1 × 10
-3
s/mm
2
at
b
value of 1000 s/mm
2
with a sensitivity of 96.77%, specificity of 66.67%, PPV of 96.77%, NPV of 55.55%, and an overall total accuracy of 92.5%.
On comparing the diagnostic accuracy of the CESM to that of the DW MRI, the sensitivity of DW MRI (96.77%) was higher than that of CESM (90.32%). The specificity of DW MRI (66.67%) was higher than that of CESM (33.33%). Total accuracy of DW MRI was higher than that of CESM; they were 90% and 77.5%, respectively. Also, PPV and NPV of DW MRI were 90.91 and 85.71% as compared with 82.35 and 50.00% in CESM, respectively. When comparing the sensitivity of CESM to DW MRI in the detection of multiple breast lesions, they were 88.8 and 100%, respectively.
Conclusion
CESM is a useful technique in identification of hidden lesions in mammographically dense breasts. DW MRI is a fast, unenhanced modality that can be used as a breast cancer screening modality. CESM and DWI demonstrated good overall diagnostic accuracy in dense breast patients; however, DW MRI has a higher diagnostic accuracy than CESM for the detection of malignant breast lesions and their multiplicity.
Background
Vascular anomalies (VAs) represent a spectrum of disorders from a simple “birthmark” to life- threatening entities. Incorrect nomenclature and misdiagnoses are commonly experienced by ...patients with these anomalies. Accurate diagnosis is crucial for appropriate evaluation and management, often requiring multidisciplinary specialists.
Aim of the Work
The aim of this study is to emphasize the role of dynamic contrast MRI and ultrasound in evaluation of soft tissue vascular anomalies and subsequently in assigning the proper treatment.
Patients and Methods
All available cases of soft tissue vascular anomalies in the pediatric age group attending to the radiology department for a 6 months period were included in the study starting from February 2021.
Results
Our results showed that the US had a sensitivity of 100%, specificity of 86.4% and accuracy of 84.0% in detection of hemangioma compared to MRI. The US had a sensitivity of 53.8 %, specificity of 91.7% and accuracy of 88% in detection of venous malformation compared to MRI. US had a sensitivity of 33.3 %, specificity of 95.5 % and accuracy of 88% in detection of Klippel trenaunay syndrome compared to MRI. While the US had a sensitivity of 33.3%, specificity of 90.9 % and accuracy of 84% in detection of lymphatic malformation compared to MRI. In the case of mixed low flow malformation US had sensitivity of 0%, specificity of 91.3% and accuracy of 84%.
Conclusion
The previously stated results denote that US has high sensitivity & specificity in diagnosis of vascular anomalies especially in hemangioma; thus when imaging is needed in diagnosis of vascular malformations US should be considered positively.
Abstract
Background
Pelviabdominal masses are common in children. It can be a leadig cause of considerable morbidity and mortality.
Objective
To review the different pelviabdominal masses and their ...diagnostic criteria using the multidetector CT scans in order to build an approach for diagnosis.
Methods
A retrospective study, conducted at Ain Shams University hospitals on children complaining of pelviabdominal masses, the patients were investigated using CT scans in the period between June 2018 till end of May 2019.
Results
pelviabdominal CT scan of 70 patients were reviewed. Their age ranged from 7 days to 18 years old, the mean was 8 years of age (SD ± 5.5). 31 male : 39 female. Abdominal masses of pediatrics were congenital ( 9 case), neoplastic ( 20 cases), inflammatory ( 23 casaes) and post traumatic in origin (3 cases).
The most common congenital masses were PUJO, neoplastic were neuroblastomas, inflammatory were abscess.
Diagnostic approach should start with determination of the organ of origin followed by determination of its morphology and pattern of contrast enhancement.
The kidney was found to be the most common organ of origin in 25.7% of cases followed by the adenxa.
Conclusion
the organ of origin and morphology of the lesion are key imaging features that will help the radiologist reach a definitive diagnosis or deliver a possible differential diagnosis.
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