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.
Display omitted
•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.
Hepatocellular carcinoma (HCC) is the third foremost cause of cancer-related deaths. HCC has a very bad prognosis because it is asymptomatic in the early stages, resulting in a late diagnosis, and it ...is highly resistant to conventional chemotherapy. Such chemotherapies have been proven disappointing because they provide extremely low survival benefits. This study discloses that the STAT3/HIF-1α is an auspicious therapeutic attack site for conceivable repression of HCC development. A site that can be targeted by simultaneous administration of a STAT3 inhibitor in the context of HSP90 inhibition. 17-DMAG binds to HSP90 and constrains its function, resulting in the degradation of HSP90 client proteins HIF-1α and STAT3. Hypoxia recruits STAT3/HIF-1α complex within the VEGF promoter. Additionally, it was acknowledged that STAT3 is an essential mediator of VEGF transcription by direct binding to its promoter. Furthermore, it induces HIF-1α stability and enhances its transcriptional activity. Herein, we revealed that the combination therapy using 17-DMAG and nifuroxazide, a STAT3 inhibitor, repressed the diethylnitrosamine-induced alterations in the structure of the liver. This effect was mediated via decreasing the levels of the HSP90 client proteins HIF-1α and pSTAT3 resulting in the suppression of the STAT3/HIF-1α complex transcriptional activity. To conclude, 17-DMAG/NFXZD combination therapy-induced disruption in the STAT3/HIF-1α loop led to a potential antiangiogenic activity and showed apoptotic potential by inhibiting autophagy and inducing ROS/apoptosis signaling. Additionally, this combination therapy exhibited promising survival prolongation in mice with HCC. Consequently, the use of 17-DMAG/NFXZD renders an inspirational perspective in managing HCC. However, further investigations are compulsory.
•17-DMAG and nifuroxazide suppressed STAT3/HIF-1α complex transcriptional activity.•17-DMAG and nifuroxazide led to potential antiangiogenic and apoptotic activity.•17-DMAG and nifuroxazide prolonged the survival of mice with HCC.•STAT3/HIF-1α is a therapeutic attack site for repression of HCC development.•17-DMAG and nifuroxazide rendered an inspirational perspective for managing HCC.
Ulcerative colitis is an idiopathic disease that is widely incident worldwide. Canagliflozin, antidiabetic agent, exhibited significant anti-inflammatory effects in a variety of animal models. ...Additionally, hyaluronic acid is considered one of the key players in the tissue regeneration process. It has been proven to modulate inflammation and cellular migration, which are the main phases of wound healing. The combination of hyaluronic acid with chitosan in microsphere fabrication was anticipated to reveal a synergistic muco-adhesiveness potential with additional advantage of the chitosan penetration enhancing effect. The current study aimed to explore the potential of canagliflozin-loaded chitosan-hyaluronic acid microspheres intrarectal administration to mitigate acetic acid-induced colitis in rats. Colon tissues were examined for macroscopic and microscopic pathological changes. ELISA and qRT-PCR techniques were applied for the detection of cytokines involved in the AMPK/NF-κB/NLRP3 axis. Intrarectal administration of this formula alleviated colitis severity, which was reflected by the reduced DAI, MES, colonic weight/length ratio and histopathological scoring values. Interestingly, canagliflozin-loaded chitosan-hyaluronic acid microspheres significantly enhanced AMPK phosphorylation and depressed NF-κB and NLRP3 expression leading to a subsequent reduction in caspase-1 cleavage and the inhibition of several inflammatory cytokines, including IL-1β, and IL-18. Overall, the current study revealed that the protective effects of the formula against acetic acid-induced colitis are primarily mediated via augmenting AMPK phosphorylation and its consequences of NF-κB inactivation. Since canagliflozin is not associated with hypoglycemic effects, clinical application of canagliflozin-loaded chitosan-hyaluronic acid microspheres represent a novel therapeutic option for the treatment of patients with ulcerative colitis.
Display omitted
•Canagliflozin-loaded chitosan-hyaluronic acid microspheres revealed coloprotective effects.•This formula prepared to possess mucoadhesiveness potential and penetration enhancing effect.•Rectal therapy using this formula enhanced autophagy by modulating AMPK/mTOR axis.•This preparation interfered with TLR4/NF-κB axis and inactivated NLRP3 inflammasome assembly.•This preparation exhibited antiapoptotic effect through upregulating BCL-2.
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.
Display omitted
•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.
Type I diabetes (TID) is generally assumed to be caused by an immune associated, if not directly immune-mediated, destruction of pancreatic β-cells. In patients with long-term diabetes, the pancreas ...lacks insulin-producing cells and the residual β-cells are unable to regenerate. Patients with TID are subjected to a lifelong insulin therapy which shows risks of hypoglycemia, suboptimal control and ketosis. In this study, we investigated the potential role of vildagliptin (Vilda) alone or in combination with pioglitazone (Pio), as treatment regimens for TID using streptozotocin (STZ)-induced TID model in rats. Daily oral administration of Vilda (5 mg/kg) alone or in combination with Pio (20 mg/kg) for 7 weeks significantly reduced blood glucose levels and HbA
1c
. It increased serum insulin levels and decreased serum glucagon. It also showed a strong antioxidant activity. Immunohistochemical analysis showed a marked improvement in β-cells in treated groups when compared with the diabetic group, which appeared in the normal cellular and architecture restoration of β-cells in the islets of Langerhans. Vilda alone or in combination with Pio has the ability to improve the overall glycemic control in type I diabetic rats and may be considered a hopeful and effective remedy for TID.
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.
Ulcerative colitis (UC), an inflammatory bowel disease, is a chronic condition of a multifaceted pathophysiology. The incidence of UC is increasing internationally. The current therapies for UC lack ...relative effectiveness and are associated with adverse effects. Therefore, novel therapeutic options should be developed. It has been well documented that modulating the Nrf2/NFκB is a promising therapeutic target in inflammation. Carbocisteine is a mucoregulatory medication and its efficacy in COPD was found to be more closely related to its antioxidant and anti-inflammatory properties. Carbocisteine has not yet been examined for the management of UC. Hence, our approach was to investigate the potential coloprotective role of carbocisteine in acetic acid-induced colitis in rats. Our results revealed that carbocisteine improved colon histology and macroscopic features and subdued the disease activity as well. Additionally, carbocisteine attenuated colon shortening and augmented colon antioxidant defense mechanisms via upregulating catalase and HO-1 enzymes. The myeloperoxidase activity was suppressed indicating inhibition of the neutrophil infiltration and activation. Consistent with these findings, carbocisteine boosted Nrf2 expression along with NFκB inactivation. Consequently, carbocisteine downregulated the proinflammatory cytokines IL-6 and TNF-α and upregulated the anti-inflammatory cytokine IL-10. Concomitant to these protective roles, carbocisteine displayed anti-apoptotic properties as revealed by the reduction in the Bax: BCL-2 ratio. In conclusion, carbocisteine inhibited oxidative stress, inflammatory response, and apoptosis in acetic acid-induced UC by modulating the Nrf2/HO-1 and NFκB interplay in rats. Therefore, the current study provides a potential basis for repurposing a safe and a commonly used mucoregulator for the treatment of UC.
The aim of this study was to evaluate the influence of phacoemulsification cataract surgery on the state of the corneal endothelium in diabetic versus non-diabetic patients. We compared the corneal ...cell morphology in 48 diabetics with good glycemic control and 72 non-diabetic patients before and after uneventful phacoemulsification. Corneal cell density, central corneal thickness, and hexagonality were measured preoperatively and post-surgery (at 1 and 4 weeks) by specular microscopy. The effect of age, gender, axial length, and anterior chamber depth on the parameters of the corneal endothelium were evaluated. We noticed a drop in the endothelial density in both groups postoperatively: a mean endothelial cell loss of 472.7 ± 369.1 in the diabetic group was recorded versus 165.7 ± 214.6 mean loss in the non-diabetic group after the first week. A significant increase in central corneal thickness was also noticed in both groups one week after phacoemulsification, but no statistical significance after 4 weeks in the diabetic group. In terms of cell hexagonality, statistically significant differences were noticed after 4 weeks in both groups. Overall, a significant difference between diabetic and non-diabetic population was noticed in terms of corneal endothelial cell loss after uneventful phacoemulsification cataract surgery. Routine specular microscopy and HbA1c evaluation is recommended before cataract surgery, while intraoperative precautions and high monitorisation in terms of pacho power intensity and ultrasound energy, along with a proper application of the dispersive viscoelastic substances are essential to reduce the risk of endothelial damage.
Overexposure to carcinogenic precursor, benzoapyrene BaP, modulates the lung immune microenvironment. The present review seeks to elucidate novel pathways behind the tumor effect of BaP in the lungs, ...emphasizing immunomodulatory mediators and immune cells. In this review, BaP reprograms lung immune microenvironment through modulating transforming growth factor-beta (TGF-β), programmed cell death 1 (PD-1), cytotoxic T lymphocyte antigen-4 (CTLA-4), Interleukin 12 (IL-12), indoleamine 2,3 dioxygenase (IDO), forkhead box protein P3 (FOXP3) and interferon-gamma (IFN-γ) levels. Moreover, BaP modulated lung immune cellular architecture such as dendritic cells, T cells, Tregs, macrophages, neutrophils, and myeloid-derived suppressor cells (MDSCs). All mentioned changes in immune architecture and mediators lead to the induction of lung cancer.
PDF
![Benzo[a]pyrene immunogeneti...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0300-483X/small "Benzo[a]pyrene immunogenetics and immune archetype reprogramming of lung")