The multifaceted role of beta-blockers in overcoming cancer progression and drug resistance: Extending beyond cardiovascular disorders.

Beta-blockers are commonly used medications that antagonize ß-adrenoceptors, reducing sympathetic nervous system activity. Emerging evidence suggests that beta-blockers may also have anticancer effects and help overcome drug resistance in cancer treatment. This review summarizes the contribution of different isoforms of beta-adrenoceptors in cancer progression, the current preclinical and clinical data on associations between beta-blockers use and cancer outcomes, as well as their ability to enhance responses to chemotherapy and other standard therapies. We discuss proposed mechanisms, including effects on angiogenesis, metastasis, cancer stem cells, and apoptotic pathways. Overall, results from epidemiological studies and small clinical trials largely indicate the beneficial effects of beta-blockers on cancer progression and drug resistance. However, larger randomized controlled trials are needed to firmly establish their clinical efficacy and optimal utilization as adjuvant agents in cancer therapy.

Cell cycle machinery in oncology: A comprehensive review of therapeutic targets.

The cell cycle is tightly regulated to ensure controlled cell proliferation. Dysregulation of the cell cycle machinery is a hallmark of cancer that leads to unchecked growth. This review comprehensively analyzes key molecular regulators of the cell cycle and how they contribute to carcinogenesis when mutated or overexpressed. It focuses on cyclins, cyclin-dependent kinases (CDKs), CDK inhibitors, checkpoint kinases, and mitotic regulators as therapeutic targets. Promising strategies include CDK4/6 inhibitors like palbociclib, ribociclib, and abemaciclib for breast cancer treatment. Other possible targets include the anaphase-promoting complex/cyclosome (APC/C), Skp2, p21, and aurora kinase inhibitors. However, challenges with resistance have limited clinical successes so far. Future efforts should focus on combinatorial therapies, next-generation inhibitors, and biomarkers for patient selection. Targeting the cell cycle holds promise but further optimization is necessary to fully exploit it as an anti-cancer strategy across diverse malignancies.

Evaluation of the Corneal Endothelium Following Cataract Surgery in Diabetic and Non-Diabetic Patients.

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.

Innovative challenge for the inhibition of hepatocellular carcinoma progression by combined targeting of HSP90 and STAT3/HIF-1α signaling.

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.

Canagliflozin-loaded chitosan-hyaluronic acid microspheres modulate AMPK/NF-κB/NLRP3 axis: A new paradigm in the rectal therapy of ulcerative colitis.

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-1ß, 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.

Ambroxol, a mucolytic agent, boosts HO-1, suppresses NF-κB, and decreases the susceptibility of the inflamed rat colon to apoptosis: A new treatment option for treating ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown etiology that increases the risk of developing colorectal cancer and imposes a lifelong healthcare burden on millions of patients worldwide. Current treatment strategies are associated with significant risks and have been shown to be fairly effective. Hence, discovering new therapies that have better efficacy and safety profiles than currently exploited therapeutic strategies is challenging. It has been well delineated that NF-κB/Nrf2 crosstalk is a chief player in the interplay between oxidative stress and inflammation. Ambroxol hydrochloride, a mucolytic agent, has shown antioxidant and anti-inflammatory activity in humans and animals and has not yet been examined for the management of UC. Therefore, our approach was to investigate whether ambroxol could be effective to combat UC using the common acetic acid rat model. Interestingly, a high dose of oral ambroxol (200 mg/kg/day) reasonably improved the microscopic and macroscopic features of the injured colon. This was linked to low disease activity and a reduction in the colonic weight/length ratio. In the context of that, ambroxol boosted Nrf2 activity and upregulated HO-1 and catalase to augment the antioxidant defense against oxidative damage. Besides, ambroxol inactivated NF-κB signaling and its consequent target pro-inflammatory mediators, IL-6 and TNF-α. In contrast, IL-10 is upregulated. Consistent with these results, myeloperoxidase activity is suppressed. Moreover, ambroxol decreased the susceptibility of the injured colon to apoptosis. To conclude, our findings highlight the potential application of ambroxol to modify the progression of UC by its anti-inflammatory, antioxidant, and antiapoptotic properties.

Carbocisteine as a Modulator of Nrf2/HO-1 and NFκB Interplay in Rats: New Inspiration for the Revival of an Old Drug for Treating Ulcerative Colitis.

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.

Combining the HSP90 inhibitor TAS-116 with metformin effectively degrades the NLRP3 and attenuates inflammasome activation in rats: A new management paradigm for 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.

Empagliflozin adjunct with metformin for the inhibition of hepatocellular carcinoma progression: Emerging approach for new application.

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.

Benzo[a]pyrene immunogenetics and immune archetype reprogramming of lung.

Overexposure to carcinogenic precursor, benzo[a]pyrene [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-ß), 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.

Blunting p38 MAPKα and ERK1/2 activities by empagliflozin enhances the antifibrotic effect of metformin and augments its AMPK-induced NF-κB inactivation in mice intoxicated with carbon tetrachloride.

AIM: Metformin and empagliflozin combined therapy may have complementary effects that go beyond the well-recognized targets of their monotherapy through AMPK activation. Therefore, the current study was designed to investigate for the first time the hepatoprotective effects of such combination therapy in the carbon tetrachloride (CCl4)-induced hepatic fibrosis model in mice. MATERIALS AND METHODS: Determination of liver enzymes and the liver content of oxidative stress parameters, and hydroxyproline were performed biochemically. ELISA was performed to measure PDGF-BB, TNF-α, TGF-ß, TIMP-1, AMPK, p-mTOR, NF-κB P65 binding activity, p38 MAPKα, JNK1/2 and ERK1/2. Real-time qPCR was conducted to determine Col1a1 and α-SMA. In addition, histopathological examination using H&E and Masson's trichrome stain were performed for determination of histopathological changes. KEY FINDINGS: Empagliflozin inhibited the activation of p38 MAPK and ERK1/2 and exhibited a weak AMPKα stimulation. On the other hand, metformin exerted a more robust stimulatory action on the AMPKα that was accompanied by a notable decrease in the NF-κB nuclear binding activity and a decline in the p-mTOR levels. Nevertheless, the effect of metformin on MAPK kinases was insignificant. Our results revealed that blunting p38 MAPKα and ERK1/2 activities by empagliflozin enhanced the antifibrotic effect of metformin and augmented its AMPK-induced NF-κB inactivation. SIGNIFICANCE: As diabetes is one of the most common risk factors for liver fibrosis, the use of antidiabetic drugs is expected to improve therapeutic outcome. Therefore, metformin/empagliflozin combined therapy could be promising in preventing hepatic inflammation and fibrosis via exhibiting complementary effects particularly in diabetic patients.

Telmisartan alleviates alcohol-induced liver injury by activation of PPAR-γ/ Nrf-2 crosstalk in mice.

Excessive consumption of alcohol may induce severe liver damage, in part via oxidative stress and inflammatory responses, which implicates these processes as potential therapeutic approaches. Prior literature has shown that Telmisartan (TEL) may provide protective effects, presumably mediated by its anti-oxidant and anti-inflammatory activities. The purpose of this study was to determine TEL's hepatoprotective effects and to identify its possible curative mechanisms in alcoholic liver disease. A mouse chronic alcohol plus binge feedings model was used in the current study for induction of alcoholic liver disease (ALD). Our results showed that TEL (10 mg/kg/day) has the ability to reduce serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). TEL also increased the activity of superoxide dismutase (SOD) and glutathione (GSH) with concomitant reduction of nitric oxide (NO) malonaldehyde (MDA) in the liver homogenate. Moreover, TEL downregulated nuclear factor kappa B (NF-κB) expression and decreased liver content of interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α). These anti-inflammatory and anti-oxidant activities were associated with a significant increase in the expression of nuclear factor erythroid 2-related factor 2 (Nrf-2), peroxisome proliferator-activated receptors -γ (PPAR-γ), and heme oxygenase-1 (Hmox-1). In conclusion, TEL's hepatoprotective effects against ALD may be attributable to its anti-inflammatory and anti-oxidant activities which may be in part via the modulation of PPAR-γ/ Nrf-2/ NF-κB crosstalk.

AKT-AMPKα-mTOR-dependent HIF-1α Activation is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma.

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 IKKß, 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-ß. 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.

Empagliflozin ameliorates ethanol-induced liver injury by modulating NF-κB/Nrf-2/PPAR-γ interplay in mice.

BACKGROUND: Excessive alcohol intake contributes to severe liver damage involving oxidative stress and inflammatory responses, which make them promising therapeutic targets. Previous studies have demonstrated that empagliflozin (EMPA) showed cardiovascular, renal, and cerebral benefits potentially mediated through its antioxidant and anti-inflammatory actions. AIMS: This experiment aimed to evaluate the hepatoprotective effect of EMPA on alcoholic liver disease (ALD) and the possible underlying mechanisms. MATERIALS AND METHODS: Serum biochemical parameters and the liver contents of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), and superoxide dismutase (SOD) were measured. Real-time qPCR was conducted to determine the gene expression of peroxisome proliferator-activated receptor gamma (PPAR-γ), nuclear factor erythroid 2-related factor 2 (Nrf-2), and heme oxygenase-1 (Hmox-1). In addition, ELISA was performed to measure tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6, Nrf-2, and PPAR-γ. Nuclear factor-kappa B (NF-κB) was detected by immunohistochemical staining using an anti-NF-κB p65 antibody. KEY FINDINGS: Our results revealed that the serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were significantly reduced by EMPA. EMPA also decreased the content of MDA and NO and increased the activities of SOD and GSH in liver homogenates. Moreover, EMPA inhibited the release of proinflammatory cytokines, including TNF-α, IL-1ß, and IL-6, via the downregulation of NF-κB. These changes were associated with an improvement in histopathological deterioration. The protective effect of EMPA against oxidative stress and inflammation was associated with the upregulation of PPAR-γ, Nrf-2, and their target gene Hmox-1. SIGNIFICANCE: EMPA showed protective activities against ethanol-induced liver injury by suppressing inflammation and oxidative stress via modulation of the NF-κB/Nrf-2/PPAR-γ axis.

Vildagliptin/pioglitazone combination improved the overall glycemic control in type I diabetic rats.

Type I diabetes (TID) is generally assumed to be caused by an immune associated, if not directly immune-mediated, destruction of pancreatic ß-cells. In patients with long-term diabetes, the pancreas lacks insulin-producing cells and the residual ß-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 HbA1c. It increased serum insulin levels and decreased serum glucagon. It also showed a strong antioxidant activity. Immunohistochemical analysis showed a marked improvement in ß-cells in treated groups when compared with the diabetic group, which appeared in the normal cellular and architecture restoration of ß-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.