Unveiling the regulatory role of miRNAs in stroke pathophysiology and diagnosis.

Stroke, a major global cause of mortality, leads to a range of problems for those who survive. Besides its brutal events, stroke also tends to have a characteristic of recurrence, making it a complex disease involving intricate regulatory networks. One of the major cellular regulators is the non-coding RNAs (ncRNA), specifically microRNAs (miRNAs), thus the possible functions of miRNAs in the pathogenesis of stroke are discussed as well as the possibility of using miRNA-based therapeutic approaches. Firstly, the molecular mechanisms by which miRNAs regulate vital physiological processes, including synaptic plasticity, oxidative stress, apoptosis, and the integrity of the blood-brain barrier (BBB) are reviewed. The miRNA indirectly impacts stroke outcomes by regulating BBB function and angiogenesis through the targeting of transcription factors and angiogenic factors. In addition, the tendency for some miRNAs to be upregulated in response to hypoxia, which is a prevalent phenomenon in stroke and various neurological disorders, highlights the possibility that it controls hypoxia-inducible factor (HIF) signaling and angiogenesis, thereby influencing the integrity of the BBB as examples of the discussed mechanisms. Furthermore, this review explores the potential therapeutic targets that miRNAs may offer for stroke recovery and highlights their promising capacity to alleviate post-stroke complications. This review provides researchers and clinicians with valuable resources since it attempts to decipher the complex network of miRNA-mediated mechanisms in stroke. Additionally, the review addresses the interplay between miRNAs and stroke risk factors as well as clinical applications of miRNAs as diagnostic and prognostic markers.

miRNAs as modulators of neuroinflammation and excitotoxicity: Implications for stroke therapeutics.

Stroke is a widespread neurological disorder associated with physical disabilities, mortality, and economic burden. In recent decades, substantial progress has been achieved in reducing the impact of this public health problem. However, further understanding of the pathophysiology of stroke and the underlying genetic pathways is required. The pathological mechanisms of stroke comprise multifaceted molecular cascades regulated by various microRNAs (miRNAs). An increasing number of studies have highlighted the role of miRNAs, which have received much attention during the last decades as an important class of post-transcriptional regulators. It was shown that miRNAs exert their role in the etiology of stroke via mediating excitotoxicity and neuroinflammation. Additionally, miRNAs could be helpful as non-invasive or minimally invasive biomarkers and therapeutic agents. Thus, the current review focused on the interplay of these miRNAs in stroke pathology to upgrade the existing therapeutic strategies.

MitoQ combats tumor cell progression in Ehrlich ascites carcinoma mice: A crosstalk between mitochondrial oxidative status, mitophagy, and NF-κB signaling.

Despite the clinical advances in cancer treatment, the high mortality rate is still a great challenge, requiring much effort to find new and efficient cancer therapies. AIMS: The present evidence investigated the potential antiproliferative impact of the mitochondrial-targeted antioxidant, Mitoquinol (MitoQ), on a mouse model of Ehrlich ascites carcinoma (EAC). MAIN METHODS: Mice-bearing tumors were administered two doses of MitoQ (0.3 mg & 0.5 mg/kg; i.p daily) or doxorubicin (2 mg/kg; i.p daily) for 20 days. KEY FINDINGS: EAC mice revealed exacerbated mitochondrial reactive oxygen species (mtROS) and impaired mitochondrial membrane potential (△Ψm). Dysfunctional mitophagy was observed in EAC mice, along with boosting aerobic glycolysis. In addition, tumor cells exhibited higher proliferation rates, thereby stimulating cell cycle, invasion, and angiogenesis biomarkers together with suppressing proapoptotic proteins, events that might be correlated with activation of NF-κB signaling. The administration of MitoQ combated tumor cell survival and dissemination in EAC mice as evidenced by reducing tumor volumes and weights and increasing the number of necrotic areas in histopathological assessment. MitoQ also repressed tumor cell cycle, invasion, and angiogenesis via preventing cyclin D1 mRNA, MMP-1, and CD34 levels as well as VEGF protein expression. These observations were associated with the abrogation of mtROS overproduction and enhancement of the mitophagy proteins, PINK1/Parkin levels, followed by inhibition of NADH dehydrogenase. Notably, NF-κB signaling was modulated. SIGNIFICANCE: This study suggests that MitoQ combated tumor cell survival and progression in EAC mice by maintaining mtROS and restoring mitophagy, thereby attenuation of NF-κB activation.

Dapagliflozin improves early acute kidney injury induced by vancomycin in rats: Insights on activin A/miRNA-21 signaling and FOXO3a expression.

Drug-induced acute kidney injury (AKI) represents a potentially serious disorder associated with increased morbidity and mortality. The presented study investigated the ability of the oral antidiabetic agent, dapagliflozin (DAPA), to preserve the kidneys of rats subjected to vancomycin (VCM)-induced AKI. Rats were injected with VCM (400 mg/kg; i.p daily) for 7 successive days to induce AKI. Rats that received VCM were pretreated with DAPA at 5 or 10 mg/kg; p.o daily for 14 successive days. Vancomycin-treated rats depicted renal tubular damage, decline in renal function, and renal morphological alterations. Impairment of renal antioxidant machinery and propagation of renal cell apoptosis was apparent in the setting of VCM overdose. Pretreatment of VCM rats with DAPA, particularly at 10 mg/kg, effectively attenuated NADPH oxidase-4 (NOX4)-induced renal ROS, hampered activin A activation, and repressed miRNA-21/PTEN/pAKT signaling. These events were associated with impeding the expression of renal p-FOXO3a/t-FOXO3a ratio and promoting the nuclear localization of FOXO3a immnoexpression, enhancing renal antioxidant enzymes. At the same time, DAPA pretreatment improved renal function indices and alleviated the kidney injury markers, NGAL, and KIM-1, accompanied by restoring the normal renal histopathological structure. Regarding renal apoptosis, DAPA suppressed the expression of Bax/Bcl2 ratio and caspase-3. This study demonstrates that DAPA ameliorates VCM-induced AKI in rats via modulating renal oxidative stress, presumably by interfering with NOX4/activin A/miRNA-21 cascade and augmenting t-FOXO3a expression as well as dampening renal cell apoptosis.

MitoQ alleviates hippocampal damage after cerebral ischemia: The potential role of SIRT6 in regulating mitochondrial dysfunction and neuroinflammation.

AIMS: Mitochondrial perturbations are the major culprit of the inflammatory response during the initial phase of cerebral ischemia. The present study explored the neuroprotective effect of the mitochondrial-targeted antioxidant, Mitoquinol (MitoQ), against hippocampal neuronal loss in an experimental model of brain ischemia/reperfusion (I/R) injury. MAIN METHODS: Rats were subjected to common carotid artery occlusion for 45 min, followed by reperfusion for 24 h. MitoQ (2 mg/kg; i.p daily) was administered for 7 successive days prior to the induction of brain ischemia. KEY FINDINGS: I/R rats exhibited hippocampal damage evidenced by aggravated mitochondrial oxidative stress, thereby enhancing mtROS and oxidized mtDNA, together with inhibiting mtGSH. Mitochondrial biogenesis and function were also affected, as reflected by the reduction of PGC-1α, TFAM, and NRF-1 levels, as well as loss of mitochondrial membrane potential (△Ψm (. These changes were associated with neuroinflammation, apoptosis, impairment of cognitive function as well as hippocampal neurodegenerative changes in histopathological examination. Notably, SIRT6 was suppressed. Pretreatment with MitoQ markedly potentiated SIRT6, modulated mitochondrial oxidative status and restored mitochondrial biogenesis and function. In addition, MitoQ alleviated the inflammatory mediators, TNF-α, IL-18, and IL-1ß and dampened GFAB immunoexpression along with downregulation of cleaved caspase-3 expression. Reversal of hippocampal function by MitoQ was accompanied by improved cognitive function and hippocampal morphological aberrations. SIGNIFICANCE: This study suggests that MitoQ preserved rats' hippocampi from I/R insults via maintenance of mitochondrial redox status, biogenesis, and activity along with mitigation of neuroinflammation and apoptosis, thereby regulating SIRT6.

Development of potent nanosized carbonic anhydrase inhibitor for targeted therapy of hypoxic solid tumors.

Overexpression of two carbonic anhydrase (CA) isoforms, CA IX and XII, in several hypoxic solid tumors provides an extracellular hypoxic microenvironment, interferes with extra- and intracellular pH regulation, thus favoring hypoxic tumor cell survival, proliferation and metastasis. In the current study, a selective inhibitor for human CA isoforms IX and XII (isatin-bearing sulfonamide, WEG-104), was incorporated into nanosized spherical niosomes at high encapsulation efficiency to allow for an enhanced and sustained antitumor activity. In vivo, administration of WEG-104 that is either free (10 mg/kg) or loaded into niosomes (5 mg/kg) into a mice model of Ehrlich ascites solid tumor resulted in comparable efficacy in terms of reduction of tumor weight and volume. Administration of WEG-104-loaded niosomes (10 mg/kg) exhibited superior antitumor activity compared to the free drug, evidenced by reduced tumor weight and volume, marked reduction in the activity of CA IX and XII, and suppression of HIF-1α and MMP-2. Moreover, prominent increase of caspase 3 and pronounced decrease in VEGF immune expression were observed in the treated animals. Hence, loading of molecularly designed compounds that targets CAs in hypoxic solid tumors into nanosized delivery systems provided an auspicious strategy for limiting solid tumor progression and malignancy.

Identification of novel furo[2,3-d]pyrimidine based chalcones as potent anti-breast cancer agents: synthesis, in vitro and in vivo biological evaluation.

Various substituted synthetic chalcones demonstrated potent anti-cancer activities. In the current study a series of novel furo[2,3-d]pyrimidine based chalcones were synthesized as potential anticancer agents. Among the different substituted derivatives, two of the halogen bearing chalcones, 5d and 5e, demonstrated potent anti-proliferative activity against an NCI 59 cell line, with mean GI50 values of 2.41 µM and 1.23 µM, respectively. Moreover, both compounds showed pronounced cytotoxic activity (5d; 1.20 ± 0.21, 5e; 1.90 ± 0.32) against the resistant MCF-7 cell line when compared to doxorubicin; 3.30 ± 0.18. Such outcomes provoked the initiation of an in vivo anticancer assessment study, where compound 5e revealed comparable results to doxorubicin.

Amelioration of Early Markers of Diabetic Nephropathy by Linagliptin in Fructose-Streptozotocin-Induced Type 2 Diabetic Rats.

BACKGROUND: Early prediction and clinical intervention are extremely important in order to delay or hinder diabetic nephropathy (DN) progression. OBJECTIVES: This study aimed to detect early signs of DN and study the potential ameliorating effect of the dipeptidyl peptidase-4 inhibitor, linagliptin, on some early markers for DN in fructose-streptozotocin (Fr-STZ)-induced diabetic rats. METHOD: Fr-STZ rats were treated with either linagliptin (3 mg/kg p.o. daily), metformin (350 mg/kg p.o. daily), or their combination for 6 weeks. RESULTS: Fr-STZ DN rats exhibited obvious tubular renal damage and glomerular podocyte injury as confirmed by renal kidney -injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and vanin-1 mRNA, as well as urinary N-acetyl-ß-D-glucosaminidase elevation and nephrin mRNA suppression, associated with the appearance of marked renal interstitial fibrosis and glomerulosclerosis despite the absence of microalbuminuria. Initiation of oxidative, inflammatory, fibrotic, and apoptotic reactions was evident in the settings of renal hyperglycemia. Linagliptin significantly modulated the aforementioned renal tubular injury makers and restored glomerular nephrin expression as well as reversed renal histopathological alterations. Oxidative, inflammatory, fibrotic and apoptotic processes were also alleviated. CONCLUSIONS: This study suggests that linagliptin exerts renoprotection against early features of DN in rats probably by inhibition of high glucose-induced renal tubular and glomerular injury thereby hampering KIM-1 and NGAL as well as vanin-1 associated with renal inflammation, fibrosis and oxidative stress.

Dapagliflozin attenuates early markers of diabetic nephropathy in fructose-streptozotocin-induced diabetes in rats.

Early detection and clinical interference are major challenges for the prevention of diabetic nephropathy (DN) progression. This study investigated the effects of dapagliflozin, a sodium glucose co-transporter 2 inhibitor, on some early markers for DN in fructose-streptozotocin (Fr-STZ)-induced diabetes in rats. Fr-STZ rats were treated with either dapagliflozin (1 mg/kg p.o. daily), metformin (350 mg/kg p.o. daily), or their combination for 6 weeks. Fr-STZ rats displayed marked early tubular renal damage and glomerular podocyte injury as evidenced by renal KIM-1, NGAL, cystatin C, and vanin-1 mRNA, as well as urinary NAG elevation and nephrin mRNA suppression, associated with the development of marked renal interstitial fibrosis and glomerulosclerosis despite the presence of normoalbuminuria. Propagation of oxidative, inflammatory, fibrotic, and apoptotic reactions was obvious in the setting of renal glucose overload. Dapagliflozin significantly attenuated the renal tubular injury makers namely KIM-1, NGAL, vanin-1 and urinary NAG. In addition, it restored glomerular nephrin expression and reversed renal histopathological changes. Oxidative, inflammatory, and fibrotic processes were also alleviated. This study suggests that dapagliflozin exerts a renoprotective effect against early features of DN in rats presumably by inhibition of diabetes-induced renal tubular and glomerular injury thereby modulating oxidative, inflammatory, and fibrotic as well as apoptotic mechanisms elicited during hyperglycemia.