Hyaluronic acid/diminazene aceturate combination ameliorates osteoarthritic anomalies in a rodent model: a role of the ACE2/Ang1-7/MasR axis.

The implication of the tissue-localized renin-angiotensin system (RAS) in the pathogenesis of osteoarthritis (OA) has been documented in the last decades. A combination of intraarticular (IA) corticosteroid and hyaluronic acid (HYAL) is approved for pain relief in patients with mild to moderate OA. Combining HYAL with an activator of angiotensin-converting enzyme 2, diminazen aceturate (DIZE), was evaluated in this study for its therapeutic potential. Monosodium iodoacetate was used to induce OA. The effects of daily administration of DIZE versus once-per-week IA injection of HYAL and a combination of both drugs for 21 days on OA deformities in rats' knees were observed. Evaluation of motor activities, pain, and inflammatory response was done using rotarod, knee bend, and knee swelling tests. RAS components, inflammatory biomarkers, and oxidative stress mediators were measured in the knee joint. X-ray radiological examination and histopathological investigations were used to assess joint degeneration and regeneration. Levels of both inflammatory and oxidative markers in knee joint homogenate of OA rats rose, and these increments were mostly improved by the three therapies with a more prominent effect of the drug combination, an effect that was also reflected in the behavioral tests. RAS markers have shown better responsiveness to the combination therapy over both drugs individually, showing a pronounced increase in the angiotensin 1-7 amount. Both radiological and histopathology investigations came to confirm the biochemical results, nominating a combination of HYAL and DIZE as a possible therapeutic option for OA.

Alpha spectrometry isotopic ratios indications in the Paleozoic sedimentary rock of El Gor area, Southwestern Sinai, Egypt: insights on uranium mobility age.

The study area is located between longitude 33° 18' 00" - 33° 21' 00" E and latitude 28° 59' - 29° 01' N and covers approximately 700 km2. Uranium and thorium isotopes were determined by alpha spectrometry. The activity concentrations of 238U, 234U and 235U were ranged between 245.5 ± 8.3-465.2 ± 15.2 Bq.kg-1 with an average 345.5 ± 10.4-452.5 ± 9.3 Bq.kg-1 and 890.5 ± 21.3 Bq.kg-1 with an average 632.3 ± 14.9-11.40 ± 0.5 Bq.kg-1 and 21.50 ± 1.4 Bq.kg-1, respectively. The activity concentration of 232Th, 230Th and 228Th were ranged between 153.1 ± 0.3-318.1 ± 2.9 Bq.kg-1, 149.5 ± 0.7-280.8 ± 2.2 Bq.kg-1 and 36.9 ± 0.1-60.5 ± 0.9 Bq.kg-1. The 230Th/232Th activity ratios in all samples were lower than 20, indicating that these samples have been contaminated by detrital 230Th. Th/U ratio varied between 1.3 and 2.1 with an average 1.8; all values were lower than 3.5, indicated enrichment of uranium. 234U/238U activity ratios that higher than unity indicates that an isotope of uranium has migrated within the rock. From the isotopes of uranium and thorium and their activity ratios, the isochron age for the collected samples was about 58.96 ka.

Long-term follow-up of living liver donors: A single-center experience.

Living donors are healthy individuals who are exposed to a major surgical procedure during which a major part of their liver is resected. Data on the long-term consequences of living liver donation are scarce. This study examined clinical, laboratory, and long-term health-related quality of life (HRQoL) in 237 living liver donors and 239 matched controls during 48-168 months of postdonation follow-up. We used the 36-item short-form health survey (SF-36), version 1. The scores for the four following subscales were higher in nondonors than in donors: physical functioning (p = 0.009), role limitations due to physical health (p = 0.002), energy/fatigue (p < 0.001), and bodily pain (p < 0.001). The scores on the eight subscales of the SF-36 were higher in donors with living recipients than in donors whose recipients died (p < 0.001). Our results suggest that living donor right hepatectomy is safe and results in a postdonation HRQoL similar to that of nondonors in those donors whose recipients are healthy, whereas donors whose recipients die have a lower HRQoL that is significantly negatively correlated with the time since recipient death and improves over time.

Uranium isotopic ratio of black shale and its role in detection of oxic-anoxic conditions of uranium depositions.

The black shale is considered one of the most important rock units in the lower part of Um Bogma Formation, where it contains the uranium, heavy metals and rare earth elements mineralization. The black shale samples were analyzed radiochemically by using alpha spectrometry technique. Most of uranium in the studied samples is authigenic and the Th/U ratio confirms the deposition of uranium in reducing environment. The activity ratios of the studied black shale samples were characterized by 234U/238U > 1 and 230Th/234U < 1, which showed relatively recent precipitation of uranium from water in reducing conditions. 234U/235U and 238U/235U activity ratio was relatively deviated from equilibrium due to the changes in the oxidation-reduction conditions. The disequilibrium of 228Th/232Th can be due to the co-precipitation of 228Ra and the migration of 228Th from the black shale into the percolating water. So, the water was percolated through the paleochannels and caves instead of the rocks causing uranium mobilization and the fractionation of uranium, forming the oxidation-reduction interface in the periods from <6 × 104 to >3 × 105 year.

"The possible implication of endothelin in the pathology of COVID-19-induced pulmonary hypertension".

COVID-19 pandemic has changed the world dramatically since was first reported in Wuhan city, China [1]. Not only as a respiratory illness that could lead to fatal respiratory failure, but also some evidences suggest that it can propagate as a chronic disease associated with a variety of persistent post COVID-19 pathologies that affect patients' life [2,3]. Pulmonary hypertension (PH) is one of the challenging diseases that may develop as a consequence of SARS-COV-2 infection in some COVID-19 survivors [4,5]. The vasopressor, proliferative, proinflammatory, and prothrombotic actions of endothelin [6] may be encountered in the COVID-19-induced PH pathology. And so, endothelin blockers may have an important role to restrict the development of serious PH outcomes with special precautions considering patients with significant hypoxemia.

Targeting the Oxytocin System to Ameliorate Early Life Depressive-Like Behaviors in Maternally-Separated Rats.

Oxytocin (OXT) -"the love hormone"- has been involved in the anti-depressant activity of some selective serotonin reuptake inhibitors (SSRIs). The exact mechanism underlying the OXT pathway in depression is not fully clear. This study aimed to investigate the effect of OXT analogue, carbetocin (CBT) and the SSRI, escitalopram (ESCIT) on depressive-like behaviors following maternal separation (MS). It is worthy to mention that intranasal CBT has been approved by U.S. Food and Drug Administration (FDA) for Prader-Willi syndrome. Adolescent Wistar albino maternally-separated rats were given CBT, (100 µg/animal/d via inhalation route), and, ESCIT, (20 mg kg-1, per os ( p.o.)) either alone or in combination for 7 d. Repeated 3-h MS demonstrated increased immobility time in forced swim test (FST) and decreased locomotor activity in open field test. MS elevated plasma level of adrenocortico-trophic hormone (ACTH) but notably reduced plasma OXT, with no effect on hippocampal OXT-R expression. Following MS, hippocampal contents of 5-hydroxytryptamine receptors (5HT1A-R), serotonin transporter (SERT) were increased. CBT and ESCIT corrected the behavioral dysfunction in FST and suppressed the high levels of ACTH. Additionally, both treatments boosted OXT level, reduced 5HT1A-R and normalized SERT contents, which reflects increased availability of serotonin. Finally, CBT markedly ameliorated the histopathological damage induced by MS and suppressed the increased glial fibrillary acidic protein. CBT and ESCIT manage depressive-like behavior by positively affecting serotonergic and oxytocinergic systems. Targeting OXT system -using CBT- ameliorated depressive like behaviors induced by maternal separation most probably via enhancing OXT plasma levels, attenuating hormonal ACTH and restoring the expression of hippocampal oxytocin and serotonin mechanisms.

In Vivo Investigation of the Ameliorating Effect of Tempol against MIA-Induced Knee Osteoarthritis in Rats: Involvement of TGF-ß1/SMAD3/NOX4 Cue.

Osteoarthritis (OA) is a complex disease characterized by structural, functional, and metabolic deteriorations of the whole joint and periarticular tissues. In the current study, we aimed to investigate the possible effects of tempol on knee OA induced by the chemical chondrotoxic monosodium iodoacetate (MIA) which closely mimics both the pain and structural changes associated with human OA. Rats were administrated oral tempol (100 mg/kg) one week post-MIA injection (3 mg/50 µL saline) at the right knee joints for 21 consecutive days. Tempol improved motor performance and debilitated the MIA-related radiological and histological alterations. Moreover, it subsided the knee joint swelling. Tempol decreased the cartilage degradation-related biomarkers as matrix metalloproteinase-13, bone alkaline phosphatase (bone ALP), and fibulin-3. The superoxide dismutase mimetic effect of tempol was accompanied by decreased NADPH oxidase 4 (NOX4), inflammatory mediators, nuclear factor-kappa B (NF-κB), over-released transforming growth factor-ß1 (TGF-ß1). Tempol decreased the expression of chemokine (C-C motif) ligand 2 (CCL2). On the molecular level, tempol reduced the phosphorylated protein levels of p38 mitogen-activated protein kinase (MAPK), and small mother against decapentaplegic 3 homologs (SMAD3). These findings suggest the promising role of tempol in ameliorating MIA-induced knee OA in rats via collateral suppression of the catabolic signaling cascades including TGF-ß1/SMAD3/NOX4, and NOX4/p38MAPK/NF-κB and therefore modulation of oxidative stress, catabolic inflammatory cascades, chondrocyte metabolic homeostasis.

Incidence of HCC in chronic hepatitis C patients with advanced hepatic fibrosis who achieved SVR following DAAs: A prospective study.

Liver cirrhosis is an important risk factor for hepatocellular carcinoma. The reported annual incidence of HCC is about 3%-8% in CHC cirrhotic patients. Based on the Cochrane systematic review, there was no clear evidence, on the long-term clinical effects of DAAs in patients achieving SVR, as regard liver cirrhosis-related HCC incidence. The aim of the study was to determine the incidence of HCC in chronic hepatitis C patients genotype IV with liver cirrhosis and advanced liver fibrosis after achieving SVR following DAA treatment in a prospective large cohort of HCV patients with long follow-up. This was a prospective observational cohort study including 2372 CHC patients with advanced liver fibrosis or cirrhosis receiving DAA therapy in outpatient clinics at the Egyptian Liver Research Institute and Hospital since January 2015. Liver fibrosis was assessed using transient elastography. Abdominal ultrasonography and AFP measurement were done at baseline and follow-up visits every 6 months, in addition to triphasic abdominal MSCT when needed. Patients were followed up after achieving SVR12 for at least 12 months. HCC developed in 109 cases during the follow-up period (mean 23.60 ± 8.25 months). Overall HCC incidence was 2.338/100 PY, 95% CI = 1.942-2.814. In patients with cirrhosis, the incidence of HCC was 2.917/100 PY, 95% CI = 2.407-3.535, while in patients with advanced liver fibrosis the incidence of HCC was 0.664/100 PY, 95% CI = 0.333-1.326. In conclusion, the incidence of HCC was reduced in chronic hepatitis C genotype 4 patients with liver cirrhosis (F4) and advanced hepatic fibrosis (F3) who achieved SVR following DAA therapy.

Cognitive enhancing effect of diapocynin in D-galactose-ovariectomy-induced Alzheimer's-like disease in rats: Role of ERK, GSK-3ß, and JNK signaling.

NADPH oxidase (NOX) has been identified as a crucial contender of oxidative damage in Alzheimer's disease (AD). However, the capability of diapocynin, a NOX inhibitor, to offer neuroprotection in AD models is still a matter of debate. Hence, the current work is dedicated to investigate the influence of diapocynin on cognitive impairment prompted by ovariectomy combined with D-galactose injection in rats (an AD animal model), and to elucidate the signaling mechanisms regulating diapocynin-induced effects. Female rats were exposed to ovariectomy or sham operation. Ovariectomized rats were injected intraperitoneally with D-galactose (150 mg/kg/day) for 70 days and, on day 43, they were orally treated with diapocynin (10 mg/kg/day) for 28 days. Diapocynin amended cognitive functions as confirmed using novel object recognition and Morris water maze tests along with histopathological improvement. It caused a prominent decrement in ß-secretase, p-tau, and amyloid ß, contrary to α-secretase elevation in hippocampus and hampered neuroinflammation and oxidative stress, manifested by declined levels of NOX1, tumor necrosis factor-α, and nuclear factor-kappa B p65. In addition, diapocynin augmented synaptophysin, brain-derived neurotrophic factor, and phospho-cAMP response element binding protein and enhanced protein expression of phosphorylated forms of phosphoinositide 3-kinase (PI3K), glycogen synthase kinase-3ß (GSK-3ß), protein kinase B (Akt), extracellular signal-regulated kinase (ERK) 1/2, ERK kinase kinase (Raf-1), and ERK kinase (MEK) 1/2, while inhibiting those of c-Jun and c-Jun N-terminal kinase (JNK). In conclusion, diapocynin attenuated memory impairment and AD-like anomalies via activating Raf-1/MEK/ERK and PI3K/Akt/GSK-3ß, while inhibiting JNK/c-Jun signaling cascades.

Metformin and trimetazidine ameliorate diabetes-induced cognitive impediment in status epileptic rats.

Patients with diabetes and epilepsy are more prone to cognitive impairment, dementia, and even Alzheimer's disease. Diabetes-induced inflammatory process is one of the main contributing factors; however, the impact on seizure is not clear. The current study is aimed to examine the role of metformin and trimetazidine in the reduction of neuronal damage caused by inflammatory mediators and apoptotic factors in diabetic epileptic rodent model. Diabetic epileptic rats received orally either metformin (100 mg/kg) or trimetazidine (10 mg/kg) for 3 weeks exhibited reduced cognitive function and ameliorated the disturbed brain neurotransmission. Besides, they improved both the inflammatory status and the histopathologic alterations. Administration of metformin or trimetazidine ameliorated the deterioration in cognitive function in Morris water maze (MWM) and reduced seizure score. Furthermore, brain neurotransmitters glutamate and γ-aminobutyric acid (GABA) were reverted back to their normal values. Both treatments reduced the rise in inflammatory cytokines interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α), apoptotic markers nuclear factor-κB (NF-κB) and caspase-3, and improved the pathological photomicrograph of the hippocampus of diabetic epileptic rats. Such effects were closely correlated to the observed increase in the adenosine triphosphate and adenosine diphosphate (ATP/ADP) ratio and reduction of death-associated protein (DAP) and mammalian target of rapamycin (mTOR). In conclusion, the current study shed light on the potential neuroprotective role of metformin and trimetazidine in the amelioration of cognitive function via hindering inflammatory processes in diabetic epileptic rats.

Perindopril ameliorates experimental Alzheimer's disease progression: role of amyloid ß degradation, central estrogen receptor and hyperlipidemic-lipid raft signaling.

Accumulating evidence indicates that over-stimulation of angiotensin-converting enzyme 1 (ACE1) activity is associated with ß-amyloid (Aß) and phosphorylated tau (p-tau)-induced apoptosis, oxido-nitrosative neuroinflammatory stress and neurodegeneration in Alzheimer's disease (AD). Alternatively, activation of the ACE2, the metalloprotease neprilysin (Neutral Endopeptidase; NEP) and the insulin-degrading enzyme (IDE) could oppose the effects of ACE1 activation. We aim to investigate the relationship between ACE1/ACE2/NEP/IDE and amyloidogenic/hyperlipidemic-lipid raft signaling in hyperlipidemic AD model. Induction of AD was performed in ovariectomized female rats with high-fat high fructose diet (HFFD) feeding after 4 weeks following D-galactose injection (150 mg/kg). The brain-penetrating ACE1 inhibitor perindopril (0.5 mg/kg/day, p.o.) was administered on a daily basis for 30 days. Perindopril significantly decreased hippocampal expression of ACE1 and increased expression of ACE2, NEP and IDE. Perindopril markedly decreased Aß1-42, improved lipid profile and ameliorated the lipid raft protein markers caveolin1 (CAV1) and flotillin 1 (FLOT1). This was accompanied by decreased expression of p-tau and enhancement of cholinergic neurotransmission, coupled with decreased oxido-nitrosative neuroinflammatory stress, enhancement of blood-brain barrier (BBB) functioning and lower expression of the apoptotic markers glial fibrillary acidic protein (GFAP), Bax and ß-tubulin. In addition, perindopril ameliorated histopathological damage and improved learning, cognitive and recognition impairment as well as depressive behavior in Morris water maze, Y maze, novel object recognition and forced swimming tests, respectively. Conclusively, perindopril could improve cognitive defects in AD rats, at least through activation of ACE2/NEP/IDE and inhibition of ACE1 and subsequent modulation of amyloidogenic/hyperlipidemic-lipid raft signaling and oxido-nitrosative stress.

Modulation of gastric acid secretion by cannabinoids in rats.

The current study aimed to evaluate the role of cannabinoid receptors in the regulation of gastric acid secretion and oxidative stress in gastric mucosa. To fulfill this aim, gastric acid secretion stimulated with histamine (5 mg/kg, subcutaneous [SC]), 2-deoxy- d-glucose (D-G) (200 mg/kg, intravenous) or -carbachol (4 µg/kg, SC) in the 4-hour pylorus-ligated rats. The CB1R agonist ( N-arachidonoyl dopamine, 1 mg/kg, SC) inhibited gastric acid secretion stimulated by D-G and carbachol but not in histamine, reduced pepsin content, and increased mucin secretion. Furthermore, it decreased malondialdehyde (MDA) and nitric oxide (NO) contents with an increase in glutathione (GSH) and paraoxonase 1 (PON-1). Meanwhile, CB2R antagonist (AM630, 1 mg/kg, SC) inhibited gastric acid secretion stimulated by D-G and reduced MDA and NO contents with an increase in GSH and PON-1. Meanwhile, CB1R antagonist rimonabant or CB2R agonist GW 405833 had no effect on stimulated gastric acid secretion. Therefore, both CB1R agonist and CB2R antagonist may exert antisecretory and antioxidant potential in the stomach.

Heat Shock Protein 90 in Parkinson's Disease: Profile of a Serial Killer.

Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized by abnormal α-synuclein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, as well as progressive death of dopaminergic neurons in the substantia nigra. Molecular chaperones play a role in stabilizing proteins and helping them achieve their proper structure. Previous studies have shown that overexpression of heat shock protein 90 (HSP90) can lead to the death of dopaminergic neurons associated with PD. Inhibiting HSP90 is considered a potential treatment approach for neurodegenerative disorders, as it may reduce protein aggregation and related toxicity, as well as suppress various forms of regulated cell death (RCD). This review provides an overview of HSP90 and its role in PD, focusing on its modulation of proteostasis and quality control of LRRK2. The review also explores the effects of HSP90 on different types of RCD, such as apoptosis, chaperone-mediated autophagy (CMA), necroptosis, and ferroptosis. Additionally, it discusses HSP90 inhibitors that have been tested in PD models. We will highlight the under-investigated neuroprotective effects of HSP90 inhibition, including modulation of oxidative stress, mitochondrial dysfunction, PINK/PARKIN, heat shock factor 1 (HSF1), histone deacetylase 6 (HDAC6), and the PHD2-HSP90 complex-mediated mitochondrial stress pathway. By examining previous literature, this review uncovers overlooked neuroprotective mechanisms and emphasizes the need for further research on HSP90 inhibitors as potential therapeutic strategies for PD. Finally, the review discusses the potential limitations and possibilities of using HSP90 inhibitors in PD therapy.

Repositioning of baricitinib for management of memory impairment in ovariectomized/D-galactose treated rats: A potential role of JAK2/STAT3-PI3K/AKT/mTOR signaling pathway.

AIMS: Neuroinflammation plays a pivotal role in amyloid ß (Aß) plaques formation which is among the hallmarks of Alzheimer's disease (AD). The present study investigated the potential therapeutic effects of baricitinib (BAR), a selective JAK2/ STAT3 inhibitor, in ovariectomized/ D-galactose (OVX/D-gal) treated rats as a model for AD. MAIN METHODS: To induce AD, adult female rats (130-180 g) underwent bilateral ovariectomy and were injected daily with 150 mg/kg, i.p. D-gal for 8 consecutive weeks. BAR (10 and 50 mg/kg/day) was then given orally for 14 days. KEY FINDINGS: BAR in a dose-dependent effect mitigated OVX/D-gal-induced aberrant activation of JAK2/STAT3 signaling pathway resulting in significant decreases in the expression of p-JAK 2, and p-STAT3 levels, along with deactivating AKT/PI3K/mTOR signaling as evidenced by deceased protein expression of p-AKT, p-PI3K, and p-mTOR. As a result, neuroinflammation was diminished as evidenced by decreased NF-κß, TNF-α, and IL-6 levels. Moreover, oxidative stress biomarkers levels as iNOS, and MDA were reduced, whereas GSH was increased by BAR. BAR administration also succeeded in reverting histopathological alterations caused by OVX/D-gal, increased the number of intact neurons (detected by Nissl stain), and diminished astrocyte hyperactivity assessed as GFAP immunoreactivity. Finally, treatment with BAR diminished the levels of Aß. These changes culminated in enhancing spatial learning and memory in Morris water maze, and novel object recognition test. SIGNIFICANCE: BAR could be an effective therapy against neuroinflammation, astrogliosis and cognitive impairment induced by OVX/ D-gal where inhibiting JAK2/STAT3- AKT/PI3K/mTOR seems to play a crucial role in its beneficial effect.

Unveiling the therapeutic prospects of EGFR inhibition in rotenone-mediated parkinsonism in rats: Modulation of dopamine D3 receptor.

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. The dopamine D3 receptor (D3R) plays a significant role in the pathogenesis and treatment of PD. Activation of receptor tyrosine kinases (RTKs) inhibits signaling mediated by G protein-coupled receptor (GPCR). Epidermal growth factor receptors (EGFRs) and dopamine D3 receptors in the brain are directly associated with PD, both in terms of its development and potential treatment. Therefore, we investigated the impact of modulating the EGFR, a member of the RTKs family, and the dopamine D3R, a member of the GPCR family. In the present study, 100 mg/kg of lapatinib (LAP) was administered to rotenone-intoxicated rats for three weeks. Our findings indicate that LAP effectively alleviated motor impairment, improved histopathological abnormalities, and restored dopaminergic neurons in the substantia nigra. This restoration was achieved through the upregulation of dopamine D3R and increase of tyrosine hydroxylase (TH) expression, as well as boosting dopamine levels. Furthermore, LAP inhibited the activity of p-EGFR, GRK2, and SCR. Additionally, LAP exhibited antioxidant properties by inhibiting the 4-hydroxynonenal (4-HNE) and PLCγ/PKCßII pathway, while enhancing the antioxidant defense mechanism by increasing GSH-GPX4 pathway. The current study offers insights into the potential repositioning of LAP as a disease-modifying drug for PD. This could be achieved by modulating the dopaminergic system and curbing oxidative stress.

Adsorption rate of uranium and thorium isotopes in soil and plants grown in a high background radiation area.

An important method for measuring radionuclide activity is alpha spectrometry. Ten soil samples were collected from the studied area. The activity concentrations of 238U and 234U in the collected soil samples ranged between 135 and 218 Bq kg-1 and between 117 and 183 Bq kg-1, respectively. 232Th, 230Th and 228Th activity concentrations ranged between 101 and 339, between 122 and 234 and between 106 and 385 Bq kg-1, respectively. When calculating the amount of radionuclide transport across the food chain, assessment models usually employ a transfer factor. Through root uptake, U and Th are transferred from the soil to food plants. To monitor the movement of radionuclides from the uranium series in diverse environments, it may be possible to use the ratios of uranium and thorium isotopes. Uranium mobility in soil depends on different physicochemical, organic and enzymatic factors and mechanisms. The high mobility of uranium is the main reason for the accumulation of uranium in the soil at root level and the possibility of its transfer to plants. A group of plants were selected that are grown in this area and the population relies on them mainly to meet their food needs. The concentration and transfer factor values of uranium isotopes were the highest in roots as compared with leaves and stems. Uranium in plants accumulates in roots and is then transferred to leaves. The mobility of uranium in plant tissues is constrained because it frequently adsorbs cell wall components. As a result, concentrations are frequently higher in tissues located in lower parts of the plant, with root surfaces having the highest concentrations.

Valsartan as a prophylactic treatment against breast cancer development and niche activation: What molecular sequels follow chronic AT-1R blockade?

AIMS: Transactivation of insulin-growth-factor-receptor (IGF-1R) by angiotensin-II-type-1-receptor (AT-1R) was only demonstrated in vascular-smooth-muscle cells and has never been tested in breast-cancer (BC). This investigation addressed the impact of chronic AT-1R blockade by valsartan (Val) on possible concurrent AT-1R/IGF-1R signaling inhibition, regressing BC-tumor-microenvironment (TME) cellular components activation, and hindering BC development. MAIN METHODS: The effect of different Val doses (10, 20, 40 & 80 mg/kg/day for 490 days) was tested on dimethylbenz(a)anthracene (DMBA)-induced progesterone-promoted-BC in rats. The influence on intratumoral/circulating angiotensin-II (ANG-II) levels and AT-1R/Mas-R immunofluorescent-expression were assessed. The potential AT-1R/IGF-1R crosstalk within TME-BC-stem-cells (BCSCs) and cancer-associated-fibroblasts (CAFs) was evaluated by fluorescently marking these cells and locating the immunofluorescently-stained AT-1R/IGF-1R in them using confocal-laser-microscopy and further quantified by flow cytometry. In addition, the molecular alterations following blocking AT-1R were inspected including determining Src; crucial for IGF-1R transactivation by AT-1R, Notch-1; IGF-IR transcriptional-regulator, and PI3K/Akt &IL-6/STAT expression. Further, the suppression of CSCs' capabilities to maintain pluripotency, stemness features, epithelial-to-mesenchymal-transition (EMT), and angiogenesis was evaluated by assessing NANOG gene, aldehyde-dehydrogenase (ALDH), N-cadherin and vascular-endothelial-growth-factor (VEGF), respectively. Furthermore, the proliferative marker; Ki-67, was detected by immunostaining, and tumors were histologically graded using Elston-Ellis-modified-Scarff-Bloom-Richardson method. KEY FINDINGS: Prophylactic Val significantly reduced tumor size, prolonged latency, reduced tumor histopathologic grade, decreased circulating/intratumoral-ANG-II levels, increased Mas-R, and decreased AT1R expression. AT-1R/IGF-1R were co-expressed with a high correlation coefficient on CAFs/BCSCs. Moreover, Val significantly attenuated IGF-1R transactivation and transcriptional regulation via Src and Notch-1 genes' downregulation and reduced Src/IGF-IR-associated PI3K/Akt and IL-6/STAT3 signaling. Further, Val significantly decreased intratumoral NANOG, ALDH, N-cadherin, VEGF, and Ki-67 levels. SIGNIFICANCE: Chronic Val administration carries a potential for repurposing as adjuvant or conjunct therapy for patients at high risk for BC.

Revolutionizing Hyperlipidemia Treatment: Nanoencapsulated CoQ10 and Selenium Combat Simvastatin-Induced Myopathy and Insulin Resistance in Rats.

Purpose: The objective of this study was to develop a nanoencapsulated platform for coenzyme Q10 nanoparticles (coQNPs) or selenium nanoparticles (SeNPs) and explore their potential therapeutic benefits in treating hyperlipidemia and combating simvastatin (SV)-induced myopathy and adverse reactions in hyperlipidemic rats. Methods: The physical and chemical properties of the solid nanoparticles, coQNPs, and SeNPs were characterized, including zeta potential studies. Male Wistar albino rats were treated with various interventions for 112 days, including a nano-vehicle only, high-fat diet (HFD), HFD with SV alone, or with coQNPs or/and SeNPs for the last 30 days. Results: The coQNPs and SeNPs exhibited uniform spherical shapes with high encapsulation efficiency (EE% 91.20±2.14 and 94.89±1.54, respectively). The results demonstrated that coQNPs and SeNPs effectively reduced hyperlipidemia, insulin resistance, SV-induced myopathy, and hepatotoxicity. However, combining SV with coQNPs and SeNPs resulted in severe liver and muscle damage. Treatment with SV and SeNPs or SV and coQNPs alone showed significant improvements compared to SV treatment alone. Conclusion: These findings suggest that the CoQNPs or SeNPs platforms offer advanced relief for hyperlipidemia and insulin resistance while limiting adverse effects such as myopathy and hepatotoxicity.

Predicting portal hypertension and variceal bleeding using non-invasive measurements of metabolic variables.

BACKGROUND & AIM: This study assessed the involvement of metabolic factors (anthropometric indices, insulin resistance (IR) and adipocytokines) in the prediction of portal hypertension, esophageal varices and risk of variceal bleeding in cirrhotic patients. MATERIAL AND METHODS: Two prospective and retrospective cohorts of cirrhotic patients were selected (n = 357). The first prospective cohort (n = 280) enrolled consecutively in three centers, underwent upper gastrointestinal endoscopy, seeking evidence of esophageal varices. Clinical, anthropometric, liver function tests, ultrasonographic, and metabolic features were recorded at the time of endoscopy, patients were followed-up every 6 months until death, liver transplantation or variceal bleeding. The second retrospective cohort (n = 48 patients) had measurements of the hepatic venous pressure gradient (HVPG). Statistical analyses of the data were with the SPSS package. RESULTS: The presence of esophageal varices was independently associated with lower platelet count, raised HOMA index and adiponectin levels. This relationship extended to subset analysis in patients with Child A cirrhosis. HOMA index and adiponectin levels significantly correlated with HVPG. Beside Child-Pugh class, variceal size and glucagonemia, HOMA index but not adiponectin and leptin plasma levels were associated with higher risk of variceal bleeding. CONCLUSION: In patients with cirrhosis, HOMA score correlates with HVPG and independently predict clinical outcomes. Three simple markers i.e. platelet count, IR assessed by HOMA-IR and adiponectin significantly predict the presence of esophageal varices in cirrhotic patients.

Diminazene aceturate or losartan ameliorates the functional, radiological and histopathological alterations in knee osteoarthritis rodent model: repurposing of the ACE2/Ang1-7/MasR cascade.

PURPOSE: Current therapies for osteoarthritis (OA) are limited to analgesics and anti-inflammatory drugs. Considering the importance of oxidative stress and inflammatory mediators in OA etiology, we tested the hypothesis that targeting the renin-angiotensin-aldosterone system (RAAS) can improve OA anomalies. Diminazene (DIZE), an activator of angiotensin-converting enzyme 2 and the angiotensin 2 type-1 receptor blocker losartan (LOS) were used for this purpose. METHODS: OA was induced by a single intra-articular injection of monosodium iodoacetate. The effects of exposure to DIZE or LOS for 21 days on OA anomalies in rats' knees were investigated. Evaluation of motor function, nociception, and inflammatory response was done using rotarod, knee bend and knee swelling tests. Markers of knee joint inflammation, and cellular oxidation in addition to the RAAS biomarkers, were assessed in knee tissues, along with radiological and histopathological investigations. RESULTS: Elevations in inflammatory and oxidative markers in knee tissues of OA rats were mostly improved by the two therapeutic drugs. Such effect was also reflected in the rotarod, knee bend and knee swelling tests. Treatment with DIZE has shown a more prominent effect than LOS in controlling OA-associated inflammation and cellular oxidation. Markers of RAAS have also shown better responsiveness to DIZE over LOS. CONCLUSIONS: DIZE has shown a prominent increase in the angiotensin 1-7 amount, highlighting the involvement of the signaling pathway in the immunomodulatory effect. The radiological and histopathology examination came to confirm the outcome of biochemical markers, nominating diminazene aceturate as a possible therapeutic option for OA.