Hedgehog signaling mastery: R51211's promise in augmenting the therapeutic efficacy of sorafenib.

Sorafenib is a multikinase inhibitor employed for managing hepatocellular carcinoma (HCC). The emergence of sorafenib resistance presents an obstacle to its therapeutic efficacy. One notable approach to overcoming sorafenib resistance is the exploration of combination therapies. The role of hedgehog signaling in sorafenib resistance has been also examined in HCC. R51211, known as itraconazole, has been safely employed in clinical practice. Through in vitro and in vivo investigations, we assessed the potential of R51211 to enhance the therapeutic efficacy of sorafenib by inhibiting the hedgehog signaling. The zero-interaction potency synergy model demonstrated a synergistic interaction between R51211 and sorafenib, a phenomenon reversed by the action of a smoothened receptor agonist. This dual therapy exhibited an increased capacity to induce apoptosis, as evidenced by alterations in the Bax/BCL-2 ratio and caspase-3, along with a propensity to promote autophagy, as indicated by changes in BECN1, p62, and the LC3I/LC3II ratio. Furthermore, the combination therapy resulted in significant reductions in biomarkers associated with liver preneoplastic alterations, improved liver microstructure, and mitigated changes in liver function enzymes. The substantial decrease in hedgehog components (Shh, SMO, GLI1, and GLI2) following R51211 treatment appears to be a key factor contributing to the increased efficacy of sorafenib. In conclusion, our study highlights the potential of R51211 as an adjunct to sorafenib, introducing a new dimension to this combination therapy through the modulation of the hedgehog signaling pathway. Further investigations are essential to validate the therapeutic efficacy of this combined approach in inhibiting the development of liver cancer.

Outcomes of Hallux Valgus Corrective Osteotomy: A Tertiary Hospital Experience.

BACKGROUND: A common form of forefoot deformity, hallux valgus (HV) is characterized by a prominent first metatarsal head, lateral deviation of the hallux, and medial deviation of the first metatarsal bone. In the case of HV, corrective osteotomies are performed with good results and patient satisfaction. METHODS: A retrospective cohort study of patients who underwent corrective osteotomy for hallux valgus from 2016 to 2022 was conducted at King Abdulaziz Medical City (KAMC), Riyadh, Saudi Arabia. Data were collected by chart review using the BestCARE system. IBM SPSS Statistics for Windows, Version 23.0 (Released 2015; IBM Corp., Armonk, New York, United States) was used for statistical analysis. RESULTS: Our study included 166 patients. The mean age of the patients was found to be 41.3 years old and about 152 (91.6%) of them were females. The most frequently reported comorbidity was hypertension (10.2%). The mean hallux valgus angle was found to be 36.1 ± 9.9 and the mean intermetatarsal angle was found to be 15 ± 4.4 degrees. Seventy-six (45.8%) patients underwent nonoperative management first. The mean age at diagnosis among males was found to be 28.5 ± 11.3 years and among females was 37.9 ± 14.4 years; a significant difference between means was noted (p-value = 0.019) with mean age at diagnosis in males being significantly lesser than in females. CONCLUSION: Significant improvement and reduction were seen in HV angle post surgery. Nearly half of the patients underwent nonoperative management first. Age at diagnosis is significantly younger in males compared to females.

Outcomes of Operative Versus Nonoperative Management for Hallux Rigidus: A Tertiary Care Center Experience.

Background This study aims to investigate and report the outcomes of various management modalities used for hallux rigidus, a common form of degenerative joint disease affecting the foot and ankle. The research focuses on understanding the pathophysiology, classification systems, and nonoperative approaches such as medical therapy, intra-articular injections, shoe modifications, and physical therapy. Surgical techniques, including joint-sparing and joint-sacrificing procedures, are explored, considering factors such as disease stage and patient preferences. Methods A retrospective cohort study was conducted at King Abdulaziz Medical City (KAMC), Riyadh. The study included all patients who were diagnosed with hallux rigidus from the period 2016 to 2022. Data were collected through the BESTCare system at KAMC. All the data were collected through Microsoft Excel (Microsoft Corporation, Redmond, Washington) and transferred for analysis. Statistical analysis was performed using the IBM SPSS Statistics for Windows, Version 25 (Released 2017; IBM Corp., Armonk, New York). Frequencies and percentages were used to detail categorical variables, whereas continuous variables were examined by the mean and standard deviation. A p-value of <0.05 was considered to report the statistical significance. Results A total of 84 patients were included. The majority were women (60.7%). Diabetes and hypertension were prevalent comorbidities, affecting 21.4% and 35.7% of patients, respectively. Nonoperative management was the most common approach (66.7%). Complications were minimal (2.4% infections, 1.2% metatarsalgia), and 67.9% of patients reported no persistence of symptoms after treatment. Conclusion The low complication rates and the lack of significant associations between treatment modalities and outcomes suggest the generally safe and effective nature of the employed interventions. These findings can guide clinicians in making informed decisions regarding the management of hallux rigidus, while also highlighting areas for further research to improve treatment strategies and outcomes.

Identification and Characterization of Preventable Adverse Drug Events in Family Medicine Clinics from Central Saudi Arabia.

Background: Medication errors can result in adverse drug events (ADEs) and cause considerable patient harm. Limited data are available from Saudi Arabia and the Middle East regarding the prevalence of preventable adverse drug events (pADEs) in primary care settings. Objectives: To estimate the period prevalence of pADEs and assess the medication error severity in primary care setting in Saudi Arabia. Methods: This retrospective study is a continuation of a previous study where 117 of 2000 adult patients managed at the Family Medicine clinics of King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, were identified to have had least one medication error in the past 15 months. The electronic health records of these 117 patients were analyzed for a 3-month post-medication error period to explore the presence of pADE. Medication errors were categorized according to the National Coordinating Council for Medication Error Reporting and Prevention index (NCC MERP) and the occurrence of pADE was assessed using the NCC MERP scheme. Results: Of the included 117 patients, 9 (7.7% [95% confidence interval (CI): 2.79-12.59]) experienced pADE (Category E), while 108 (92.3% [95% CI: 87.97-98.35]) did not (Category C). All patients who experienced pADE were using over-the-counter medications and were on polypharmacy. Outcomes 2a and 2b (asthma and ß-blocker) accounted for two and four cases, respectively, while Outcomes 6 (warfarin and international normalized ratio), 7 (lithium and lithium level), 16 (new oral anti-coagulant or warfarin and antiplatelet), and 17 (acetylsalicylic acid [aspirin] and antiplatelet) each accounted for one case. Conclusions: This study provides the period prevalence of patients with pADEs from Family Medicine clinics at a major tertiary hospital of Saudi Arabia, and highlights the need for a multicenter study of clinically important medication errors at the prescribing and monitoring stages for the development of quality improvement programs.

Clinical outcomes of percutaneous screw fixation of acetabular fracture: A minimally invasive procedure.

Objective: Open reduction with internal fixation is the surgical intervention of choice for acetabular fractures (AFs). Percutaneous screw fixation for AFs is a new procedure that is desirable because of the complex anatomy of the pelvis. In this study, we aimed to assess the functional outcomes, mobility, healing, and distal neurovascular abnormalities in patients who underwent percutaneous retrograde screw fixation. Methods: Our study included 36 patients with AFs treated with percutaneous screw fixation between January 2016 and June 2021. There were 18 cases with anterior column AF, 7 cases with transverse AF, and 11 cases with associated AF, 6 of which had a T-shaped AF. Frequencies and percentages were used to describe characteristics and clinical outcomes. Mean and standard deviation were used for continuous variables. SPSS version 23 (IBM Corporation, Armonk, NY, USA) was used for statistical analysis. Results: The average time to regain full mobility with full weight bearing was 12.9 ± 5.4 weeks, and approximately 11.1 ± 2.8 weeks was required for patients to be pain-free with satisfactory fracture healing. Only a minority (8.3%) of patients had abnormalities affecting the distal neurovascular system, and 11.1% experienced sexual dysfunction. Pain severity was assessed with a visual analogue scale. The average pain severity on the first and third post-operative days was 4 ± 2.4 and 3.8 ± 2.6, respectively. However, the average pain intensity before discharge was 1.7 ± 2.6. Conclusion: Percutaneous screw fixation is the most efficient surgical choice for most pelvic/AFs.

Kaempferol attenuates diabetic nephropathy in streptozotocin-induced diabetic rats by a hypoglycaemic effect and concomitant activation of the Nrf-2/Ho-1/antioxidants axis.

This study examined the protective effect of Kaempferol against streptozotocin-induced diabetic nephropathy (DN) in rats and studies the underlying mechanisms. Rats were divided into 4 groups as control, control + Kaempferol, STZ, and STZ + Kaempferol. All treatments were conducted for 8 weeks daily after the induction of diabetes. Kaempferol prevented STZ-induced weight and food loss and attenuated renal damage and the alterations in all biochemical related parameters. Concomitantly, Kaempferol reduced renal levels of TNF-α and IL-6, cleaved caspase-3, p38, and Bax, suppressing JNK phosphorylation and NF-κB p65 transactivation, and upregulation of Bcl-2. In both control and STZ-diabetic rats, Kaempferol reduced fasting glucose levels, increased fasting insulin levels and HOMA-ß, reduced the levels of ROS and MDA, stimulated SOD and GSH levels, and increased the expression of Nrf2 and HO-1. In conclusion, Kaempferol prevents STZ-induced diabetic nephropathy, mainly, by antioxidant potential, mediated by the upregulation of the Nrf-2/HO-1 axis.

The ameliorative effect of kaempferol against CdCl2- mediated renal damage entails activation of Nrf2 and inhibition of NF-kB.

This study evaluated the nephroprotective effect of kaempferol against cadmium chloride (CdCl2) -induced nephropathy in rats. It also investigated if activation of Nrf2 is a common mechanism of action. Adult male rats ((150 ± 15 g) were divided into 4 groups (n = 8/each) as a control (1% DMSO, orally), control + kaempferol (200 mg/kg, orally), CdCl2 (50 mg/l in drinking water), and CdCl2 + kaempferol (200 mg/kg)-treated rats. All treatments were conducted for 8 weeks. Kaempferol significantly attenuated CdCl2-induced weight loss, reduction in kidney weights, and the injury in the glomeruli, proximal tubules, and distal tubules in the treated rats. It also significantly lowered serum levels of urea and creatinine, increased urine output and urinary creatinine levels and clearance but reduced urinary levels of albumin urinary albumin exertion (UAER), and urinary albumin/creatinine ratio (UACR) in these rats. In parallel, kaempferol downregulated renal levels of cleaved caspase-3 and Bax and unregulated those of Bcl2. In the kidney tissues of the control animals and CdCl2 rats, kaempferol significantly attenuated oxidative stress, inflammation and significantly boosted levels of manganese superoxide dismutase and glutathione. Also, and in both groups, kaempferol suppressed the nuclear levels of NF-κB p65, downregulated Keap1, and stimulated the nuclear activation and protein levels of Nrf2. In conclusion, kaempferol is a potential therapeutic drug to prevent CdCl2-induced nephropathy due to its anti-inflammatory and anti-oxidant effects mediated by suppressing NF- NF-κB p65 and transactivating Nrf2.

Left lower limb deep venous thrombosis, May-Thurner syndrome and endovascular management.

OBJECTIVES: To determine the prevalence of May-Thurner syndrome (MTS) in left lower limb deep venous thrombosis (DVT) cases and to analyze the outcome of endovascular intervention in these patients. METHODS: A record-based descriptive study was carried out in Radiology Department, King Fahad Military Medical Complex, Dhahran, Saudi Arabia, including patients who underwent lower limb duplex ultrasounds between January 2015-2021. Patients with bilateral DVTs, known pelvic masses, and pelvic surgeries were excluded. All patients positive for DVTs were identified and further imaging was reviewed. Left common iliac vein compression of 50% or more on computed tomography (CT) was considered positive for MTS. Endovascular interventions (venoplasty alone or with stenting) were evaluated and success recorded by observing patency of vein on follow-up imaging or improvement of symptoms on follow-up visits. RESULTS: Of 182 patients with left lower limb duplex studies, 51 patients were positive for DVTs. A total of 37 patients had CTs and 21 patients had MTS (17 females, 3 males). A total of 15 patients underwent endovascular interventions, 2 patients had venoplasties alone (one successful) and 13 patients had venoplasties with stenting (10 successful). CONCLUSION: Patients with MTS as cause of DVT may benefit from early endovascular intervention.

Kaempferol prevents cadmium chloride-induced liver damage by upregulating Nrf2 and suppressing NF-κB and keap1.

This study evaluated the protective effect of kaempferol, a natural flavonoid, against cadmium chloride (CdCl2)-induced liver damage and examined the possible anti-inflammatory and antioxidant mechanisms of protection. Adult male rats were divided into 4 groups (each of 8 rats) as control, kaempferol (50 mg/kg/day orally), CdCl2 (15 ppm/day), and CdCl2 (15 ppm/day) + kaempferol (50 mg/kg/day). All treatments were given for 30 days. With no effect on attenuating the reduced food intake, kaempferol significantly increased body weight and lowered serum levels of liver injury markers including bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase 1 (γ-GTT1) in the CdCl2-treated rats. It also restored normal liver architectures, prevented hepatocyte, loss, and swelling and reduced inflammatory cell infiltration. These effects were associated with a reduction in mitochondrial permeability transition pore, as well as in the expression of cytochrome-c and cleaved caspase-3, markers of mitochondrial damage, and intrinsic cell death. In both the control positive and CdCl2-treated rats, kaempferol significantly lowered the hepatic levels of reactive oxygen species, malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), Interleukine-6 (IL-6), and the nuclear activity and localization of NF-κB p65. Besides, kaempferol significantly increased the hepatic total and nuclear levels of the nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1, as well as levels of superoxide dismutase (SOD) and reduced glutathione (GSH) but reduced the cytoplasmic protein levels of keap1. In conclusion, the protective effect of kaempferol against CdCl2-induced hepatic damage is mediated by antioxidant and anti-inflammatory effects driven by upregulating Nrf2/HO-1 axis and suppressing the NF-κB p65 and keap1.

Cadmium chloride induces non-alcoholic fatty liver disease in rats by stimulating miR-34a/SIRT1/FXR/p53 axis.

Cadmium (Cd) is associated with non-alcoholic fatty liver disease (NAFLD). The hepatic activation of p53/miR-43a-induced suppression of SIRT1/FXR axis plays a significant role in the development of NAFLD. In this study, we have investigated CdCl2-induced NAFLD in rats involves activation of miR34a/SIRT1/FXR axis. Adult male rats were divided into 4 groups (n-8/each) as a control, CdCl2 (10 mg/l), CdCl2 + miR-34a antagomir (inhibitor), and CdCl2 + SRT1720 (a SIRT1 activator) for 8 weeks, daily. With no effect on fasting glucose and insulin levels, CdCl2 significantly reduced rats' final body, fat pads, and liver weights, and food intake. Concomitantly, it increased the circulatory levels of liver markers (ALT, AST, and γ-GTT), increased the serum and hepatic levels of total cholesterol and triglycerides coincided with increased hepatic lipid accumulation. Besides, it increased the mRNA and protein levels of SREBP1, SREBP2, FAS, and HMGCOA reductase but reduced mRNA levels of PPARα, CPT1, and CPT2. Interestingly, CdCl2 also increased mRNA levels of miR34 without altering mRNA levels of SIRT1 but with a significant reduction in protein levels of SIRT1. These effects were associated with increased total protein levels of p53 and acetylated protein of p53, and FXR. Of note, suppressing miR-34a with a specific anatomic or activating SIRT1 by SRT1720 completely prevented all these effects and reduced hepatic fat accumulations in the livers of rats. In conclusion, CdCl2 induced NAFLD by increasing the transcription of miR-34a which in turn downregulates SIRT1 at the translational level.

Salidroside induces cell apoptosis and inhibits the invasiveness of HT29 colorectal cells by regulating protein kinase R, NF-κB and STAT3.

BACKGROUND: Protein kinase R (PKR) can suppress various types of solid tumors by inducing cellular oxidative stress and apoptosis. Likewise, Slaidorside, a plant flavonoid, was shown to have anti-tumorigenesis in many solid tumors. OBJECTIVE: This study evaluated anti-tumorigenesis of Salidroside in HT29 colorectal cancer and investigated if the underlying mechanism involves activation of PKR. METHODS: Control or PKR deficient cells were cultured in DMEM media treated with 100 µM Salidroside and cell survival, apoptosis, and other biochemical-related markers were evaluated. RESULTS: Salidroside significantly reduced cell survival and proliferation and increased the release of lactate dehydrogenase (LDH) and levels of single-stranded DNA (ssDNA). It also increased the protein levels of caspases 3 and 8. Concomitantly, Salidroside increased the protein level and activity of PKR and increased the expression of its downstream targets, p-eIF2α (Ser51), p53 MAPK, and p53. On the contrary, it inhibited the nuclear activation of STAT-3 and NF-κB p65. In PKR deficient cells, the partial effects of Salidroside on cell survival, proliferation, and apoptotic markers were observed coincided with no effects on the expression of eIF-2α, and JNK, p53, p38 MAPK, and caspase 8 but with a significant decrease in the nuclear activities of STAT3 and NF-κB. CONCLUSION: Salidroside suppresses the tumorigenesis of HT29 CRC by increasing activation of eIF-2α and JNK and upregulation of p53, p38 MAPK, and caspase-8 through upregulating and activation of PKR. However, the tumor suppressor effect of Salidroside requires also inhibition of STAT3 and NF-κB in a PKR-independent mechanism.

Cadmium Chloride Induces Memory Deficits and Hippocampal Damage by Activating the JNK/p66Shc/NADPH Oxidase Axis.

This study investigated whether the mechanism underlying the neurotoxic effects of cadmium chloride (CdCl2) in rats involves p66Shc. This study comprised an initial in vivo experiment followed by an in vitro experiment. For the in vivo experiment, male rats were orally administered saline (vehicle) or CdCl2 (0.05 mg/kg) for 30 days. Thereafter, spatial and retention memory of rats were tested and their hippocampi were used for biochemical and molecular analyses. For the in vitro experiment, control or p66Shc-deficient hippocampal cells were treated with CdCl2 (25 µM) in the presence or absence of SP600125, a c-Jun N-terminal kinase (JNK) inhibitor. Cadmium chloride impaired the spatial learning and retention memory of rats; depleted levels of glutathione and manganese superoxide dismutase; increased reactive oxygen species (ROS), tumor necrosis factor α, and interleukin 6; and induced nuclear factor kappa B activation. Cadmium chloride also decreased the number of pyramidal cells in the CA1 region and induced severe damage to the mitochondria and endoplasmic reticulum of cells in the hippocampi of rats. Moreover, CdCl2 increased the total unphosphorylated p66Shc, phosphorylated (Ser36) p66Shc, phosphorylated JNK, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, cytochrome c, and cleaved caspase-3. A dose-response increase in cell death, ROS, DNA damage, p66Shc, and NADPH oxidase was also observed in cultured hippocampal cells treated with CdCl2. Of note, all of these biochemical changes were attenuated by silencing p66Shc or inhibiting JNK with SP600125. In conclusion, CdCl2 induces hippocampal ROS generation and apoptosis by promoting the JNK-mediated activation of p66Shc.