Design and synthesis of novel JNK inhibitors targeting liver pyruvate kinase for the treatment of non-alcoholic fatty liver disease and hepatocellular carcinoma.

Non-alcoholic fatty liver disease (NAFLD) comprises a broad range of liver disease including hepatocellular carcinoma (HCC) with is no FDA-approved drug. Liver pyruvate kinase (PKL) is a major regulator of metabolic flux and ATP generation in liver presenting a potential target for the treatment of NAFLD. Based on our recent finding of JNK-5A's effectiveness in inhibiting PKLR expression through a drug repositioning pipeline, this study aims to improve its efficacy further. We synthesized a series of JNK-5A analogues with targeted modifications, guided by molecular docking studies. These compounds were evaluated for their activities on PKL expression, cell viability, triacylglyceride (TAG) levels, and the expressions of steatosis-related proteins in the human HepG2 cell line. Subsequently, the efficacy of these compounds was assessed in reducing TAG level and toxicity. Compounds 40 (SET-151) and 41 (SET-152) proved to be the most efficient in reducing TAG levels (11.51 ± 0.90 % and 10.77 ± 0.67 %) and demonstrated lower toxicity (61.60 ± 5.00 % and 43.87 ± 1.42 %) in HepG2 cells. Additionally, all synthesized compounds were evaluated for their anti-cancer properties revealing that compound 74 (SET-171) exhibited the highest toxicity in cell viability with IC50 values of 8.82 µM and 2.97 µM in HepG2 and Huh7 cell lines, respectively. To summarize, compounds 40 (SET-151) and 41 (SET-152) show potential for treating NAFLD, while compound 74 (SET-171) holds potential for HCC therapy.

Ellagic Acid and Its Metabolites as Potent and Selective Allosteric Inhibitors of Liver Pyruvate Kinase.

Liver pyruvate kinase (PKL) has recently emerged as a new target for non-alcoholic fatty liver disease (NAFLD), and inhibitors of this enzyme could represent a new therapeutic option. However, this breakthrough is complicated by selectivity issues since pyruvate kinase exists in four different isoforms. In this work, we report that ellagic acid (EA) and its derivatives, present in numerous fruits and vegetables, can inhibit PKL potently and selectively. Several polyphenolic analogues of EA were synthesized and tested to identify the chemical features responsible for the desired activity. Molecular modelling studies suggested that this inhibition is related to the stabilization of the PKL inactive state. This unique inhibition mechanism could potentially herald the development of new therapeutics for NAFLD.

Association of High Immunohistochemical Expression of Minichromosome Maintenance 3 with Human Oral Squamous Cell Carcinoma-A Preliminary Study.

BACKGROUND: Oral squamous cell carcinoma (OSCC) may arise from premalignant oral lesions (PMOL) in most cases. Minichromosome maintenance 3 (MCM3) is a proliferative marker that has been investigated as a potential diagnostic biomarker in the diagnosis of oral cancer. OBJECTIVES: To evaluate the association of MCM3 expression, its clinicopathologic parameters and to identify snuff (also called naswar) as a potential risk factor for changes in MCM3 expression in PMOL and OSCC. METHODOLOGY: Immunohistochemistry (IHC) of MCM3 was performed on 32 PMOL, 32 OSCC and 16 normal controls after optimization of IHC methodology. Histoscore (0-300) was used as a scoring system and seven different cut-offs were identified for analyses. Data were analyzed using various statistical tests. RESULTS: Among the seven cutoffs, 40% strong positive cells were found to be a better cut-off as they were associated with many pathological variables (Broder's grade, Aneroth's grade, and mitotic activity). The differential MCM3 expression in oral lesions (PMOL and OSCC) was statistically significant (p = 0.03). Moreover, MCM3 expression is raised with increased duration and frequency of snuff use. CONCLUSION: High MCM3 expression is associated with disease progression and is a potential indicator of malignant transformations from PMOL to OSCC. Moreover, the use of snuff is associated with MCM3 over-expression.

Awareness about Vulvovaginal Aesthetics Procedures among Medical Students and Health Professionals in Saudi Arabia.

OBJECTIVE: The present study aimed to explore the opinion and ethical consideration of vulvovaginal aesthetics procedures (VVAPs) among health professionals and medical students in Saudi Arabia. METHODS: This is a cross-sectional study performed between January 2020 and April 2020. Data was collected through electronic media, WhatsApp, and emails. The results were analyzed by applying the Students t-test, and correlations were considered significant if they presented a p-value < 0.05. RESULTS: There is significant demand to educate doctors, health professionals, medical students, and gynecologists for the VVAPs to have a solid foundation, justified indications, and knowledge about various aesthetic options. Although female doctors, medical students, young doctors, and gynecologists have more knowledge about VVAPs, all health professionals ought to be aware of recent trends in vulvovaginal aesthetics (VVA). The present analysis determined that VVA should be under the domain of gynecologists, rather than under that of plastic surgeons, general surgeons, and cosmetologists. The majority of the participants considered that vaginal rejuvenation, "G-spot" augmentation, clitoral surgery, and hymenoplasty are not justifiable on medical grounds. CONCLUSION: The decision to opt for different techniques for vaginal tightening and revitalization should be taken very carefully, utilizing the shared decision-making approach. Ethical aspects and moral considerations are important key factors before embarking in the VVAPs purely for cosmetic reasons. Further research is required to determine the sexual, psychological, and body image outcomes for women who underwent elective VVAPs. Moreover, medical educators must consider VVAPs as part of the undergraduate and postgraduate medical curriculum.

Awareness about vulvovaginal aesthetics procedures among medical students and health professionals in saudi arabia

Abstract Objective The present study aimed to explore the opinion and ethical consideration of vulvovaginal aesthetics procedures (VVAPs) among health professionals and medical students in Saudi Arabia. Methods This is a cross-sectional study performed between January 2020 and April 2020. Data was collected through electronic media, WhatsApp, and emails. The results were analyzed by applying the Students t-test, and correlations were considered significant if they presented a p-value<0.05. Results There is significant demand to educate doctors, health professionals, medical students, and gynecologists for the VVAPs to have a solid foundation, justified indications, and knowledge about various aesthetic options. Although female doctors, medical students, young doctors, and gynecologists have more knowledge about VVAPs, all health professionals ought to be aware of recent trends in vulvovaginal aesthetics (VVA). The present analysis determined that VVA should be under the domain of gynecologists, rather than under that of plastic surgeons, general surgeons, and cosmetologists. Themajority of the participants considered that vaginal rejuvenation, "G-spot" augmentation, clitoral surgery, and hymenoplasty are not justifiable on medical grounds. Conclusion The decision to opt for different techniques for vaginal tightening and revitalization should be taken very carefully, utilizing the shared decision-making approach. Ethical aspects and moral considerations are important key factors before embarking in the VVAPs purely for cosmetic reasons. Further research is required to determine the sexual, psychological, and body image outcomes for women who underwent elective VVAPs. Moreover, medical educators must consider VVAPs as part of the undergraduate and postgraduate medical curriculum.

A comparative study between a single-dose and 24-hour multiple-dose antibiotic prophylaxis for elective hysterectomy.

INTRODUCTION: Surgical site infections (SSIs) are a major health issue in surgical specialties in terms of health care costs and patients' clinical outcomes. At the level of the patient, prolonged hospital stays or readmissions for SSIs, can affect the patient's quality of life. At the level of the health care system, it exhausts the hospital's resources and increases the burden on the medical staff due to the need for continuous wound care, microbiological cultures, laboratory tests and medications. In this study, we assessed the effectiveness of two antibiotic prophylaxis regimens for the prevention of SSIs in patients undergoing elective hysterectomy surgeries. METHODOLOGY: A retrospective cohort, analyzing 141 patients, was conducted between November 2016 and January 2019 at a university hospital. We compared the efficacy of a single dose vs. 24-hour multiple doses of Cefazolin in patients who underwent elective hysterectomy for benign or malignant indications. The secondary objective was to identify potential risk factors associated with SSIs. RESULTS: There was no statistically significant difference between both groups (p = 0.872). Obesity and a laparotomy surgical approach are risk factors to the development of SSIs (p = 0.001 and 0.014, respectively). Other potential risk factors include the duration of hospital stay, the duration of the surgery and the amount of blood loss. CONCLUSIONS: Although the rate of SSIs is not significantly different between both groups, risk stratification can be done after screening patients and the prophylactic regimen must be tailored for each patient in a cost-effective manner and using a multidisciplinary approach.

A CREATIVE approach to designing a contemporary medical curriculum.

This article was migrated. The article was marked as recommended. In medical education, Outcome-based Education (OBE) is facing many challenges due to the rapid proliferation in biomedical sciences; technology-enhanced learning; globalization of health system, and the availability of various pedagogical techniques. A steady stream of evidence-based developments challenges those who are responsible for sustaining and improving their medical curricula. Curriculum reform is a dynamic process and there is no explicit approach that can serve as a guide for a curriculum reviewer while making amendments in the OBE integrated curriculum. This study took place in a medical college in Saudi Arabia and it highlights the key components to be considered while reviewing the Bachelor in Medicine and Surgery (MBBS) course specifications and curriculum. It suggests the importance of course reports as the main driving force for curriculum reforms. Delineating major and minor changes in the curriculum and frequency of amendments in course specifications also remains a questionable task and requires established institutional guidelines. Furthermore, based on practical experience in the periodic curriculum review process, the authors suggest some best practice. We present a "CREATIVE" way forward which we have found invaluable, both for curriculum developers and for engaging with our stakeholders. This mnemonic spells out the key factors to consider while revisiting the curriculum from various angles. These factors are: Course Report recommendations, Evaluation tools (internal and external), Alignment of pedagogical strategies with assessment, Technology, Innovation, Variations in the learning environment, and Establishment of institutional guidelines. Application of these fundamental elements allowed us the development of a curriculum that meets the standards for international accreditation and helped the institution to form a cohesive team of educationalists.

Evaluation of Matrix Metalloproteinases, Cytokines and Their Potential Role in the Development of Ovarian Cancer.

BACKGROUND: Ovarian cancer is the 5th most common cause of deaths in the women among gynecological tumors. There are many growing evidences that stress and other behavioral factors may affect cancer progression and patient survival. The purpose of this study is to determine the key role of matrix metalloproteinases (MMPs), and cytokines in the aggregation and progression of ovarian cancer. METHODOLOGY: Stress variables (MDA, AGEs, AOPPs, NO), profile of antioxidants (SOD, Catalase, Vitamin E & A, GSH, GRx, GPx) and inflammatory biomarkers (MMP-9, MMP-2, MMP-11, IL-1α and TNF-α) were biochemically assessed from venous blood of fifty ovarian cancer patients and twenty healthy control subjects. The results of all parameters were analyzed statistically by independent sample t-test. RESULTS: The results of the study demonstrated that the levels of stress variables like MDA (3.38±1.12nmol/ml), AGEs (2.72±0.22 ng/ml), AOPPs (128.48±27.23 ng/ml) and NO (58.71±8.67 ng/ml) were increased in the patients of ovarian cancer as compared to control individuals whereas the profile of antioxidants like SOD, Catalase, Vitamin E, Vitamin A, GSH and GRx were decreased in ovarian cancer patients (0.11±0.08 µg/ml, 2.41±1.01µmol/mol of protein, 0.22±0.04 µg/ml, 45.84±9.07µg/ml, 4.88±1.18µg/ml, 5.33±1.26 µmol/ml respectively). But the level of GPx antioxidant was increased in ovarian cancer patients (6.58±0.21µmol/ml). Moreover the levels of MMP-9 (64.87±5.35 ng/ml), MMP-2 (75.87±18.82 ng/ml) and MMP-11 (63.58±8.48 ng/ml) were elevated in the patients. Similarly, the levels of various cytokines TNF-α and IL-1α were also increased in the patients of ovarian cancer (32.17±3.52 pg/ml and 7.04±0.85 pg/ml respectively). CONCLUSION: MMPs are commonly expressed in ovarian cancer which are potential extrapolative biomarkers and have a major role in metastasis. Due to oxidative stress, different cytokines are released by tumor associated macrophages (TAMs) that result in the cancer progression. Consequently, tissue inhibitors of matrix metalloproteinases (TIMPs) are the valuable therapeutic approaches to complement conservative anticancer strategies.

Oral Leiomyoma in Retromolar Trigone.

Leiomyoma is benign tumour arising from smooth muscle that occurs between 40 and 49 years of age. Leiomyomas are a rare entity in the oral cavity and if present they are usually localized on tongue, lips and palate. Leiomyoma appears to be well-defined mass, with slow growth. The treatment is surgical excision. We report a 10-year girl child, with a lump in the right retromolar trigone region intraorally. Excisional biopsy performed under general anaesthesia revealed the specimen to be a leiomyoma. The low incidence of this pathology, the age of the patient and the location are unusual.