Identification of Putative Plant-Based ALR-2 Inhibitors to Treat Diabetic Peripheral Neuropathy.

Diabetic peripheral neuropathy (DPN) is a common diabetes complication (DM). Aldose reductase -2 (ALR-2) is an oxidoreductase enzyme that is most extensively studied therapeutic target for diabetes-related complications that can be inhibited by epalrestat, which has severe adverse effects; hence the discovery of potent natural inhibitors is desired. In response, a pharmacophore model based on the properties of eplarestat was generated. The specified pharmacophore model searched the NuBBEDB database of natural compounds for prospective lead candidates. To assess the drug-likeness and ADMET profile of the compounds, a series of in silico filtering procedures were applied. The compounds were then put through molecular docking and interaction analysis. In comparison to the reference drug, four compounds showed increased binding affinity and demonstrated critical residue interactions with greater stability and specificity. As a result, we have identified four potent inhibitors: ZINC000002895847, ZINC000002566593, ZINC000012447255, and ZINC000065074786, that could be used as pharmacological niches to develop novel ALR-2 inhibitors.

Computational analysis of PTP-1B site-directed mutations and their structural binding to potential inhibitors.

Protein tyrosine phosphatase-1B (PTP-1B) is a well-known therapeutic target for diabetes and obesity as it suppresses insulin and leptin signaling. PTP-1B deletion or pharmacological suppression boosted glucose homeostasis and insulin signaling without altering hepatic fat storage. Inhibitors of PTP-1B may be useful in the treatment of type 2 diabetes, and shikonin, a naturally occurring naphthoquinone dye pigment, is reported to inhibit PTP-1B and possess antidiabetic properties. Since the cell contains a large number of phosphatases, PTP-1B inhibitors must be effective and selective. To explore more about the mechanism underlying the inhibitor's efficacy and selectivity, we investigated its top four pharmacophores and used site-directed mutagenesis to insert amino acid mutations into PTP-1B as an extension of our previous study where we identified 4 pharmacophores of shikonin. The study aimed to examine the site-directed mutations like R24Y, S215E, and S216C influence the binding of shikonin pharmacophores, which act as selective inhibitors of PTP-1B. To achieve this purpose, docking and molecular dynamics simulations of wild-type (WT) and mutant PTP-1B with antidiabetic compounds were undertaken. The simulation results revealed that site-directed mutations can change the hydrogen bond and hydrophobic interactions between shikonin pharmacophores and many residues in PTP-1B's active site, influencing the drug's binding affinity. These findings could aid researchers in better understanding PTP-1B inhibitors' selective binding mechanism and pave the path for the creation of effective PTP-1B inhibitors.

Role of Alkannin in the Therapeutic Targeting of Protein-Tyrosine Phosphatase 1B and Aldose Reductase in Type 2 Diabetes: An In Silico and In Vitro Evaluation.

Alkannin is a plant-derived naphthoquinone that is isolated from the Boraginaceae family plants. In our previous studies, we found that shikonin, which is the R-enantiomer of alkannin, has potent antidiabetic activity by inhibiting the action of the aldose reductase (AR) enzyme and the protein-tyrosine phosphatase 1B (PTP1B). Therefore, in this study, we aim to explore the antidiabetic effect of alkannin targeting PTP1B and AR by employing in silico and in vitro techniques. For in silico, we used different parameters such as ADMET analysis, molecular docking, MD simulation, Root Mean Square Deviation (RMSD), protein-ligand mapping, and free binding energy calculation. The in vitro evaluation was done by assessing the inhibitory activity and enzyme kinetics of PTP1B and AR inhibition by alkannin. The in silico studies indicate that alkannin possesses favorable pharmacological properties and possesses strong binding affinity for diabetes target proteins. Hydrogen bonds (Val297, Ala299, Leu300, and Ser302) and hydrophobic interactions (Trp20, Val47, Tyr48, Trp79, Trp111, Phe122, Trp219, Val297, Cys298, Ala299, Leu300, and Leu301) are established by the compound, which potentially improves specificity and aids in the stabilization of the protein-ligand complex. The results from in vitro studies show a potent dose-dependent PTP1B inhibitory activity with an IC50 value of 19.47 µM, and toward AR it was estimated at 22.77 µM. Thus, from the results it is concluded that a low IC50 value of alkannin for both PTP1B and AR along with favorable pharmacological properties and optimal intra-molecular interactions indicates its utilization as a potential drug candidate for the management of diabetes and its end complications.

Inconsistencies in Pregnant Mothers' Attitudes and Willingness to Donate Umbilical Cord Stem Cells: A Cross-Sectional Analysis from Saudi Arabia.

The collection and storage of umbilical cord stem cells (UCSCs) have a crucial role in improving and expanding stem cell-based therapies, which are becoming popular in Saudi Arabia and other Middle East countries. Many patients and families in Saudi Arabia depend on private cord banks in foreign countries to purchase stem cells, which has financial and medical implications. The current study aims at determining the predictors of current registration status and willingness to donate cord blood stem cells among expectant mothers in Saudi Arabia. A cross-sectional study collected data from 714 expectant mothers from all thirteen regions of Saudi Arabia in December 2022. The online survey questionnaire assessed women's awareness, direct and indirect exposure to stem-cell therapy, sources of knowledge, willingness, reluctance, and current registration status to donate cord blood. Although women demonstrated higher acceptance and lower rejection towards the donation of UCSCs, just one percent (n = 7; 1%) of expectant mothers in this sample are registered with the Saudi Stem Cell Registry. Overall, 48% indicated their willingness to register in the future. Both correlational analysis and multiple regression analysis demonstrated that awareness significantly predicted willingness to donate (p < 0.01), and rejection attitudes were negatively related to willingness to donate (p < 0.001). Although the mean scores on acceptance were high, they were not found to be significantly associated with willingness to donate. Prior direct and indirect exposure to stem cell therapy appeared to be the strongest predictor of pregnant women's willingness to register (p < 0.001). Findings suggest that acceptance attitudes do not have a symmetrical relationship with intention. Women's prior exposure to stem cell therapy was the most significant factor; therefore, findings demonstrate that currently women are relying on their firsthand experience to decide about cord blood donation rather than the information obtained from other sources, such as social media and the internet. Though attitudes were not identified as significant predictors in the statistical models, awareness was a relevant factor, and the findings signify increasing awareness in various target populations to enhance the probability of intention to donate cord stem cells.

Medical Professionals' Knowledge, Sensitivity, and Attitudes Towards Social and Ethical Aspects of Stem-Cell Donation, Therapy, and Research: Implications for Healthcare Risk Management.

Background: Knowledge, sensitivity, and acceptance attitudes towards social, moral and ethical aspects of stem-cell donation and treatment are important factors in preventing professional negligence and improving healthcare risk management and health justice in this specialized area of health services. Objective: To assess knowledge, sensitivity, acceptance and rejection attitudes towards stem-cell transplantation and research and its associated factors among medical professionals in Saudi Arabia. Methods: A quantitative and cross-sectional study was conducted in December 2022. Data were collected from 260 medical workers from various regions in Saudi Arabia. T-tests, ANOVA, and multiple linear regression were applied to find variations and associations of gender, age, profession, nationality, religious orientation, and work experiences of professionals with knowledge, sensitivity, acceptance and rejection attitude towards stem-cell donation, therapy, and research. A confidence interval (CI) of 95% and a significance level of p≤ 0.05 was chosen for testing statistical models. Results: A total of (n=260) medical professionals, among which clinicians (n=98;38%), pharmacists (n=78;30%), and nurses (n=84;32%) completed the survey questionnaire. Findings show that (n=27; 10%) participants have work experience in stem-cell donation, (n=67; 26%) in stem-cell therapy, and (n=124; 48%) in stem-cell research. Clinicians and pharmacists, in comparison to nurses, had better knowledge (p<0.01 and p<0.05); pharmacists had higher sensitivity (p<0.05) than nurses. Compared to those who do not have work experience in stem-cell research, those who had work experience had higher levels of knowledge, sensitivity, and acceptance attitudes at (p<0.001) and (p<0.01). Acceptance attitudes are considerably higher among male participants than females and similarly higher among older participants than younger participants (p<0.05). Compared to non-Saudi nationals, Saudi nationals scored higher on rejection attitudes (p<0.01). Compared to those having work experience in stem-cell donation and research, those without work experience are more likely to hold rejection attitudes (p<0.01). Conclusion: Findings suggest female professionals, Saudi nationals and those who do not have prior work experience in stem-cell donation, therapy, or research had low levels of knowledge, less sensitivity, and less acceptance attitude and are more likely to hold rejection attitude, signifying the need to address them to improve healthcare risk management.

Knowledge about stem cell sources and obstacles in donation of bone marrow and peripheral blood stem cells: a cross-sectional survey from Ha'il city to track the prospects of regenerative medicine in Saudi Arabia.

BACKGROUND: Promoting stem cell donation behaviors could be crucial in advancing stem cell-based treatment, research and improving public health in Saudi Arabia. Donation of stem cells can be considered an act of social welfare just like blood donation because stem-cell-based therapies are emerging as a hope for those suffering from chronic health conditions and/or terminal illnesses. AIM: This study aims at assessing levels of awareness about sources of stem-cells, donor organizations and predictors of stem cell donation behavior in target population. METHODS: The study employed a cross-sectional online survey method. The study sample comprises 1325 educated Saudi people living in Ha'il city. The survey questionnaire collected data about respondents' demographic background, awareness about various sources of stem cells and stem-cell donor registries, willingness to donate stem cells, registration status and obstacles in stem cell donation registration. Percentages, Chi-square analysis and Odd Ratios were computed to analyze the data. RESULTS: In this sample, (n = 696; 52%) were males and (n = 629; 48%) were females. Although (n = 1308; 98%) percent of respondents reported willingness to donate stem cell, less than one percent (n = 6; 0.5) were registered with Saudi Stem Cell Registry. Over 50% of respondents hold inaccurate perceptions about sources of stem cell. Odd Ratio (OR) values from binary logistic regression model identified four factors as significant predictors of non-registration status. These included (i) unaware about donor agencies and procedures (OR = 10.07; p < 0.05), (ii) unaware about possibility to donate stem cells (OR = 8.08; p < 0.05) (iii) concerns about impact on health (OR = 10.01; p < 0.05) and (iv) have health issues that does not permit donation (OR = 10.50; p < 0.05). CONCLUSION: Stem cell registrations can be enhanced through appropriate health education programs that focus on increasing awareness about donation procedures, trustworthy donor organizations and reducing people apprehensions related to donation.

Molecular interactions of cucurbitacins A and B with anaplastic lymphoma kinase for lung cancer treatment.

Lung cancer is a major global public health issue and the leading cause of cancer-related deaths. Several medications are commonly used to treat lung cancer, either alone or in combination with other treatments. The anaplastic lymphoma kinase (ALK) protein is one of several target proteins that are thought to be potential therapeutic targets in the context of lung cancer. Several ALK inhibitors have been identified, but many of these have been associated with side effects and toxicity concerns. In this study, we intend to computationally predict the binding potential of cucurbitacins (CBNs), A and B to the active pockets of ALK, in order to estimate their potential ALK inhibitors. Compared to CBN-A, which has a binding energy of -7.9 kcal/mol, CBN B exhibits significantly better binding efficacy with a binding energy of -8.1 kcal/mol. This is closely comparable to the binding energy of Crizotinib, which is -8.2 kcal/mol. The results of the molecular dynamics simulation indicated that the docked complexes remained stable for the duration of the 100 ns simulation period. CBN inhibited the proliferation of both non-small cell lung cancer cell lines, H1299 and A549, in a dose-dependent manner. CBN-B inhibited the proliferation of lung cancer cells, showing IC50 values of 0.08 µM for H1299 cells and 0.10 µM for A549 cells. The computational analyses provide strong evidence that CBN-B has the potential to act as a potent natural inhibitor against ALK, and could prove to be a valuable treatment option for lung cancer.Communicated by Ramaswamy H. Sarma.

A mixed-method analysis to identify the current focus, trends, and gaps in health science research in Saudi Arabia.

Background: The identification of current gaps in high-impact medical research in Saudi Arabia has international significance due to the trend of collaborative research in the field of health and medicine and the focus on knowledge-sharing. The purpose of this study is to assess the current focus, gaps, and priorities in health research in Saudi Arabia. Methods: We employed a mixed-method research approach to achieve research objectives. (1) a systematic review of scientific research studies that are published between January 2020 to January 2022 in the top fifty Q1 medical science journals (2) a cross-sectional survey collected data from professionals employed in various organizations including the Ministry of Health (MoH), Ministry of Education (MoE), health organizations and universities, and the health industry. The close-ended survey questions inquired about the broad and specific areas of ongoing health research projects by these researchers and organizations in Saudi Arabia. Results: The literature search on databases identified Science Direct (n = 741), Pub Med (n = 244) and Google Scholar (n = 15,600). After screening, (n = 26) original studies were selected for detailed evaluation and synthesis. Among these (n = 7) studied infectious diseases, (n = 7) cancer, and cardiac disease (n = 5). These studies focused on the etiology, treatment management and therapy outcomes of these health conditions. The survey was completed by (n = 384) respondents from these organizations. Most of the ongoing research projects focus on clinical sciences (27%) followed by basic sciences (24%) and public health research (24%) and a limited number of researchers were involved in healthcare management (2%) and informatics (2%). Most research focused on kidney and liver disorders (80%), obesity (74%), diabetes (74%), hormonal diseases (64%), and infectious disease (66%); it is equally important to design and fund research in some of the neglected areas including reproductive health (3%), physical and mental disabilities (1%). Conclusion: Findings suggest that current gaps in original research from Saudi Arabia are in healthcare service quality, reproductive health, physical and mental disabilities and health informatics. Researchers and funding agencies and international collaborative projects should prioritize these areas.

Role of community-based measures in adherence to self-protective behaviors during first wave of COVID-19 pandemic in Saudi Arabia.

Background: The expected second wave of the COVID-19 pandemic has started in various regions of the world. Public health experts warned that it could be as lethal as the first wave if people did not comply with self-protective measures. Currently, there is a gap in the literature on the relationship between peoples' assessment of the effectiveness of community-based measures regarding adherence to self-protective behaviors for COVID-19 prevention and control. This study aimed to assess the role of the perceived effectiveness of community-based measures in adherence to self-protective behaviors during the COVID-19 pandemic. Methods: The cross-sectional online survey conducted from March 24 to June 22, 2020. The study sample Included 400 participants (49% male and 51% female) from the Kingdom of Saudi Arabia (KSA). The outcome measure was compliance to four self-protective behaviors i.e., "social distancing;" "wearing facemask;" "washing hands more frequently;" and "disinfecting surfaces in homes." We computed Chi-square statistics and odds ratios (ORs) using 95% confidence intervals (CIs). Results: The findings demonstrated that participants aged 25-34 years old were 25% less likely to comply with hand hygiene (OR = 0.75; 95% CI: 0.33-0.95) and social distancing (OR = 0.76; 95% CI: 0.34-0.98). Misconceptions related to COVID-19 significantly decreased compliance with self-protective behaviors by up to 27%. Participants who rated government decisions as useful were approximately 1.7 times more likely to comply with self-protective behaviors. Conclusion: Community-based measures should focus on engaging segments of the population That are currently less compliant. Health education policies should also focus on enhancing the perceived sense of control and personal responsibility and reduce anxiety levels. A continuous commitment to the implementation of preventive interventions and the clarification of misconceptions are required to combat the expected second wave.

Generalized Richards model for predicting COVID-19 dynamics in Saudi Arabia based on particle swarm optimization Algorithm.

COVID-19 pandemic is spreading around the world becoming thus a serious concern for health, economic and social systems worldwide. In such situation, predicting as accurately as possible the future dynamics of the virus is a challenging problem for scientists and decision-makers. In this paper, four phenomenological epidemic models as well as Suspected-Infected-Recovered (SIR) model are investigated for predicting the cumulative number of infected cases in Saudi Arabia in addition to the probable end-date of the outbreak. The prediction problem is formulated as an optimization framework and solved using a Particle Swarm Optimization (PSO) algorithm. The Generalized Richards Model (GRM) has been found to be the best one in achieving two objectives: first, fitting the collected data (covering 223 days between March 2nd and October 10, 2020) with the lowest mean absolute percentage error (MAPE = 3.2889%), the highest coefficient of determination (R2 = 0.9953) and the lowest root mean squared error (RMSE = 8827); and second, predicting a probable end date found to be around the end of December 2020 with a projected number of 378,299 at the end of the outbreak. The obtained results may help the decision-makers to take suitable decisions related to the pandemic mitigation and containment and provide clear understanding of the virus dynamics in Saudi Arabia.

CD34 defines an osteoprogenitor cell population in mouse bone marrow stromal cells.

Bone marrow stromal cells (BMSCs, also known as bone marrow-derived mesenchymal stem cells) and their progenitors have been identified based on retrospective functional criteria. CD markers are employed to define cell populations with distinct functional characteristics. However, defining and prospective isolation of BMSCs and committed progenitors are lacking. Here, we compared the transcriptome profile of CD markers expressed at baseline and during the course of osteoblast and adipocyte differentiation of two well-characterized osteogenic-committed murine BMSCs (mBMSC(Bone)) and adipogenic-committed mBMSCs (mBMSC(Adipo)), respectively. Bioinformatic analysis revealed the presence of a core set of canonical mBMSC CD markers with comparable expression levels in mBMSC(Bone) and mBMSC(Adipo) at baseline and during their differentiation. We identified 11 CD markers that are differentially expressed between mBMSC(Adipo) and mBMSC(Bone). Among these, we identified osteoprogenitor-associated CD markers expressed only in mBMSC(Bone): CD34, CD54, CD73, CD132, CD200, CD227 and adipoprogenitor-associated CD markers expressed only in mBMSC(Adipo): CD53, CD80, CD134, CD141 and CD212. FACS analysis confirmed these results. We selected CD34 for further analysis. CD34 was expressed at baseline of mouse stromal cell line ST2, primary mBMSCs, mBMSC(Bone) and its expression decreased during osteoblast differentiation. FACS-sorted CD34(+) primary mBMSCs exhibited higher expression of 70% osteoblast-associated genes, and formed significantly higher heterotopic bone in vivo when implanted subcutaneously in immune-deficient mice compared with CD34(-) primary mBMSCs. Our results demonstrate that a set of CD markers can distinguish osteoprogenitor versus adipoprogenitor populations of mBMSCs. CD34 is suitable for prospective isolation of mouse bone marrow osteoprogenitors.