QSAR modelling to predict structural features of certain sulfonamide as Urokinase-type Plasminogen Activator inhibitors

The serine hydrolase family includes serine proteases. It is essential for hydrolyzing protein peptide bonds and breaking them. The urokinase-type plasminogen activator (uPA) selectively binds to the uPAR on numerous cell types, including cancer cells. Pericellular proteolysis of cell-bound proteins requires this interaction. High uPA and uPAR levels regularly worsen cancer prognoses. Thus, small chemical active-site inhibitors that block uPA may diminish cancer cell invasion and metastasis. In compliance with Organization for Economic Corporation and Development guidelines, this research performed a complete Quantitative structure activity relationship analysis of sulfonamide compounds as Urokinase-type Plasminogen Activator inhibitors. Py-Descriptors were used for this investigation. PyDescriptor uses PyMOL standards and idioms to calculate 11,145 simple molecular descriptors. This plugin calculates molecular descriptors irrespective of molecular representation properties like atom numbering or labelling, spatial reference frame, translational and rotational invariance, etc. The investigation sought to find essential and hidden structural characteristics that regulate sulfonamide-type drugs’ Urokinase-type Plasminogen Activator Inhibitory action. Twenty-eight sulfonamide chemicals are used in the Quantitative structure activity relationship study to generate statistically robust and highly predictive univariate and multivariate models. All models were thoroughly evaluated and meet several statistical parameter thresholds (e.g., R 2 =0.9259–0.9280, Q 2 Loo =0.8579–0.8558, Q 2 LMO =0.8013–0.7865). The analysis reveal that occurance of ring carbon atoms exactly at 3 A0 from carbon atom, number of negatively charged atoms from sulphur atoms within 5 bonds, presence of hydrogen atom exactly at 3 bonds from donar atoms, presence of carbon atom exactly at 4 A0 from donar atom, presence of acceptor atom exactly at 5 A0 from sulphur atom and sum of partial charges of lipo atoms within 6 bonds from sulphur atom are important pharmacophoric features for Urokinase- type Plasminogen Activator Inhibition binding affinity. Thus, the developed Quantitative structure activity relationship study has an equilibrium of quantitative and qualitative tactics. The results could be useful for future optimizations of sulfonamide analogues

Leveraging nitrogen occurrence in approved drugs to identify structural patterns

Background The process of drug development and discovery is costly and slow. Although an understanding of molecular design principles and biochemical processes has progressed, it is essential to minimize synthesis-testing cycles. An effective approach is to analyze key heteroatoms, including oxygen and nitrogen. Herein, we present an analysis focusing on the utilization of nitrogen atoms in approved drugs. Research design and methods The present work examines the frequency, distribution, prevalence, and diversity of nitrogen atoms in a dataset comprising 2,049 small molecules approved by different regulatory agencies (FDA and others). Various types of nitrogen atoms, such as sp3-, sp2-, sp-hybridized, planar, ring, and non-ring are included in this investigation. Results The results unveil both previously reported and newly discovered patterns of nitrogen atom distribution around the center of mass in the majority of drug molecules. Conclusions This study has highlighted intriguing trends in the role of nitrogen atoms in drug design and development. The majority of drugs contain 1–3 nitrogen atoms within 5Å from the center of mass (COM) of a molecule, with a higher preference for the ring and planar nitrogen atoms. The results offer invaluable guidance for the multiparameter optimization process, thus significantly contributing toward the conversion of lead compounds into potential drug candidates

Screening of synthesized nanoparticle and antineoplastics cytotoxicity against drug resistant breast cancer cells

Breast cancer is regarded as a major global health issue due to its high incidence and mortality rate. They are also becoming harder to treat due to the emergence of multidrug resistance (MDR), rendering anticancer drugs less sensitive than ever. Therapeutic nanoparticles and novel bio-derived drugs can be used as a potential replacement for chemo-drug-resistant breast cancer. This study was performed to investigate the resistance of breast cancer cells against a multitude of drugs, as well as to evaluate whether certain nanoparticles could induce cytotoxicity. Four antineoplastic agents, Cisplatin (CDDP), Paclitaxel (PTX), Alpha-Mangostin (A-MG), and Andrographolide (Andr-G), as well as three nanoparticles, synthesized gold nanoparticles (AuNPs), silver nanoparticles (AgNPs), and graphene oxide (GO), were investigated for cytotoxicity against non-chemo-resistant breast cancer MCF-7, chemo-resistant MCF-7-CR, and MDR MDA-MB-231 cell lines. AuNPs and AgNPs were synthesized via chemical reduction using reducing agents NaBH4 and ascorbic acid, where they were further characterized. Treatment of GO was coupled with UV-B irradiation to determine the influence on cytotoxicity against breast cancer cells. It was found that PTX was the most potent yet easiest to be desensitized among all four drugs, whereas A-MG and Andr-G were less prone to be desensitized in longer duration treatment, with 25 µM of A-MG resulting in about 20% cell viability. Ascorbic acid-reduced AuNPs were found to be spherical with a size of 170 nm, zeta potential of -36 mV, and polydispersity index of about 17%. NaBH4-reduced AgNPs were also characterized to have irregular shapes at around 680 nm in size and a zeta potential of -21 mV. AgNPs and AuNPs were less potent against drug-resistant breast cancer cells. In MCF-7 cells, ascorbic acid-reduced AgNPs and NaBH4-reduced AuNPs caused 50% and 25% cell death using 10 µM, respectively. GO was observed to be toxic to both MCF-7 and MDA-MB-231, with viability observed at 70% on MCF-7 for 100 µg/mL GO. UV-B irradiation influenced cytotoxicity in MCF-7 by increasing potency from 80% to 50% cell viability after 3h of GO incubation and 10 mJ/cm2 exposure. GO was more toxic on MCF-7 and MDA-MB-231 cells, whereas MCF-7-CR was more susceptible to both AgNPs and AuNPs. Further studies on the mechanism of action between nanoparticles, drugs, and cancer cells are necessary. The inclusion of different drug-resistant breast cancer cells as well as normal cells is also necessary to further compound the potential therapeutic importance of the study

Efficacy of Mobile Mindfulness-based Intervention (M-MBI) in reducing stress in emerging adults transitioning out of university – a mixed-method study

Transitioning out of university is a multi-layered experience that can be highly stressful for emerging adults (EAs). Evidence suggests that mindfulness-based interventions (MBIs) may improve aspects of psychological well-being. This study aimed to investigate the effectiveness of mobile-MBI (m-MBI) in alleviating stress and improving mental well-being (i.e., worry, mindfulness, and self-compassion) in EAs. The study employed a mixed-methods design, with a 9-week randomised controlled trial (RCT; i.e., 5-week intervention and 4-week follow-up), followed by qualitative interviews. Ninety-two final-year university students (91.5% female, mean age 22.55), the majority with no prior mindfulness experience (77.2%), were randomly assigned to either a 5-week m-MBI group (n=47) or a waitlist group (n=45). Half of the participants randomized to the study did not complete it. Daily mindfulness practices were required, and adherence was tracked within the application. Intention-to-treat (ITT) and per-protocol (PP) analyses were performed. Findings from both analyses suggested that relative to waitlist control, m-MBI exerted a significantly small-to-moderate positive impact on worry (dITT=.40;dPP=.49), even after Bonferroni correction at post-intervention and 1-month follow-up. Perceived stress, self-compassion, and mindfulness were not significantly improved across the three time points after adjusting for multiple comparisons. More participants in the m-MBI group, in comparison with the waitlist group, showed significant and reliable improvements in worry and mindfulness scores throughout the study. Mediation analyses showed that mindfulness and self-compassion together contributed as mediators to perceived stress and that the amount of mindfulness practices was positively associated with the outcomes assessed. Qualitative findings supplemented the benefits found in self-reported measures and further illustrated adherence issues encountered by the participants. These findings suggested the feasibility of a 5-week m-MBI in mental health enhancement, especially worry for EAs in transition. Findings also highlight the importance of including components cultivating mindfulness and self-compassion in m-MBI. Nevertheless, researchers should implement methodologically more rigorous RCTs and examine withdrawals in future m-MBI studies

Experience first: investigating smart wearable technology acceptance among elderly citizens with Smart Wearables Technology Acceptance Model (SWTAM)

As the population ages, there is a greater demand for health care services and support, especially through smart wearable technology to monitor the elderly’s health, at the same time resolving the psychological, psychosocial, and mobility inadequacies. This study looked at the aspects that may have helped older people embrace smart wearable technologies to expedite and promote the use of smart wearable technology. After consulting the earlier related studies, a structural equation modeling-based model of smart wearables acceptance for elderly citizens will be developed. This model will include an extra construct—individual context—by including elements such as anxiety and self-efficacy. This study mainly focused on developing countries, which as Malaysia in this case, as the available studies on the acceptance of smart wearable technology are still lacking in our country. The population of this study is mainly older adults with basic knowledge of Smart Wearable Technology or users of the technology. In the data collection phase, 300 datasets were collected, and 266 examples were used for model validation after data filtering in the data processing phase. The validity and reliability of the constructs in the model were assessed through the method of partial least squares. In the assumption testing, normality and common method variance were applied. For further assessment, convergent validity, discriminant validity, internal consistency reliability, and indicator reliability (outer loadings) were all used to evaluate the measuring model. Difficulties with collinearity, path coefficients, confidence intervals, and effect size (f2) were also evaluated for the structural model’s validation. The findings of this study identified a few factors that significantly impact older people's desire to employ smart wearable technology in both positive and negative ways, where external factors seem to be more having a significant effect on perceived usefulness when compared with perceived ease of use. Furthermore, perceived values are better factors to be explored in influencing the decisions of the elderly

Knowledge, attitude and practice towards COVID-19 post-vaccination in Malaysian and Arabian population

COVID-19 is an infectious disease caused by Coronavirus 2 of the severe acute respiratory syndrome (SARS-CoV-2). As of January 2020, the World Health Organization (WHO) declared a public health emergency of international (PHEIC) concern regarding COVID-19. Since then, there have been continuous attempts in battling the virus including, complete lockdowns, social distancing, and complying with necessary preventive measures. Scholars have reported that the public's knowledge, attitude, and practice (KAP) of COVID-19 are likely to influence compliant preventive measures towards the virus. Evidence suggests that public KAPs are critical in combating pandemics. Now that more than 80% of both populations have been vaccinated, it is relevant to study the KAPs post-vaccination and post-lockdown phase to determine the public’s compliance with practice towards the virus. The objective of this study is to determine the association between socio-demographic characteristic and KAPs towards Coronavirus Disease 2019 (COVID-19) virus, vaccines, and infection status of a cohort in Malaysia and Saudi Arabia. A binational, cross-sectional study consisting of 530 participants was conducted between December 2021 and May 2022. The study was aimed to demonstrate KAPs on a binational level to observe KAPs in two populations towards the virus and vaccine post-lockdown phase and to analyse the association of their socio-demographic characteristics with their KAPs. Of the 530 participants, 213 were reported to have previously encountered a COVID-19 infection and 317 have not. This study was conducted online, and the questionnaire was distributed in a convenience sampling strategy via social media platforms (WhatsApp, Twitter, Facebook, and other social media platforms) and responses were collected through online Google forms. Only those fully vaccinated and above 18 years of age were eligible for participation in the study. The data was extracted in an excel sheet form and analysed in IBM SPSS 27. To analyse the results of the study, statistical analysis of descriptive statistics, Chi-square analysis, and binary logistic regressions were performed. Descriptive statistics were used to display the sociodemographic characteristics of participants. Whereas Chi-square analysis was performed at 95% confidence interval for each population to analyse the association between KAPs and demographic characteries and their KAPs according to their infection status. The findings of the study showed that participants in Saudi Arabia had better knowledge levels (p<0.05) than those in Malaysia. Female residents in both populations also displayed better knowledge levels than males. In Saudi Arabia, participants with lower degrees were found to have better vaccine knowledge (p<0.05) which opposed other findings in the study that revealed better KAPs for higher degree holders. Post-infection attitude levels of individuals did not reveal much of a difference between infected and non-infected. However, the practices and knowledge levels were drastically different – infected individuals exhibited better practices and knowledge than non-infected. Our study revealed alarming levels of knowledge for non-infected participants in Malaysia (GL:28.5%, PL:71.5%) and Saudi Arabia (GL39.2%, PL:60.8%). This raises a concern of gaps in knowledge levels including preventive measures and viral transmission. It is anticipated that the reported poor levels may have influenced their attitudes and practices, particularly in Malaysia, poor attitude and practices levels were reported. The identification of such gaps and specific groups in the society associated with them could provide useful information to health policymakers about the KAPs post-vaccination and post-lockdown that could aid in future pandemic educational and awareness programs

The Sulu zone: a maritime cultural complex

A Maritime Cultural Complex revisits enduring links for the conceptualisation of the Sulu Zone as a present-day cultural complex. Honouring Ric Trimillos, a leading ethnomusicologist researching and supporting the study of music and dance in the southern Philippines since 1960, this volume explores heritage, language, social, and political facets in the Southern Philippines, the east Malaysian state of Sabah, east Kalimantan, Central and North Sulawesi in Indonesia, and the surrounding Sulu and Celebes seas. This project ultimately seeks to contribute to society’s understanding of the history, contemporary cultures, and rich traditions of communities within the Sulu Zone

Investigation of the association and carcinogenesis of Fusobacterium nucleatum, DNMT3a, and the hypermethylation of SEPT9 in colorectal cancer (CRC)

The FDA has recently approved the screening of colorectal cancer (CRC) using methylated SEPT9 (mSEPT9) as a highly sensitive biomarker. Meanwhile, Fusobacterium nucleatum (FN) has been implicated in CRC progression. However, the association between FN and SEPT9 in CRC remains unexplored, as does the role of DNMT3a, a DNA methyltransferase known to methylate SEPT9 in liver cells but with an unknown function towards SEPT9 in CRC. To address these gaps, this study primarily aims to demonstrate the clinical significance of FN and SEPT9 methylation in CRC patients, investigate the involvement of DNMT3a in regulating SEPT9 methylation in CRC, and define the relationship between FN, DNMT3a expression, and SEPT9 methylation in CRC. Quantitative polymerase chain reaction (qPCR) analysis of the DNA from FFPE tissue collected from CRC patients reveals that FN is prevalent in CRC patients (87.95 %) and more abundant in cancer tissue than in normal tissue (p < 0.05). Although no significant associations were found between FN and clinicopathological features of CRC patients, a high bacterial load of FN was significantly associated with larger tumour size and the presence of KRAS mutations (p < 0.05). Moreover, SEPT9 is more prevalent in CRC patients (90.36 %). Elevated levels of mSEPT9 were detected in CRC tissue, particularly in patients aged 50 years and above, and were associated with larger tumour size (p < 0.05). Importantly, high levels of mSEPT9 were correlated with elevated levels of FN in CRC tissue, regardless of the cancer status of the tissue. For the in vitro study, we see a reduction in SEPT9 hypermethylation due to the silencing of DNMT3a in HCT116 colon cancer cells. However, the resulting downregulation of SEPT9 protein was unexpected. This finding revealed the complex and multifaceted roles of DNMT3a in the regulation of SEPT9 at the methylation, gene expression, and protein expression levels. On the other hand, the FN infection assay demonstrated that FN induces greater changes in CRC cell line (HCT116) compared to normal colon cell line (CCD-112). Interestingly, we see a downregulation of DNMT3a and SEPT9 protein expression in response to FN infection despite an upregulation of the mRNA expression of DNMT3a and SEPT9 in HCT116 and CCD-112 cells. No observable trends in SEPT9 hypermethylation were observed in the FN infected cells. In summary, this study provides valuable insights into the association between FN and SEPT9 methylation in CRC. It sheds light on the complex involvement of DNMT3a in regulating SEPT9 methylation in CRC cells. These findings contribute to a better understanding of CRC and may pave the way for the development of novel diagnostic and therapeutic approaches targeting FN, SEPT9, and DNMT3a in the management of CRC

miR-21 Expression and its Correlation with Demographics, Subtypes, and Tumour Suppressor Genes; PTEN and PDCD4 in Breast Cancer Tissues in Malaysia

Objectives: Despite extensive research in breast cancer (BC) genomics, most studies are from Western countries, which do not reflect the multi-ethnic make-up of Malaysia. Hence, microribonucleic acid-21 (miRNA-21), which is known to be an oncogenic stimulator of BC will be investigated by comparing its expression between breast tumour tissues and normal adjacent tissues excised from 67 BC patients, ethnic groups, age groups distribution, neo-adjuvant chemotherapy (NAC) treated and untreated patients, as well as BC subtypes. Methods: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to measure the distribution of miR-21 expression in the paired BC tissues. The expression of the tumour suppressors; PTEN and PDCD4 was also investigated via RT-qPCR and Western Blot for its gene and protein expressions. Results: The results only showed the significance of miR-21 and PTEN expression between the normal adjacent tissues and BC tissues (p<0.05). Additionally, there was a lack of correlation between gene expression of miR-21 against PTEN and PDCD4. Protein expression analysis did not show a significant difference in tumour suppressor proteins; PTEN and PDCD4 expression in both tissue types. Conclusion: miR-21 has a notable presence in BC and is a suitable biomarker to be evaluated further in patients of all ethnicities and age groups

Herbs Used for the Management of Hypertension: A Systematic Review

Background: Hypertension is characterized by persistent high blood pressure and has emerged as a critical risk factor for severe cardiovascular diseases. Although several drugs have been designated to reduce blood pressure, these drugs can potentially cause side effects for patients. Therefore, medicinal plants are used to complement conventional drugs to treat various ailments. Methods: This study reviews the anti-hypertensive potential of herbs and plants and their mechanism of action in reducing blood pressure at their evaluated effective doses. Databases such as PubMed, Scopus, Science Direct, and Google Scholar were used to search articles from January 2016 to Sept 2022. The key search terms included “hypertension”, “lowers blood pressure”, “antihypertensive”, and “plants”. These generated 807 documents and using the PRISMA guidelines, thirty plants were identified for this review. Research studies with similar plant parts extracted from similar solvents, more than one dose, and animal models with a positive control were considered in this review. Studies that did not show significant blood pressure reduction were excluded. Results: Based on this criterion, the mechanism of actions of these plants was thematically grouped into three categories, namely 1) antioxidant, 2) angiotensin-converting enzyme (ACE) inhibition, and 3) calcium influx in vascular smooth muscle. The effective doses, plant parts used, and traditional medicine usage are presented in this review. Conclusion: Further research is highly recommended to identify the active compounds and to potentially develop them into anti-hypertensive drugs as well as to establish the safe doses and standardization of these plant extracts. This review is partially funded by grants from the Ministry of Higher Education