Extrapancreatic actions of incretin-based therapies on bone in diabetes mellitus

Diabetes mellitus is correlated with modifications in bone microarchitectural and mechanical strength, leading to increased bone fragility. The incretin hormones, with a classical effect to increase insulin secretion following food ingestion, are now postulated to have important direct effects on bone. As such, glucose-dependent insulinotropic polypeptide (GIP) has dual actions on bone cells; enhancing bone�forming activity of osteoblasts and suppressing bone resorption by osteoclasts. The sister incretin of GIP, glucagon-like peptide-1 (GLP-1), is also suspected to directly influence bone health in a beneficial manner, although mechanism are less clear at present. The physiological actions of incretins are attenuated by dipeptidyl peptidase (DPP-4) activity and it is speculated that introduction of DPP-4 inhibitor may also positively affect quality of the skeleton. As such, this thesis evaluates the potential beneficial effects of a DPP-4 resistant GIP analogue, namely [D-Ala2 ]GIP, on osteoblastic-derived, SaOS-2 cells, and also preliminary in vivo studies on the impact of genetic deficiencies of GIPRs and GLP-1Rs on bone mineral density and content. Further studies characterised the beneficial effects of incretin-based therapies on metabolic control, bone microstructure and bone mechanical integrity in animal models of pharmacologically-, genetically- and environmentally-induced diabetes. GIP and related stable analogue increased bone-forming biomarkers in SaOS-2 cells and importantly, [D-Ala2 ]GIP was shown to be more potent than native GIP. Knockout mouse studies revealed that both GIPR and GLP-1R signaling are important for optimum bone mass. All diabetic mouse models displayed reduced bone mass, altered bone micromorphology and impairment of bone mechanical strength, similar to the human situation, confirming their appropriateness. The incretin-based therapeutics, [D-Ala2 ]GIP and Liraglutide, in streptozotocin-diabetic significantly increased bone matrix properties, indicating recovery of bone strength at the tissue level. The beneficial effects of administration of [D-Ala2 ]GIP�oxyntomodulin on bone health in db/db mice were more prominent as the Oxm analogue did not only improve bone strength at tissue level, but also at whole-bone level. These modifications were independent of metabolic status. Twice-daily Exendin-4 therapy improved glycaemic control and increased work required to resist bone fracture in high-fat fed mice. It was also established that Sitagliptin had neutral effects on bone microstructure and mechanical strength in high-fat mice. In summary, these data demonstrate the negative impact of diabetes mellitus on normal skeleton development and bone quality. Moreover, this thesis highlights the growing potential of incretin-based therapies for ameliorating bone defects and improving the increased fragility fracture risk associated with diabete

A Study on The Potential Pathways For Existing Drugs Against COVID-19

Coronavirus infectious disease 2019 (COVID-19) is a global pandemic declared by the World Health Organization (WHO) in March 2020. This emerging infectious disease is rapidly transmitted and does not only pose a global threat to public health but also badly affects the economy. At present, there is no effective drug to treat COVID-19, leading to a significant challenge upon current global attempts at restraining the outbreak. There are several currently available drugs, also considered as the repurposed drugs are in use for treatment against COVID-19. However, these drugs are not as efficient as it is hoped. Therefore, this study is conducted to further explore into other established antivirus that could function better for COVID-19 treatment. In addition, the pathways that associated with the drugs are identified and potential targeted proteins for the repurposed drugs are also pointed out. The articles for review were selected from several search engine databases, which are ScienceDirect, SpringerLink, PubMed, and Scopus including the keywords COVID-19, SARS, MERS, potential pathways for antiviral drugs as well as repurposed drugs, with more than 50 primary research articles identified. Findings and analysis have discovered potential repurposed drugs that could be used for COVID-19, namely bisoxatin, nitazoxanide and teicoplanin which could be involved in corona-related pathways. Meanwhile, the associated pathways are JAK-STAT, Neprilysin (NEP) and cGAS-STING that counteract excessive immune response and act as a medium for the drugs to access antiviral activities. The repurposed drugs target protein identification is also a critical significance and it was found that S-protein, TMPRSS2, RdRp and RDB which are the signalling protein can be interrupted by the repurposed drugs, presenting a promising antivirus against SARS-CoV-2.  It is concluded that this study will provide information to assist logical design of the repurposed drug for its effectiveness as antivirus against COVID-19

Qualitative Phytochemical Analysis and Antibacterial Potential of Chromolena Odorata Leaves as affected by Soxhlet and Maceration Extraction

Chromolaena odorata is locally known as “Pokok Kapal Terbangâ€. This species is a perennial weed of plantation crops and cleared lands and it comes from the family of Asteraceae (Compositae) and can be found abundantly in Malaysia. The fresh leaves and extract of this plant commonly related to herbal treatment in some developing countries for burns, soft tissue wounds, and skin infections. However, it has not been thoroughly investigated and their phytochemical and cytotoxicity potential virtually unknown. The objective of this study is to investigate the antibacterial potential of C. odorata leaves extract and its phytochemicals content. The Soxhlet and maceration method of extraction were carried out and then were tested for its phytochemicals content namely saponins, terpenoids, tannin and flavonoids. The antibacterial activity of extracted samples was tested against gram-positive Staphylococcus epidermidis and gram-negative Escherichia coli by using disc diffusion method. The results showed that the percentage yield of leaves extract using Soxhlet method for 12 hours was 21.60 %, which is higher than maceration method (with 18.10% of yield for 120 hours extraction). Qualitative phytochemicals analyses revealed that both Soxhlet and maceration- extracted of C. odorata leaves contain tannins, flavonoids, saponins and terpenoids. All the extract showed a good antibacterial properties against both S. epidermidis and E.coli strain with inhibition zone ranging from 8.33 mm to 11.00 mm and 6.00 mm-10.50 mm, respectively. The extract was then further applied onto a cream and the anti-bacterial activity against S.epidermidis was recorded in which the largest inhibition zone of 9.50 mm was obtained. Whereas anti-bacterial activity against E. coli was found only in Soxhlet extracted sample (12 hours treatment time) with 12.00 mm diameter of inhibition zone. This study showed  that C. odorata leaves extract has a great potential to be developed as antibacterial agent which can be incorporated with a cream for medical and pharmaceutical use

A comparative study on characteristic and Antimicrobial activity of cinnamon (c. Zeylanicum) oil small-sized emulsion by phase Inversion composition and phase inversion Temperature methods

Cinnamomum zeylanicum (C. zeylanicum) is species of cinnamon, which a native plant to Sri Lanka, India and Madagascar that consist of a variety of biologically active compounds that makes C. zeylanicum as an antimicrobial agent against both Gramnegative and Gram-positive bacteria. The ability of C. zeylanicum to act as antimicrobial agent could make it as a natural preservative in food products. However, the cinnamon oil that extracted from C. zeylanicum is in a lipophilic compound and hard to be applied directly to the food products as preservatives. These problems may be overcome by formulating essential oils into small-sized emulsions to increase solubility and stability of droplets. This study will help to produce small-sized emulsions from cinnamon oil as natural preservative in food products by using phase inversion composition (PIC) and phase inversion temperature (PIT) methods. Different formulation ratios between cinnamon essential oil to grape seed carrier oil were used. The antibacterial activity of small-sized emulsions was evaluated using minimum inhibitory concentration (MIC) and minimum inhibitory zone (MIZ) assays against Bacillus cereus (B. cereus), Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Small-sized emulsions produced by PIT are smaller than small-sized emulsions by PIC with 2.84 μm average droplet size. All sample mixtures of cinnamon oil with grape seed oil were found to be more acidic in the range of 4.23 to 4.78. Turbidity of small-sized emulsions produced by PIT method have a lower absorbance value than small-sized emulsions produced by PIC which could promote a better stability of emulsions. The antibacterial study found that all sample mixture small-sized emulsions of cinnamon oil able to inhibit B. cereus, E. coli and S. aureus at minimum concentration 12.5%, 6.25% and 12.5% respectively. Development of inhibition zone against B. cereus, E. coli and S. aureus were found with 0.70 cm, 0.95 cm and 0.80 cm respectively. Therefore, application of high concentration of surfactant and high temperature does give impact to the size and uniformity of emulsions and its ability in inhibit bacteria. The small-sized emulsions produced by PIC and PIT methods of cinnamon oil with combination grape seed oil is proven to be an alternative treatment with antibacterial activity and also can act as an antibacterial agent in preservation of foods