Advancements in Molecular Medicine and Tailor-Made Therapeutics

The marvelous success in the field of molecular therapeutics is being witnessed by science over the past few decades. From single cell RNA sequencing to circulating cell free DNA detection in the blood, astonishing accomplishments have been achieved. These advancements, however, are still confronting the challenges of the old times, such as non-specificity, inter-individual variability, and off-target effects. Molecular medicine as a science has provided a platform to address these problems, by tailoring according to the molecular and genetic profile of the individuals to increase the specificity of the treatment, to reduce variability, and to minimize adverse side effects.

Regional Cerebral Oximetry as an Indicator of Acute Brain Injury in Adults Undergoing Veno-Arterial Extracorporeal Membrane Oxygenation–A Prospective Pilot Study

Background: Regional cerebral oxygen saturation (rScO2) measured by near-infrared spectroscopy (NIRS) can be used to monitor brain oxygenation in extracorporeal membrane oxygenation (ECMO). ECMO patients that develop acute brain injuries (ABIs) are observed to have worse outcomes. We evaluated the association between rScO2 and ABI in venoarterial (VA) ECMO patients.Methods: We retrospectively reviewed prospectively-collected NIRS data from patients undergoing VA ECMO from April 2016 to October 2016. Baseline demographics, ECMO and clinical characteristics, cerebral oximetry data, neuroradiographic images, and functional outcomes were reviewed for each patient. rScO2 desaturations were defined as a >25% decline from baseline or an absolute value < 40% and quantified by frequency, duration, and area under the curve per hour of NIRS monitoring (AUC rate, rScO2*min/h). The primary outcome was ABI, defined as abnormalities noted on brain computerized tomography (CT) or magnetic resonance imaging (MRI) obtained during or after ECMO therapy.Results: Eighteen of Twenty patients who underwent NIRS monitoring while on VA ECMO were included in analysis. Eleven patients (61%) experienced rScO2 desaturations. Patients with desaturations were more frequently female (73 vs. 14%, p = 0.05), had acute liver dysfunction (64 vs. 14%, p = 0.05), and higher peak total bilirubin (5.2 mg/dL vs. 1.4 mg/dL, p = 0.02). Six (33%) patients exhibited ABI, and had lower pre-ECMO Glasgow Coma Scale (GCS) scores (5 vs. 10, p = 0.03) and higher peak total bilirubin levels (7.3 vs. 1.4, p = 0.009). All ABI patients experienced rScO2 desaturation while 42% of patients without ABI experienced desaturation (p = 0.04). ABI patients had higher AUC rates than non-ABI patients (right hemisphere: 5.7 vs. 0, p = 0.01, left hemisphere: 119 vs. 0, p = 0.06), more desaturation events (13 vs. 0, p = 0.05), longer desaturation duration (2:33 vs. 0, p = 0.002), and more severe desaturation events with rScO2 < 40 (9 vs. 0, p = 0.05). Patients with ABI had lower GCS scores (post-ECMO initiation) before care withdrawal or discharge than those without ABI (10 vs. 15, p = 0.02).Conclusions: The presence and burden of cerebral desaturations noted on NIRS cerebral oximetry are associated with secondary neurologic injury in adults undergoing VA ECMO

Chiral AuI- and AuIII-isothiourea complexes : synthesis, characterization and application

ADS thanks the Royal Society for a Wolfson Research Merit Award. We also thank the EPSRC UK National Mass Spectrometry Facility at Swansea University. SPN thanks King Abdullah University of Science and Technology (Award No. SR-2015-CCF-1974-03) and King Saud University for support.During an investigation into the potential union of Lewis basic isothiourea organocatalysis and gold catalysis, the formation of gold‐isothiourea complexes was observed. These novel gold complexes were formed in high yield and were found to be air‐ and moisture stable. A series of neutral and cationic chiral gold(I) and gold(III) complexes bearing enantiopure isothiourea ligands was therefore synthesized and fully characterized. The steric and electronic properties of the isothiourea ligands was assessed through calculation of their percent buried volume and the synthesis and analysis of novel iridium(I)‐isothiourea carbonyl complexes. The novel gold(I)‐ and gold(III)‐isothiourea complexes have been applied in preliminary catalytic and biological studies, and display promising preliminary levels of catalytic activity and potency towards cancerous cell lines and clinically‐relevant enzymes.PostprintPeer reviewe

ANTI-NEUROINFLAMMATORY AND NEUROPROTECTIVE EFFICACY OF N-(2-HYDROXY PHENYL) ACETAMIDE IN RESPONSE TO LPS-STIMULATED PRIMARY CELL CULTURE

<p><strong>Abstract</strong></p><p>The irreversible and continuing loss of neurons is the fundamental cause of neurodegenerative diseases (ND). The most common age-associated neurodegenerative condition is Alzheimer's disease (AD), and its etiology appears to have a chronic inflammatory component. The stimulation, proliferation, phenotypic and functional modifications in glia can be brought on by a variety of stresses in the central nervous system (CNS), and these modifications are modulated by anti-neuroinflammatory substances. This study evaluated the anti-neuroinflammatory and pro-neurogenic effects of N-(2-hydroxy phenyl) acetamide (NA-2) in primary neuronal and glial co-cultures using in vitro model of neuroinflammation associated with neurodegenerative disorders. Neurons and glial cells were co-cultured from the pup's brain of wistar rats. In primary neuronal/glial co-culture, the MTT assay was performed to assess the pro-neurogenic and anti-neuroinflammatory properties of test compound. The proportion of viable cells were increased at 50μM dose of NA-2 as compared to the untreated control, which shows its proneurogenic potential at low dose. Lipopolysaccharide (LPS) was used to induce the neuroinflammatory response. It was observed that treatment group at 50μM of NA-2 followed by LPS stimulation demonstrated anti-neuroinflammatory potential when compared to the LPS treated cells. Furthermore, it reduces oxidative stress induced by H2O2 and significantly inhibits the generation of ROS. These results demonstrated that NA-2 possesses anti-neuroinflammatory and neuroprotective properties in in-vitro model of neuroinflammation and could potentially be an important neuroimmunomodulatory compound in the management of neurodegenerative disorders.</p&gt

Parental Genetics Communicate with Intrauterine Environment to Reprogram Newborn Telomeres and Immunity

Telomeres, markers for cellular senescence, have been found substantially influenced by parental inheritance. It is well known that genomic stability is preserved by the DNA repair mechanism through telomerase. This study aimed to determine the association between parents–newborn telomere length (TL) and telomerase gene (TERT), highlighting DNA repair combined with TL/TERT polymorphism and immunosenescence of the triad. The mother–father–newborn triad blood samples (n = 312) were collected from Ziauddin Hospitals, Pakistan, between September 2021 and June 2022. The telomere length (T/S ratio) was quantified by qPCR, polymorphism was identified by Sanger sequencing, and immunosenescence by flow cytometry. The linear regression was applied to TL and gene association. The newborns had longest TL (2.51 ± 2.87) and strong positive association (R = 0.25, p ≤ 0.0001) (transgenerational health effects) with mothers’ TL (1.6 ± 2.00). Maternal demographics—socioeconomic status, education, and occupation—showed significant effects on TL of newborns (p < 0.015, 0.034, 0.04, respectively). The TERT risk genotype CC (rs2736100) was predominant in the triad (0.6, 0.5, 0.65, respectively) with a strong positive association with newborn TL (β = 2.91, <0.0011). Further analysis highlighted the expression of KLRG 1+ in T-cells with shorter TL but less frequent among newborns. The study concludes that TERT, parental TL, antenatal maternal health, and immunity have a significantly positive effect on the repair of newborn TL

Cathepsin-K inhibition enhances anti-cancerous activity within oral squamous cell carcinoma cells:Uncloaking the potency of new K21 formulation

BACKGROUND: The ability of cancer cells to be invasive and metastasize depend on several factors, of which the action of protease activity takes center stage in disease progression.PURPOSE/OBJECTIVE: To analyze function of new K21 molecule in the invasive process of oral squamous cell carcinoma (OSCC) cell line.MATERIALS &amp; METHODS: The Fusobacterium (ATCC 23726) streaks were made, and pellets were resuspended in Cal27 (ATCC CRL-2095) OSCC cell line spheroid cell microplate. Cells were seeded and Lysotracker staining performed for CathepsinK red channel. Cell and morphology were evaluated using Transmission Electron microscopy. Thiobarbituric acid assay was performed. OSCC was analyzed for Mic60. Raman spectra were collected from the cancer cell line. L929 dermal fibroblast cells were used for Scratch Assay. ELISA muti arrays were used for cytokines and matrix molecules. Internalization ability of fibroblast cells were also analyzed. Structure of K21 as a surfactant molecule with best docked poses were presented.RESULTS: Decrease in lysosomal staining was observed after 15 and 30 min of 0.1% treatment. Tumor clusters were associated with cell membrane destruction in K21 primed cells. There was functional silencing of Mic60 via K21, especially with 1% concentration with reduced cell migration and invasiveness. Raman intensity differences were seen at 700 cm-1, 1200 cm-1 and 1600 cm-1 regions. EVs were detected within presence of fibroblast cells amongst K21 groups. Wound area and wound closure showed the progress of wound healing.CONCLUSION: Over expression of CatK can be reduced by a newly developed targeted K21 based drug delivery system leading to reduced migration and adhesion of oral squamous cell carcinoma cells. The K21 drug formulation can have great potential for cancer therapies due to targeting and cytotoxicity effects.</p

Antipsychotics drug aripiprazole as a lead against breast cancer cell line (MCF-7) in vitro.

Breast cancer is the second leading cause of death among women globally. The existing treatment options for breast cancer are largely associated with severe toxicities, and lower efficacies. Therefore, there is an urgent need for the development of non-toxic effective drugs against breast cancer. For this purpose, drug repositioning strategy was used to evaluate the anti-cancer potential of a library of heterocyclic drugs. The major advantage of drug repurposing is that the pharmacokinetic, pharmacodynamic, and toxicity profiles of drugs are well documented. In the current study, we screened 97 drugs of different chemical classes, and among them aripiprazole, an antipsychotic drug, was found to be sufficiently active against breast cancer cell line MCF-7. Aripiprazole showed a cytotoxicity (IC50 = 12.1 ± 0.40 μM) to MCF-7 cells, comparable to the standard anticancer drug doxorubicin (IC50 = 1.25 ± 0.34 μM). Aripiprazole was also found to be active against other cancer cell lines, including MDA-MB-231 (IC50 = 19.83 ± 0.27 μM), AU565 (IC50 = 18.02 ± 0.44 μM), and BT-474 (IC50 = 36.42 ± 0.12 μM). Aripiprazole significantly inhibited the cell cycle progression at subG0G1 phase, and enhanced apoptosis in MCF-7 breast cancer cells. The drug was also able to significantly increase the nuclear condensation, and modulated the expression of certain genes involved in breast cancer, such as caspases 3, and 9, BAK-1, C-MYC, BCL2L1, BCL-10, and BCL-2. Further studies are needed to explore the effect of aripiprazole on intrinsic and extrinsic pathways of apoptosis in cancer cells

Investigating the biological activity of imidazolium aurate salts

We report herein the biological activities of several imidazolium aurate(I) salts. The cytotoxicity on three cell-lines (i. e. Hela, H460 and 3T3), enzyme inhibition on a panel of five enzymes (i. e. prolyl endopeptidase, butyrylcholinesterase, tyrosinase, dipeptidyl peptidase and carbonic anhydrase), iron chelation and in vitro Leishmanicidal assay for promastigotes are described. A comparison with other data found in the literature using similar standards to our control experiment is also discussed. Finally, all these data lead us to establish some structure-activity correlations and to determine the potential importance of the gold moiety in these salts