Automated Alternative Compression/Traction of Lower Extremities AACT as a Musculoskeletal Countermeasure to Mitigate Bone Loss and Muscle Atrophy in Microgravity
Space Medicine and relevant sciences are still considered a new era; the first humankind steps toward the space took place since less than 60 years. It has been noticed the adverse effects of microgravity on the human body in different aspects, our concern here is the musculoskeletal aspect. On the ground we didn’t notice how we can stand up, or how our muscles and bones of the lower limbs can keep us standing up right. This is by a complicated process including the bones, the equilibrium, and the anti-gravitational muscles of the lower limbs which occurred without thinking about it. The force of Earth gravity against our bones of the lower limbs makes them harder and makes the muscles stronger, because they are interfacing the earth gravitational force every moment we are standing up, as per Newton’s third law (for every action in nature there is an equal and opposite reaction), such forces are unavailable in space and its effect being obvious on arrival to earth after long stay space flights, so being unable to keep standing upright easily on their arrival. On return to earth the routine medical examinations revealed loss of astronaut muscle mass and bone density particularly of their lower extremities because they did not use them in space for a long time. Currently, astronauts on board of ISS (International Space Station) they accomplish daily tasks including resistive exercises ARED “Advanced Resistive Exercise Device” in form of treadmill, ergometer, and weightlifting machine, to decrease the loss of bone density and muscle mass of their lower limbs. Despite their discipline to those exercises they still lose 1-2% of the muscle mass and bone density that give importance to add some protective measures to keep their muscles and bones healthy. Through this article, the idea is to make a device such AACT (Automated Alternative Compression/Traction) to be applied daily to the astronauts lower limbs as part of their daily exercise during space flight to give push/traction forces to astronauts lower limbs to prevent or at least decrease such loss, by AACT we are mimicking the gravitational force of earth on astounds lower limbs during long space flights to let them be healthy till they come back.
Eradicating Cystic Fibrosis Biofilms by a Novel Non-Toxic, Multi-Pathway Salicylate Therapy
1.1. Cystic Fibrosis Biofilms Biofilms are bacterial aggregates in a matrix of polysaccharides, proteins and nucleic acids (Donlan, 2002). They account for 80% of all chronic infections and cause over 500,000 deaths annually. Cystic fibrosis (CF) is a genetic disorder characterized by mucus accumulation in the respiratory tracts (Morrison et al., 2020). This impairs mucociliary clearance, allowing chronic colonization by bacterial biofilms, leading to fatal respiratory failure, lung scarring, and necrosis of pulmonary epithelial tissues (Martin et al., 2021). 1.2. Obstacles in Current Treatments Three major therapies are used against CF biofilms: (1) aminoglycoside antibiotics like tobramycin, (2)non-aminoglycoside antibiotics such as ciprofloxacin and vancomycin, and (3) non-antibiotic therapies including flushing, chlorination, and ultraviolet disinfection. These have two major flaws. First, they are cytotoxic; 30% of patients experience acute kidney injury after three days of intravenous aminoglycoside therapy (Joyce et al., 2017). Furthermore, non-aminoglycoside therapies can cause phospholipid buildup in lysosomes of proximal tubule epithelial cells, accounting for 10-20% of acute renal failure cases. Second, antibiotic resistance due to horizontal gene transfer and mutations has significantly reduced treatment effectiveness. Therefore, cystic fibrosis biofilms remain a critical threat with few effective treatments. 1.3. Salicylate Derivatives This project tackled this issue using an innovative non-antibiotic approach with salicylate derivatives. Salicylates, a class of benzoic acids—benzene-based carboxylic acids (Figure 1)—used in painkillers and blood thinners, were investigated for their antibiofilm potential through a 3-step process: 1. Literature review: Identified three key biofilm therapeutic targets: quorum sensing, bacterial adhesion, and cell motility. Disrupting these pathways would result in biofilm eradication. 2. Molecule Identification: Recognized key molecules in each pathway: LasR, adhesins, and flagellin. Inhibiting these molecules would disrupt the pathways. 3. Screening: Found that salicylates could inhibit the identified molecules, though they had never been tested against cystic fibrosis biofilms.
Natural resources utilization for the in-house production of fluorescence lipid nanoparticles
Nanotechnology, a transformative force, has steadily gained traction across multiple scientific disciplines, including physics, chemistry, engineering, and biology. It offers unprecedented capabilities, especially in the realm of nanoscale particles, ushering in new paradigms in various applications. One of the most revolutionary applications of nanotechnology is in the pharmaceutical sector. Here, nanoparticles have transformed drug and vaccine delivery systems, offering both efficacy and precision. Among these nanoparticles, lipid nanoparticles (LNPs) have stood out, especially for their role in delivering nucleic acid-based drugs and vaccines. These LNPs are intricate assemblies composed of lipids and nucleic acid complexes, offering an amalgamation of stability and deliverability. Such properties have rendered LNPs as invaluable tools in enhancing therapeutic efficacy while minimizing off-target side effects. The myriad of nanoparticles available includes the likes of silver, gold, and lipid nanoparticles. However, the emphasis of this research lies with lipid nanoparticles, given their widespread success in the pharmaceutical arena. LNPs have showcased their potential in delivering drugs with low therapeutic indices, emphasizing their capability to act as versatile platforms for novel drug development. Recent advances have further expanded the horizons of LNPs, paving the way for novel antisense oligonucleotides, innovative vaccines, and complex lipid nanoparticle formations. Characterizing these nanoparticles is paramount, not only for the development of novel drugs but also to comprehend their in vivo behavior. Their multifaceted nature, stemming from their unique excipients, core-bilayer design, and varying sizes, makes their characterization a critical step in the research and development pipeline.
In silico Screening of Forty Antiviral Phytochemicals as Inhibitors to the Envelope Protein of Dengue Virus Serotype 2 (DENV-2)
Infections by the Dengue virus (DENV) cause a disease amonghumansreferred to as Dengue fever, which causes thousands of fatalities globally. There is no existing treatment as of yet that successfully targets DENV. Among the factors thatdeterminetheentry of the virus and severity of the disease is the envelope(E) protein of DENV. This study aimed to examine forty antiviral phytochemicals enumeratedinpaststudiesaspossibleinhibitorstotheEprotein of DENV to provide candidates to aid in drug discovery against DENV. The phytochemicals were screened for their likelihood of inhibition of the E protein using AutoDock Suite and LigPlot+. Seven phytochemicals produced favorable binding affinities to the E protein, which are based on the interactions between the phytochemicals and amino acidsintheactivesiteoftheEprotein.Lipinski’s rule of 5 was then used to screen the seven phytochemicals for oral bioavailability. Glabridin has a binding affinity of -7.6 kcal/mol and was predicted to be orally bioavailable. This phytochemical interacts with amino acids in the E protein active site through hydrogen bonds to Asn355, andPhe337, as well as ten hydrophobic interactions. These interactions ensure that glabridin is able to specifically target and fit intotheactivesiteoftheEprotein, preventing its binding to the host cell and activating its viral proliferation. Glabridin is known to be found in the roots of licorice plants, providing anatural source for a possible cure for Dengue fever.
利用 Verapamil 引發斑馬魚胚胎心衰竭模式並探討臨床心衰竭用藥 Dapagliflozin 和 Valsartan 之成效與機制
本研究利用 Verapamil 誘導斑馬魚胚胎心衰竭模式，並探討 Dapagliflozin 對斑馬魚胚胎表皮離子細胞的調控機制，以加深對 SGLT2 inhibitors 機制的了解。受精後第四天的斑馬魚在暴露於Verapamil 24小時後，除了抑制卵黃囊吸收以及造成心包膜水腫以外，對心臟整體功能(HR, EDV,ESV, SV, EF, CO)具負面影響。以粒線體染劑標記離子細胞，發現Verapamil使其密度上升，使用掃描式電子顯微鏡觀察，則可看到離子細胞頂端開口有明顯的萎縮，影響到正常功能。以抗體標記染色的方式檢測不同離子細胞亞型，顯示 Dapagliflozin 使富含 Na⁺-K⁺ ATPase 的 HR 細胞和富含 H⁺-ATPase 的 NaR 細胞密度上升。同時，心臟功能診斷標誌物的 mRNA 水平(naap, nppb,gata4, vmhc)暴露於Verapamil後上升，促進離子細胞代償性上調。
Trojan Horses in the Fight against Skin Cancer
In photodynamic therapy (PDT), reactive oxygen species are generated within the cytoplasm to destroy cancer cells selectively. Using porphyrinic structures (PS) as photosensitizers holds promise for targeting cancer cells. However, direct incorporation of the porphyrins into cancer cells remains elusive. Hence, Dr. Martina Vermathen’s research introduced specific membranous phospholipid nanocarriers for topical porphyrin applications. However, since a sufficiently high enough concentration of PS in cancer cells has not yet been achieved, this study aimed to improve skin uptake of the nanocarriers. Two approaches were examined: (1) comparing polar and nonpolar porphyrins and (2) assessing the effect of a penetration enhancer, DMSO, through a neat and diluted application. The polarity of the porphyrins was first quantified with a log P test. The nanocarriers were assembled by incorporating two different PS compounds, either the mono- or tetra-4-carboxy substituted phenyl porphyrin. They were then characterized by 1D and 2D-NMR analysis. The porphyrin permeation was tested by Franz diffusion tests on pig ear skin. For the second approach, DMSO was added in the Franz diffusion test, either directly applied on the skin (“neat“) or diluted in the nanocarriers (“diluted”). The log P test for the mono- and the tetra-carboxyphenyl porphyrin resulted in values of 4.5 and -1.1, respectively. The more polar tetra-carboxyphenyl porphyrin exhibited 2.8 times better skin uptake compared to the mono-carboxyphenyl porphyrin. The neat DMSO application increased uptake by a factor of 5.5. The diluted DMSO application worsened skin uptake slightly. Analytical techniques revealed differences in porphyrin encapsulation: The mono-carboxyphenyl porphyrins were encapsulated in the centre, whereas tetra-carboxyphenyl porphyrins were localised around the nanocarriers. Results indicated potential instability of the nanocarriers. The more polar tetra-substituted porphyrins showed superior skin diffusion than the mono-substituted derivative. The neat DMSO application facilitated enhanced skin uptake by inducing membrane destabilization and pore formation but may have limited applicability. Further research is suggested to explore porphyrinic PS with alternative polar substitution patterns and tailored penetration enhancers for lipid-based delivery systems. Overall, the study underscores the importance of molecular properties of the PS system and demonstrates the potential of penetration enhancers in optimizing PDT for skin cancer treatment.