Mitochondrial toxicity of aluminium nanoparticles in comparison to its ionic form on isolated rat brain mitochondria.

OBJECTIVES: The aim of this study was to evaluate the toxic effect of AlNPs on rat brain mitochondria and compare it with that of aluminium's ionic form. METHODS: Mitochondria were isolated from rat brain. Isolated mitochondria were treated with normal saline (Control) and different concentrations of aluminium ions (AlIs) and AlNPs (50, 100 and 200 µM). Then, the effect of AlNPs on electron transport chain complexes as well as various endpoints such as mitochondrial oxidative damage (reactive oxygen species, lipid peroxidation, glutathione, and protein carbonyl) and mitochondrial function were assessed. Also, apoptosis was evaluated by cytochrome c release, mitochondrial membrane potential and swelling. RESULTS: When compared to the control group, the exposure to AlNPs showed a marked elevation in oxidative stress markers and inhibition of complex III which was accompanied by disturbance in mitochondrial function. Also, AlNPs induced a significant collapse of mitochondrial membrane potential, mitochondrial swelling, and cytochrome c release. CONCLUSIONS: The comparison of mitochondrial toxicity markers between both forms of aluminium revealed that the toxic effect of AlNPs on isolated brain mitochondria was substantially greater than that that caused by AlIs, which can probably be ascribed to its higher reactivity (Tab. 1, Fig. 8, Ref. 45).

Organocatalyzed stereospecific C-C bond formation of ß-lactams.

Herein, we report the development of mild, organocatalyzed routes to novel carbapenam derivatives through aldol, Mannich and Michael C-C bond forming reactions.

Cationic Chitosan Derivatives for the Inactivation of HIV-1 and SARS-CoV-2 Enveloped Viruses.

Cationic chitosan derivatives have been widely studied as potential antimicrobial agents. However, very little is known about their antiviral activity and mode of action against enveloped viruses. We investigated the ability of hydroxypropanoic acid-grafted chitosan (HPA-CS) and N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride (HTCC) to inactivate enveloped viruses like the human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The membrane-disrupting potential of the chitosan derivatives was initially investigated in a hemolysis assay. At 1.0 mg/mL, about 80% hemolysis was observed for the cationic chitosan derivatives, which was significant when compared to almost no membrane-disrupting activity by the unmodified chitosan. Virus inhibition was evaluated using the luciferase-based antiviral assay against the HIV-1 NL4.3 virus (400 TCID). The IC50 of HPA-CS was 4.109 mg/mL, while the HTCC showed a higher antiviral activity at an IC50 = 0.225 mg/mL. For practical application, the antiviral efficacies of the HTCC-coated and uncoated nonmedical masks were evaluated for SARS- CoV-2 virus capture. The coated masks demonstrated an almost excellent performance with nearly 100% viral inhibition compared to less than 60% inhibition by the uncoated masks. Molecular docking predictions suggest that the HTCC polymers interact with the viral spike protein, blocking the coronavirus interaction with the target host cell's angiotensin-converting enzyme 2 cellular receptors.

A Water-Soluble Polymer-Lumefantrine Conjugate for the Intravenous Treatment of Severe Malaria.

Uncomplicated malaria is effectively treated with oral artemisinin-based combination therapy (ACT). Yet, there is an unmet clinical need for the intravenous treatment of the more fatal severe malaria. There is no combination intravenous therapy for uncomplicated due to the nonavailability of a water-soluble partner drug for the artemisinin, artesunate. The currently available treatment is a two-part regimen split into an intravenous artesunate followed by the conventional oral ACT . In a novel application of polymer therapeutics, the aqueous insoluble antimalarial lumefantrine is conjugated to a carrier polymer to create a new water-soluble chemical entity suitable for intravenous administration in a clinically relevant formulation . The conjugate is characterized by spectroscopic and analytical techniques, and the aqueous solubility of lumefantrine is determined to have increased by three orders of magnitude. Pharmacokinetic studies in mice indicate that there is a significant plasma release of lumefantrine and production its metabolite desbutyl-lumefantrine (area under the curve of metabolite is ≈10% that of the parent). In a Plasmodium falciparum malaria mouse model, parasitemia clearance is 50% higher than that of reference unconjugated lumefantrine. The polymer-lumefantrine shows potential for entering the clinic to meet the need for a one-course combination treatment for severe malaria.

Fluorinated Quaternary Chitosan Derivatives: Synthesis, Characterization, Antibacterial Activity, and Killing Kinetics.

Chitosan has become an established platform biopolymer with applications in biomedical engineering, nanomedicine, and the development of new materials with improved solubility, antimicrobial activity, and low toxicity. In this study, a series of chitosan derivatives were synthesized by conjugating various perfluorocarbon chains to chitosan via Schiff base formation or nucleophilic substitution, followed by quaternization with glycidyl trimethylammonium chloride to confer non-pH-dependent permanent positive charges. Synthesized fluorinated N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride polymers were characterized and investigated for their antibacterial efficacies against multidrug-resistant bacteria including clinical isolates. The polymers showed activity against both Gram-positive and Gram-negative bacteria (MIC = 64-512 µg/mL) but with greater potency against the former. They displayed rapid bactericidal properties, based on the MBC/MIC ratio, which were further confirmed by the time-kill kinetic assays. Given the properties presented here, fluorinated quaternary chitosan derivatives can serve as great candidates to be investigated as environmentally more benign, nontherapeutic antimicrobial agents that could serve as alternatives to the heavy reliance on antibiotics, which are currently in a very precarious state due to increasing occurrence of drug resistance.

Evaluation of immune response to recombinant Bacillus anthracis LFD1-PA4 chimeric protein.

BACKGROUND: Anthrax is a particularly dangerous infectious disease that affects humans and livestock. Efficacious vaccines that can rapidly induce a long-term immune response are required to prevent anthrax infection in humans. Domains 4 and 1 of the protective antigen (PA) and lethal factor (LF), respectively, have very high antigenic properties. AIMS: In this experimental study, the pET28a-lfD1-pa4 expression vector was designed, constructed and transferred into E. coli BL21 (DE3) plysS. METHODS: For this purpose, pa4 gene was amplified by polymerase chain reaction (PCR) and cloned in a pGEM T-easy vector. The pGEM-pa4 and pGEM-lfD1 were digested by XbaI and HindIII enzymes. The ligation reaction was performed by ligase T4 enzyme and the gene cassette, lfD1-pa4, was subcloned in pET28a and transferred to E. coli BL21 (DE3) PlysS. Expression and purification of chimeric proteins were confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting techniques. The chimera LFD1-PA4 and mixed LFD1+PA4 proteins were injected four times into mice and antibody production was relativity evaluated by enzyme-linked immunosorbent assay (ELISA) test. RESULTS: The results showed that both chimeric and mixed proteins are immunogenic, but LFD1-PA4 has a higher potential to stimulate mice immune system. CONCLUSION: LFD1-PA4 chimeric protein induced a higher immune response than LFD1+PA4 mixed protein and elicited antibody responses to LF and edema factor (EF), therefore, it holds promise to be a more effective trivalent vaccine candidate to use in anthrax prevention.

Acrylamide attenuated immune tissues' function via induction of apoptosis and oxidative stress: Protection by l-carnitine.

Acrylamide (ACR), with high prevalence in starchy food, has been associated with the development of several organ toxicities such as immunotoxicity. This study aimed to demonstrate the role of oxidative stress and apoptosis as the mechanisms involved in ACR-induced immunotoxicity in mice. Mice were randomly assigned to six groups and treated as follows: control (normal saline), cyclophosphamide (200 mg kg-1), ACR groups (12.5, 25 and 50mg kg-1, orally), and l-carnitine (l-CAR; 100 mg kg-1) + ACR (50 mg kg-1). After 30 days of exposure, mice were killed and immunotoxic response was evaluated via immune blood cells count and body/organ weights. Oxidative stress parameters and pathological examination were done in thymus and spleen. Also, the apoptosis was evaluated via flow cytometric by annexin V/FITC kit in the splenocytes. Our results indicated that ACR could induce immunotoxicity characterized by reduction in immune blood cells, body/organ weights, and pathological changes in spleen. The assessment of oxidative stress markers revealed increase in lipid peroxidation, protein carbonyl content, and depletion of glutathione level. Also, increased apoptosis was observed in splenocytes after ACR administration compared to the control group. These alterations were markedly normalized by coadministration of l-CAR (as a potent antioxidant). Taken together, the results of this study showed the potential of ACR to induce immunotoxicity through provoking oxidative stress and inducing apoptosis and the protective effect of l-CAR to attenuate this toxicity. These findings will help in elucidating the toxicity mechanism induced by ACR.

Investigation of the entrance surface dose and dose to different organs in lumbar spine imaging.

BACKGROUND: Dose assessment using proper dosimeters is especially important in radiation protection optimization and imaging justification in diagnostic radiology. OBJECTIVE: The aim of this study is to obtain the Entrance Skin Dose (ESD) of patients undergoing lumbar spine imaging using two thermoluminescence dosimeters TLD-100 (LiF: Mg, Ti) and GR-200 (LiF: Mg, Cu, P) and also to obtain the absorbed dose to different organs in lumbar spine imaging with several views. METHODS: To measure the ESD values of the patients undergoing lumbar spine imaging, the two TLD types were put on their skin surface. The ESD values for different views of lumbar spine imaging were also measured by putting the TLDs at the surface of the Rando phantom. Several TLD chips were inserted inside different organs of Rando phantom to measure the absorbed dose to different organs in lumbar spine imaging. RESULTS: The results indicate that there is a close agreement between the results of the two dosimeters. Based on the results of this experiment, the ESD dose of the 16 patients included in this study varied between 2.71 mGy and 26.29 mGy with the average of 11.89 mGy for TLD-100, and between 2.55 mGy and 27.41 mGy with the average of 12.32 mGy for GR-200 measurements. The ESDs obtained by putting the two types of TLDs at the surface of Rando phantom are in close agreement. CONCLUSION: According to the results, the GR200 has greater sensitivity than the TLD-100.