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Fulltext Hepatic histopathological and ultrastructural alterations induced by 10 nm silver nanoparticles

Al-Doaiss A, Jarrar Q, Moshawih S

IET Nanobiotechnol, 2020 Jul;14(5):405-411.
PMID: 32691743 DOI: 10.1049/iet-nbt.2020.0039

Silver nanoparticles (Ag NPs) are invested in various sectors and are becoming more persistent in our ambient environment with potential risk on our health and the ecosystems. The current study aims to investigate the histological, histochemical and ultrastructural hepatic changes that might be induced by 10 nm silver nanomaterials. Male mice (BALB/C) were exposed for 35 injections of daily dose of 10 nm Ag NPs (2 mg/kg). Liver tissues were subjected to examination by light and electron microscopy for histological, histochemical and ultrastructural alterations. Exposure to Ag NPs induced Kupffer cells hyperplasia, sinusoidal dilatation, apoptosis, ground glass hepatocytes appearance, nuclear changes, inflammatory cells infiltration, hepatocytes degeneration and necrosis. In addition, 10 nm Ag NPs induced histochemical alterations mainly glycogen depletion with no hemosiderin precipitation. Moreover, these nanomaterials exhibited ultrastructure alterations including mitochondrial swelling and cristolysis, cytoplasmic vacuolation, apoptosis, multilammellar myelin figures formation and endoplasmic destruction and reduction. The findings revealed that Ag NPs can induce alterations in the hepatic tissues, the chemical components of the hepatocytes and in the ultrastructure of the liver. One may also conclude that small size Ag NPs, which are increasingly used in human products could cause various toxigenic responses to all hepatic tissue components.
Synthesis of Novel Esters of Mefenamic Acid with Pronounced Anti-nociceptive Effects and a Proposed Activity on GABA, Opioid and Glutamate Receptors

Ayoub R, Jarrar Q, Ali D, Moshawih S, Jarrar Y, Hakim M, et al.

Eur J Pharm Sci, 2021 Aug 01;163:105865.
PMID: 33979659 DOI: 10.1016/j.ejps.2021.105865

BACKGROUND: Mefenamic acid (MFA), a commonly prescribed non-steroidal anti-inflammatory drug (NSAID), possesses a greater risk of dose-related central nervous system (CNS) toxicity than other NSAIDs. In this study, α-tocopherol and α-tocopherol acetate were selected as prodrug moieties for MFA in an attempt to reduce the CNS toxicity and enhance the therapeutic efficacy.
METHOD: α-tocopherol monoester of MFA (TMMA) and α-tocopherol di-ester of MFA (TDMA) were synthesized by esterification reaction and were subjected to various in vivo characterizations.
RESULTS: Masking of the carboxylate group of MFA with the proposed pro-moieties significantly (p<0.05) delayed the onset of tonic-clonic seizure in mice. Besides, the intraperitoneal administration of TMMA and TDMA in mice produced significantly (p<0.05) stronger anti-inflammatory effects in the carrageenan-induced paw edema test and greater anti-nociceptive effect in the acetic acid-induced writhing test than MFA at an equimolar dose of 20 mg/kg. Treatment with TMMA and TDMA caused a significant (p<0.05) inhibition of pain at 1st and 2nd phases of formalin-induced licking test in mice, whereas treatment with MFA inhibited the 2nd phase only. Pretreatment with naloxone and flumazenil significantly (p<0.05) reversed the anti-nociceptive effect of MFA, TMMA and TDMA in the acetic acid-induced writhing test. In addition, treatment with TMMA and TDMA caused significantly (p<0.05) a higher inhibition of pain in the glutamate-induced licking response in mice than MFA.
CONCLUSION: Masking the carboxylate moiety of MFA by α-tocopherol and α-tocopherol acetate has a great potential for reducing CNS toxicity, enhancing the therapeutic efficacy and altering the mode of anti-nociceptive action.
Fulltext Hydroxychloroquine Toxicity in the Vital Organs of the Body: In Vivo Study

Alruwaili M, Jarrar B, Jarrar Q, Alruwaili M, Goh KW, Moshawih S, et al.

Front Biosci (Landmark Ed), 2023 Jul 13;28(7):137.
PMID: 37525906 DOI: 10.31083/j.fbl2807137

BACKGROUND: Hydroxychloroquine (HCQ) toxicity can adversely affect vital organs, cause pathologic ocular damage, and can have direct cardiovascular effects. This study aims to identify the biochemical, hematological, and histological alterations of the vital organs associated with the effects of HCQ.
METHODS: Male albino rats were exposed to the equivalent of HCQ therapeutic doses given to human patients being affected by malaria, lupus erythematosus, and COVID-19. The animal blood samples were subjected to hematological analysis, biochemical analysis, liver function tests, kidney function tests, and cardiac biomarkers. Liver, kidney, heart, spleen, and testis biopsies were subjected to histological examination.
RESULTS: HCQ significantly lowered the values of erythrocytes, hemoglobin, hematocrit, platelets, leucocytes, and lymphocytes but significantly increased the values of aspartate aminotransferase (AST), alanine aminotransferase (ALT), amylase, alkaline phosphatase, lactate dehydrogenase, cholesterol, and chlorine ions. The renal tissues of HCQ-treated animals demonstrated glomerular fragmentation, partial atrophy degeneration, renal tubules hydropic degeneration, hyaline cast formation, and interstitial edema formation. Additionally, the heart exhibited myofiber necrosis, myolysis, wavy appearance, disorganization, and disarray. The testicular tissues also demonstrated spermatocyte degeneration, spermatogenic cell sloughing, testicular interstitial edema, and occasional spermatogenic arrest. Additionally, the spleen showed a decrease in the number and size of the white pulp follicles, a decrease in the number of apoptotic activity, and a decline in the number of T-rich cells. However, the red pulp demonstrated a diffuse decline in B rich-lymphocytes and macrophages. The liver was also the least affected but showed Kupffer cell hyperplasia and occasional hepatocyte dysplasia.
CONCLUSIONS: The results indicate that chronic exposure to HCQ could alter the structures and functions of the vital organs.
Fulltext Evaluating NSAIDs in SARS-CoV-2: Immunomodulatory mechanisms and future therapeutic strategies

Moshawih S, Jarrar Q, Bahrin AA, Lim AF, Ming L, Goh HP

Heliyon, 2024 Feb 15;10(3):e25734.
PMID: 38356603 DOI: 10.1016/j.heliyon.2024.e25734

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely recognized for their analgesic and anti-inflammatory properties. Amidst the SARS-CoV-2 pandemic, the role of NSAIDs in modulating viral and bacterial infections has become a critical area of research, sparking debates and necessitating a thorough review. This review examines the multifaceted interactions between NSAIDs, immune responses, and infections. Focusing on the immunomodulatory mechanisms of NSAIDs in SARS-CoV-2 and their implications for other viral and bacterial infections, we aim to provide clarity and direction for future therapeutic strategies. NSAIDs demonstrate a dual role in infectious diseases. They reduce inflammation by decreasing neutrophil recruitment and cytokine release, yet potentially compromise antiviral defense mechanisms. They also modulate cytokine storms in SARS-CoV-2 and exhibit the potential to enhance anti-tumor immunity by inhibiting tumor-induced COX-2/PGE2 signaling. Specific NSAIDs have shown efficacy in inhibiting viral replication. The review highlights NSAIDs' synergy with other medications, like COX inhibitors and immunotherapy agents, in augmenting therapeutic effects. Notably, the World Health Organization's analysis found no substantial link between NSAIDs and the worsening of viral respiratory infections. The findings underscore NSAIDs' complex role in infection management. Understanding these interactions is crucial for optimizing therapeutic approaches in current and future pandemics. However, their dual nature warrants cautious application, particularly in vulnerable populations. NSAIDs present a paradoxical impact on immune responses in viral and bacterial infections. While offering potential benefits, their usage in infectious diseases, especially SARS-CoV-2, demands a nuanced understanding to balance therapeutic advantages against possible adverse effects.
Fulltext Prolonged Maternal Separation Reduces Anxiety State and Increases Compulsive Burying Activity in the Offspring of BALB/c Mice

Jarrar Q, Ayoub R, Alhussine K, Goh KW, Moshawih S, Ardianto C, et al.

J Pers Med, 2022 Nov 17;12(11).
PMID: 36422097 DOI: 10.3390/jpm12111921

BACKGROUND: The elevated plus maze (EPM) and the marble burying (MB) tests are common behavioral tests used for behavioral phenotyping in mouse models for neurodevelopmental disorders. However, the behavioral effects of maternal separation (MS), a standard paradigm for early life stress in animals, in both the EPM and MB tests remain incompletely known.
OBJECTIVES: This study aimed to investigate the behavioral effects of prolonged MS in the offspring of mice using the EPM and MB tests.
METHODS: Male BALB/c mice were isolated from their mothers for 4 h each day during the first 30 days after birth. On day 50 postnatal, groups of separated and non-separated mice (n = 18/each group) were subjected to the EPM and MB tests for comparative behavioral evaluations. In addition, the locomotor activity of mice was evaluated using the actophotometer test.
RESULTS: The findings of the EPM test revealed that separated mice exhibited anxiolytic-like behaviors, as evidenced by a significant increase in the latency to closed arms and the time spent in the open arms compared with non-separated mice. Separated mice also showed compulsive burying activity in the MB test, as determined by a significant increase in the number of buried marbles. The results of the actophotometer test did not show any significant change in locomotor activity.
CONCLUSIONS: Prolonged MS caused the adult offspring of mice to exhibit a decrease in anxiety state and increased compulsive burying activity, which were not associated with a change in locomotor activity. Further investigations with validated tests are needed to support these findings.
Fulltext Flumazenil Pretreatment Reduces Mefenamic Acid-Induced Central Nervous System Toxicity in Mice

Jarrar Q, Ayoub R, Jarrar Y, Aburass H, Goh KW, Ardianto C, et al.

J Integr Neurosci, 2023 Jul 26;22(4):104.
PMID: 37519168 DOI: 10.31083/j.jin2204104

BACKGROUND: Mefenamic acid (MFA), a common analgesic, causes central nervous system (CNS) toxicity at high doses with a proposed activity on the Gamma-aminobutyric acid (GABA) system. However, it remains unknown whether flumazenil (FMZ), a GABA type A receptor (GABAAR) antagonist, can reverse MFA toxicity.
METHODS: The behavioral and neurophysiological effects of MFA were investigated in mice with and without FMZ pre-treatment. The elevated zero maze (EZM) and marble burying tests were used to assess anxiety-like behaviors and burying activities, respectively. The standard bar test was used to evaluate catalepsy, while the actophotometer test was used to measure locomotor activity. Seizure intensity was scored, and fatalities were counted.
RESULTS: Without FMZ pre-treatment, MFA induced behavioral and neurophysiological effects in a dose-dependent manner as follows: At a dose of 20 mg/kg, i.p, MFA-treated mice exhibited anxiety-like behaviors, which was determined by a significant increase in the time spent in the closed areas and a significant decrease in the number of entries to the open areas of the EZM apparatus. These mice also showed a significant decrease in the burying activity, manifested as a significant decrease in the number of buried marbles. At 40 mg/kg, i.p., MFA-treated mice showed catalepsy that was associated with a significant decrease in locomotor activity. At a dose of 80 mg/kg, i.p., mice developed fatal tonic-clonic seizures (seizure score = 4). Pre-treatment with FMZ (5 mg/kg, i.p.) significantly reversed the anxiety-like behaviors and restored marble-burying activity. Additionally, FMZ prevented catalepsy, significantly restored locomotor activity, reduced seizure intensity (seizure score = 0.3) and significantly reduced mortalities.
CONCLUSIONS: The present study's findings indicate that activation of the GABAAR is involved in the CNS toxicity of MFA, and FMZ reverses MFA toxicity by interfering with this receptor.