Metformin Attenuates Postinfarction Myocardial Fibrosis and Inflammation in Mice

Diabetes is a major risk factor for the development of cardiovascular disease with a higher incidence of myocardial infarction. This study explores the role of metformin, a first-line antihyperglycemic agent, in postinfarction fibrotic and inflammatory remodeling in mice. Three-month-old C57BI/6J mice were submitted to 30 min cardiac ischemia followed by reperfusion for 14 days. Intraperitoneal treatment with metformin (5 mg/kg) was initiated 15 min after the onset of reperfusion and maintained for 14 days. Real-time PCR was used to determine the levels of COL3A1, αSMA, CD68, TNF-α and IL-6. Increased collagen deposition and infiltration of macrophages in heart tissues are associated with upregulation of the inflammation-associated genes in mice after 14 days of reperfusion. Metformin treatment markedly reduced postinfarction fibrotic remodeling and CD68-positive cell population in mice. Moreover, metformin resulted in reduced expression of COL3A1, αSMA and CD68 after 14 days of reperfusion. Taken together, these results open new perspectives for the use of metformin as a drug that counteracts adverse myocardial fibroticand inflammatory remodeling after MI.

SARS-CoV-2 Mpro inhibitors with antiviral activity in a transgenic mouse model

The COVID-19 pandemic caused by the SARS-CoV-2 virus continually poses serious threats to global public health. The main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing Mpro inhibitors derived from either Boceprevir or Telaprevir, both of which are approved antivirals. All compounds inhibited SARS-CoV-2 Mpro activity in vitro with IC50 values ranging from 7.6 to 748.5 nM. The co-crystal structure of Mpro in complex with MI-23, one of the most potent compounds, revealed its interaction mode. Two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays. In a SARS-CoV-2 infection transgenic mouse model, oral or intraperitoneal treatment with MI-09 or MI-30 significantly reduced lung viral loads and lung lesions. Both also displayed good pharmacokinetic properties and safety in rats.

Role of Olive leaves Zinc Oxide Nanoparticles in Alleviating The Molecular and Histological Changes of Kidney in Female Goats-Induced by Gentamicin (Part III)

This study aimed to investigate the protective influence of olive leave extract zinc oxidenanoparticles (OLEZnONPs) complex against gentamicin–induced kidney dysfunctions ingoats. Twenty five adult female goats were randomly divided into five equal groups andtreated as follows: control group (C) administered sterile distilled water (IM) for 10 days,group G administered 25 mg/kg BW gentamicin (IM) for 7 days, group Z administered 10μg/kg BW of OLEZnONPs (IP) for 3 days, group GTZ administered 25 mg/kg BW gentamicin(IM) for 7 days and then 10 μg/kg BW of OLEZnONPs (IP) for 3 days, group GWZadministered 25 mg/kg BW gentamicin (IM) and 10 μg/kg BW of OLEZnONPs (IP) togetherfor first 3 days and then followed by gentamicin only for 4 days. After seven days of theexperiment, the gene expression of kidney injury molcule-1(KIM-1) and neutrophilgelatinase-association lipocalin (NGAL) gene expression of kidney tissue were measured. Inaddition, samples of kidney were obtained for histopathological examination. Gentamicinmedication induced a marked elevation in kidney tissue KIM-1 and NGAL gene expressionin G and GTZ groups compared to control and other groups. Intraperitoneal treatment ofgoats with OLEZnONPs did not significantly affect NGAL and KIM-1 gene expression in Z,GWZ, and control groups. Histologically, in contrast to control, gentamicin induced moreextensive kidney damages such as necrotized glomeruli, atrophic glomeruli, and renaltubular epithelial necrosis, while it was found that these alterations in kidney tissues wereimproved in goats given OLEZnONPs with gentamicin compared to group G. In conclusion,our results demonstrate that OLEZnONPs reduce the deleterious effects of gentamicin withsignificantly decreasing of KIM-1 and NGAL gene expression and remodeling the histologicalchanges of kidney in goats

Morphine Antinociception Restored by Use of Methadone in the Morphine-Resistant Inflammatory Pain State

The antinociceptive effect of methadone in the morphine-resistant inflammatory pain state was described in the paw-withdrawal test using the complete Freund’s adjuvant (CFA)-induced mouse inflammatory pain model. After intraplantar (i.pl.) injection of CFA, thermal hyperalgesia was observed in the ipsilateral paw. The antinociceptive effects of subcutaneous (s.c.) injection of morphine, fentanyl, and oxycodone against thermal hyperalgesia in the inflammatory pain state were reduced in the ipsilateral paw 7 days after CFA pretreatment. On the contrary, the antinociceptive effect of s.c. injection of methadone was maintained in the ipsilateral paw 7 days after CFA pretreatment. The suppressed morphine antinociception in the CFA model mice was bilaterally restored following s.c. treatment with methadone 20 min prior to or 3 days after CFA pretreatment. The suppressed morphine antinociception was also bilaterally restored by intraperitoneal treatment with MK-801 30 min prior to CFA pretreatment; however, the s.c. injection of morphine 30 min prior to CFA pretreatment failed to restore the suppressed morphine antinociception in the CFA model mice. The expression level of mRNA for µ-opioid receptors 7 days after i.pl. pretreatment was not significantly changed by i.pl. pretreatment with CFA or s.c. pretreatment with methadone. In conclusion, methadone is extremely effective against thermal hyperalgesia in the morphine-resistant inflammatory pain state, and restores suppressed morphine antinociception in the inflammatory pain state without altering the expression level of mRNA for µ-opioid receptors.

Beneficial Influence of Agomelatine Treatment on Behavioral Impairments in AΒ-Induced Rat Model of Alzheimer’s Disease

Summary An increased risk of developing Alzheimer’s disease (AD) exists in patients with a history of depression. In the present study, we demonstrated that chronic agomelatine intraperitoneal treatment, at a dose of 40 mg/ kg for 21 days, starting one month after inducing AD by intracerebroventricular injection of amyloid-beta (Aβ) corrected anhedonia, decreased anxiety, and showed a potential to mitigate working memory errors during the last session in a radial arm maze. Altogether, our findings suggest that chronic agomelatine administration treatment could alleviate the burden of AD and may be considered a promising therapeutic approach to some adverse symptoms caused by the disease.

Synthesis and Antileishmanial Activity of 1,2,4,5-Tetraoxanes against Leishmania donovani

A chemically diverse range of novel tetraoxanes was synthesized and evaluated in vitro against intramacrophage amastigote forms of Leishmania donovani. All 15 tested tetraoxanes displayed activity, with IC50 values ranging from 2 to 45 µm. The most active tetraoxane, compound LC140, exhibited an IC50 value of 2.52 ± 0.65 µm on L. donovani intramacrophage amastigotes, with a selectivity index of 13.5. This compound reduced the liver parasite burden of L. donovani-infected mice by 37% after an intraperitoneal treatment at 10 mg/kg/day for five consecutive days, whereas miltefosine, an antileishmanial drug in use, reduced it by 66%. These results provide a relevant basis for the development of further tetraoxanes as effective, safe, and cheap drugs against leishmaniasis.

Novel dihydroartemisinin dimer containing nitrogen atoms inhibits growth of endometrial cancer cells and may correlate with increasing intracellular peroxynitrite

In the present study, a novel dimer, SM1044, selected from a series of dihydroartemisinin (DHA) derivatives containing nitrogen atoms comprising simple aliphatic amine linkers, showed strong growth inhibition in six types of human endometrial cancer (EC) cells, with half maximal inhibitory concentration (IC50) and 95% confidence interval (CI) < 3.6 (1.16~11.23) μM. SM1044 evoked apoptosis and activated caspase-3, −8 and −9 in a concentration- and time-dependent manner, and these effects were manifested early in RL95-2 compared to KLE cells, possibly correlated with the induction of intracellular ONOO−. Catalase and uric acid attenuated the growth inhibitory effects of SM1044 on EC cells, but sodium pyruvate did not. In vivo, the average xenograft tumour growth inhibition rates ranged from 35.8% to 49.9%, respectively, after 2.5 and 5.0 mg/kg SM1044 intraperitoneal treatment, and no obvious behavioural and histopathological abnormalities were observed in SM1044-treated mice in this context. SM1044 predominantly accumulated in the uteri of mice after a single injection. SM1044 displayed efficacy as a tumour suppressor with distinct mechanism of action and unique tissue distribution, properties that distinguish it from other artemisinin analogues. Our findings provide a new clue for artemisinin analogue against cancer.