Focus on chirality of HIV-​1 non-​nucleoside reverse transcriptase inhibitors

Chiral HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) are of great interest since one enantiomer is often more potent than the corresponding counterpart against the HIV-1 wild type (WT) and the HIV-1 drug resistant mutant strains. This review exemplifies the various studies made to investigate the effect of chirality on the antiretroviral activity of top HIV-1 NNRTI compounds, such as nevirapine (NVP), efavirenz (EFV), alkynyl- and alkenylquinazolinone DuPont compounds (DPC), diarylpyrimidine (DAPY), dihydroalkyloxybenzyloxopyrimidine (DABO), phenethylthiazolylthiourea (PETT), indolylarylsulfone (IAS), arylphosphoindole (API) and trifluoromethylated indole (TFMI) The chiral separation, the enantiosynthesis, along with the biological properties of these HIV-1 NNRTIs, are discussed

Current state-of-the-art in preclinical and clinical development of novel non-nucleoside HIV-1 reverse transcriptase inhibitors

In spite of the tremendous advance in our understanding of the HIV-1 life cycle and of the molecular mechanisms underlying its pathogenesis, it is still not possible to fully control the HIV-1 infection for long periods of time, not to mention eradicate it. However, as it is still unclear whether an effective vaccine could be developed in a short time, therapeutic approaches based on the combination of different potent antiviral drugs are now thought to be the best option for the control of HIV-1 infection in patients. For this reason, development of novel molecules that are safer, more potent and less sensitive to drug resistance than available drugs is mandatory. Among the currently exploited anti-HIV drugs, non-nucleoside reverse transcriptase inhibitors play a major role. This review will summarise the most recent advances and evolutionary trends for this class of anti-HIV drugs

Mitotic cell death induction by targeting the mitotic spindle with tubulin-inhibitory indole derivative molecules

Tubulin-targeting molecules are widely used cancer therapeutic agents. They inhibit microtubule-based structures, including the mitotic spindle, ultimately preventing cell division. The final fates of microtubule-inhibited cells are however often heterogeneous and difficult to predict. While recent work has provided insight into the cell response to inhibitors of microtubule dynamics (taxanes), the cell response to tubulin polymerization inhibitors remains less well characterized. Arylthioindoles (ATIs) are recently developed tubulin inhibitors. We previously identified ATI members that effectively inhibit tubulin polymerization in vitro and cancer cell growth in bulk cell viability assays. Here we characterise in depth the response of cancer cell lines to five selected ATIs. We find that all ATIs arrest mitotic progression, yet subsequently yield distinct cell fate profiles in time-lapse recording assays, indicating that molecules endowed with similar tubulin polymerization inhibitory activity in vitro can in fact display differential efficacy in living cells. Individual ATIs induce cytological phenotypes of increasing severity in terms of damage to the mitotic apparatus. That differentially triggers MCL-1 down-regulation and caspase-3 activation, and underlies the terminal fate of treated cells. Collectively, these results contribute to define the cell response to tubulin inhibitors and pinpoint potentially valuable molecules that can increase the molecular diversity of tubulin-targeting agents

Muscle degeneration in inguinal hernia specimens.

There are few articles in the literature reporting the histological changes of groin structures affected by inguinal hernia. A deeper knowledge of this matter could represent an important step forward in the identification of the causes of hernia protrusion. This study aimed to recognise the pathological modifications of muscular structures in autopsy specimens excised from tissues surrounding the hernia orifice. METHODS: Inguinal hernia was identified in 30 autopsied cadavers, which presented different varieties of hernia, including indirect, direct and mixed. Tissue specimens were resected for histological study from structures of the inguinal area surrounding the hernia opening, following a standardised procedure. The histological examination was focussed on the detection of structural changes in the muscle tissues. The results were compared with biopsy specimens resected from corresponding sites of the inguinal region in a control group of 15 fresh cadavers without hernia. RESULTS: Significant modification of the muscular arrangement of the inguinal area was recognized. Pathological alterations such as atrophy, hyaline and fibrotic degeneration, as well as fatty dystrophy of the myocytes were detected. These findings were observed consistently in the context of multistructural damage also involving vessels and nerves. In cadavers with hernia these alterations were always present independent of hernia type. No comparable damage was found in control cadavers without hernia. CONCLUSIONS: The high degree of degenerative changes in the muscle fibres in the inguinal area involved in hernia protrusion described in this report seems to be consistent with chronic compressive damage. These alterations could embody one important factor among the multifactorial sources of hernia genesis. Conjectures concerning its impact on the physiology and biodynamics of the inguinal region are made. The relationship between the depicted degenerative injuries and the genesis of inguinal hernia is also a focus of discussion in this article

Damage to the vascular structures in inguinal hernia specimens.

BACKGROUND: Few scientific reports to date describe the histological modification of structures outlining a hernia opening. This article is focused on the identification of the pathological changes in vascular structures in tissues excised from cadavers with inguinal hernia. A deeper comprehension of this topic could lead to essential improvements in the detection of hernia genesis. MATERIALS AND METHODS: Different kinds of hernia, including indirect, direct and mixed, were identified in 30 autopsied subjects. Tissue samples were resected for histological study from abdominal wall structures close to the hernia opening. Histological examination focused on the detection of structural changes in arteries and veins. The results were compared with tissue specimens excised from equivalent sites of the inguinal area in a control group of 15 fresh cadavers without hernia. RESULTS: Significant modification of vascular structures were identified in the tissue specimens examined. The veins demonstrated parietal fibrosis, perivascular edema and vascular dilation due to congestion and stasis. The arterial structures detected showed thickening of the media due to medial hyperplasia, ranging from luminal sub-occlusion to a manifest artery occlusion. These findings are present independent of hernia type in cadavers with inguinal hernia. These pathological changes were lacking in the control group of cadavers without hernia. CONCLUSIONS: The notable changes in vascular structures described in the report could be the result of a steady compressive effect exerted by the abdominal viscera in the inguinal area. These pathological changes could represent one of the factors involved in the weakening of the inguinal region leading to hernia protrusion

Violacein, an indole-derived purple-colored natural pigment produced by Janthinobacterium lividum, inhibits the growth of head and neck carcinoma cell lines both in vitro and in vivo

Violacein (VIO; 3-[1,2-dihydro-5-(5-hydroxy-1H-indol-3-yl)-2-oxo-3H-pyrrol-3-ylidene]-1,3-dihydro-2H-indol-2-one), an indole-derived purple-colored pigment, produced by a limited number of Gram-negative bacteria species, including Chromobacterium violaceum and Janthinobacterium lividum, has been demonstrated to have anti-cancer activity, as it interferes with survival transduction signaling pathways in different cancer models. Head and neck carcinoma (HNC) represents the sixth most common and one of the most fatal cancers worldwide. We determined whether VIO was able to inhibit head and neck cancer cell growth both in vitro and in vivo. We provide evidence that VIO treatment of human and mouse head and neck cancer cell lines inhibits cell growth and induces autophagy and apoptosis. In fact, VIO treatment increased PARP-1 cleavage, the Bax/Bcl-2 ratio, the inhibition of ERK1 and ERK2 phosphorylation, and the expression of light chain 3-II (LC3-II). Moreover, VIO was able to induce p53 degradation, cytoplasmic nuclear factor kappa B (NF-κB) accumulation, and reactive oxygen species (ROS) production. VIO induced a significant increase in ROS production. VIO administration was safe in BALB/c mice and reduced the growth of transplanted salivary gland cancer cells (SALTO) in vivo and prolonged median survival. Taken together, our results indicate that the treatment of head and neck cancer cells with VIO can be useful in inhibiting in vivo and in vitro cancer cell growth. VIO may represent a suitable tool for the local treatment of HNC in combination with standard therapies

In vitro characterisation of a pleconaril/pirodavir-like compound with potent activity against rhinoviruses

Abstract BACKGROUND: Rhinovirus infections do not only cause common colds, but may also trigger severe exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Even though rhinoviruses have been the focus of extensive drug development efforts in the past, an anti-rhinoviral drug still has to make it to the market. In the past, the viral capsid protein VP1 has been shown to be an important target for the development of antiviral molecules. Furthermore, many different chemical scaffolds appear to possess the properties that are required to inhibit virus replication by this mechanism of action. I-6602, an analogue of the rhinovirus inhibitor pirodavir, was previously identified as a potent inhibitor of rhinovirus infection. Here, we describe the antiviral activity of its analogue ca603, a molecule with a modified linker structure, and corroborate its mechanism of action as a capsid binder. FINDINGS: The molecule ca603 shows antiviral activity against a panel of rhino-and enteroviruses. Cross-resistance is observed against viruses with mutations that render them resistant to the inhibitory effect of the capsid binder pleconaril and thermostability assays demonstrate that the compound binds and stabilizes the viral capsid. Binding of the molecule to the VP1 protein is corroborated by in silico modeling. CONCLUSIONS: It is confirmed that ca603 inhibits rhinovirus replication by interaction with the VP1 protein and, by this, allows to further expand the chemical diversity of capsid-binding molecules

RS4651 suppresses lung fibroblast activation via the TGF-β1/SMAD signalling pathway.

ABSTRACT Background Idiopathic pulmonary fibrosis (IPF) is a progressive disease resulting in respiratory failure with no efficient treatment options. We investigated the protective effect of RS4651 on pulmonary fibrosis in mice and the mechanism. Methods Intratracheal injection of bleomycin (BLM) was used to induce pulmonary fibrosis in mice. RS4561 was administered intraperitoneally at different doses. Histopathological changes were observed. The level of alpha-smooth muscle actin (α-SMA) were also tested. In vitro, the proliferation and migratory effects of RS4651 treatment on MRC-5 cells pre-treated with transforming growth factor (TGF-β1) were examined. RNA-sequencing was used to detect differentially expressed target genes. Then, the expression of α-SMA, pSMAD2 and SMAD7 were analysed during RS4651 treatment of MRC-5 cells with or without silencing by SMAD7 siRNA. Results Histopathological staining results showed decreased collagen deposition in RS4651 administered mice. Additionally, a lower level of α-SMA was also observed compared to the BLM group. The results of in vitro studies confirmed that RS4651 can inhibit the proliferation and migration, as well as α-SMA and pSMAD2 expression in MRC-5 cells treated with TGF-β1. RNA-sequencing data identified the target gene SMAD7. We found that RS4651 could upregulate SMAD7 expression and inhibit the proliferation and migration of MRC-5 cells via SMAD7, and RS4651 inhibition of α-SMA and pSMAD2 expression was blocked in SMAD7-siRNA MRC-5 cells. In vivo studies further confirmed that RS4651 could upregulate SMAD7 expression in BLM-induced lung fibrosis in mice. Conclusions Our data suggest that RS4651 alleviates BLM-induced pulmonary fibrosis in mice by inhibiting the TGF-β1/SMAD signalling pathway

A Screen for Kinetochore-Microtubule Interaction Inhibitors Identifies Novel Antitubulin Compounds

Protein assemblies named kinetochores bind sister chromatids to the mitotic spindle and orchestrate sister chromatid segregation. Interference with kinetochore activity triggers a spindle checkpoint mediated arrest in mitosis, which frequently ends in cell death. We set out to identify small compounds that inhibit kinetochore-microtubule binding for use in kinetochore-spindle interaction studies and to develop them into novel anticancer drugs