Protective effects of microbial biosurfactants produced by Bacillus halotolerans and Candida parapsilosis on bleomycin-induced pulmonary fibrosis in mice: Impact of antioxidant, anti-inflammatory and anti-fibrotic properties via TGF-ß1/Smad-3 pathway and miRNA-326.

Idiopathic pulmonary fibrosis (IPF) is an irreversible disease which considered the most fatal pulmonary fibrosis. Pulmonary toxicity including IPF is the most severe adverse effect of bleomycin, the chemotherapeutic agent. Based on the fact that, exogenous surfactants could induce alveolar stabilization in many lung diseases, the aim of this study was to explore the effects of low cost biosurfactants, surfactin (SUR) and sophorolipids (SLs), against bleomycin-induced pulmonary fibrosis in mice due to their antioxidant, and anti-inflammatory properties. Surfactin and sophorolipids were produced by microbial conversion of frying oil and potato peel wastes using Bacillus halotolerans and Candida parapsilosis respectively. These biosurfactants were identified by FTIR, 1H NMR, and LC-MS/MS spectra. C57BL/6 mice were administered the produced biosurfactants daily at oral dose of 200 mg kg-1 one day after the first bleomycin dose (35 U/kg). We evaluated four study groups: Control, Bleomycin, Bleomycin+SUR, Bleomycin+SLs. After 30 days, lungs from each mouse were sampled for oxidative stress, ELISA, Western blot, histopathological, immunohistochemical analyses. Our results showed that the produced SUR and SLs reduced pulmonary oxidative stress and inflammatory response in the lungs of bleomycin induced mice as they suppressed SOD, CAT, and GST activities also reduced NF-κß, TNF-α, and CD68 levels. Furthermore, biosurfactants suppressed the expression of TGF-ß1, Smad-3, and p-JNK fibrotic signaling pathway in pulmonary tissues. Histologically, SUR and SLs protected against lung ECM deposition caused by bleomycin administration. Biosurfactants produced from microbial sources can inhibit the induced inflammatory and fibrotic responses in bleomycin-induced pulmonary fibrosis.

The mechanistic interplay between Nrf-2, NF-κB/MAPK, caspase-dependent apoptosis, and autophagy in the hepatoprotective effects of Sophorolipids produced by microbial conversion of banana peels using Saccharomyces cerevisiae against doxorubicin-induced hepatotoxicity in rats.

BACKGROUND: Doxorubicin (DOX) is a well-known chemotherapeutic agent which causes serious adverse effects due to multiple organ damage, including cardiotoxicity, nephrotoxicity, neurotoxicity, and hepatotoxicity. The mechanism of DOX-induced organ toxicity might be attributed to oxidative stress (OS) and, consequently, activation of inflammatory signaling pathways, apoptosis, and blockage of autophagy. Sophorolipids (SLs) as a glycolipid type of biosurfactants, are natural products that have unique properties and a wide range of applications attributed to their antioxidant and anti-inflammatory properties. AIMS: Production of low-cost SLs from Saccharomyces cerevisiae grown on banana peels and investigating their possible protective effects against DOX-induced hepatotoxicity. MAIN METHODS: The yeast was locally isolated and molecularly identified, then the yielded SLs were characterized by FTIR, 1H NMR and LC-MS/MS spectra. Posteriorly, thirty-two male Wistar rats were randomly divided into four groups; control (oral saline), SLs (200 mg/kg, p.o), DOX (10 mg/kg; i.p.), and SL + DOX (200 mg/kg p.o.,10 mg/kg; i.p., respectively). Liver function tests (LFTs), oxidative stress, inflammatory, apoptosis as well as autophagy markers were investigated. KEY FINDINGS: SLs were produced with a yield of 49.04% and treatment with SLs improved LFTs, enhanced Nrf2 and suppressed NF-κB, IL-6, IL-1ß, p38, caspase 3 and Bax/Bcl2 ratio in addition to promotion of autophagy when compared to DOX group. SIGNIFICANCE: Our results revealed a novel promising protective effect of SLs against DOX-induced hepatotoxicity in rats.

A biochemical, theoretical and immunohistochemical study comparing the therapeutic efficacy of curcumin and taurine on T-2 toxin induced hepatotoxicity in rats.

Introduction: Foodborne trichothecene T-2 Toxin, is a highly toxic metabolite produced by Fusarium species contaminating animal and human food, causing multiple organ failure and health hazards. T-2 toxins induce hepatotoxicity via oxidative stress causing hepatocytes cytotoxicity and genotoxicity. In this study, curcumin and taurine were investigated and compared as antioxidants against T-2-provoked hepatotoxicity. Methods: Wistar rats were administrated T-2 toxin sublethal oral dose (0.1 mg/kg) for 2 months, followed by curcumin (80 mg/kg) and taurine (50 mg/kg) for 3 weeks. Biochemical assessment of liver enzymes, lipid profiles, thiobarbituric acid reactive substances (TBARs), AFU, TNF-α, total glutathione, molecular docking, histological and immunohistochemical markers for anti-transforming growth factor-ß1 (TGFß1), double-strand DNA damage (H2AX), regeneration (KI67) and apoptosis (Active caspase3) were done. Results and Discussion: Compared to T-2 toxin, curcumin and taurine treatment significantly ameliorated hepatoxicity as; hemoglobin, hematocrit and glutathione, hepatic glycogen, and KI-67 immune-reactive hepatocytes were significantly increased. Although, liver enzymes, inflammation, fibrosis, TGFß1 immunoexpressing and H2AX and active caspase 3 positive hepatocytes were significantly decreased. Noteworthy, curcumin's therapeutic effect was superior to taurine by histomorphometry parameters. Furthermore, molecular docking of the structural influence of curcumin and taurine on the DNA sequence showed curcumin's higher binding affinity than taurine. Conclusion: Both curcumin and taurine ameliorated T-2 induced hepatotoxicity as strong antioxidative agents with more effectiveness for curcumin.

Kisspeptin and kisspeptin receptor immunoreactivity in euploid and aneuploid choriodecidual tissues of recurrent pregnancy losses.

OBJECTIVE: To study choriodecidual immunoreactivity of kisspeptin (KISS1) and its receptor (KISS1R) in recurrent pregnancy loss (RPL) due to aneuploidy (AnE) and unexplained (UE) RPL in comparison to control elective abortions (EAbs). DESIGN: This is a case-control study. SETTING: Tertiary care facility and affiliated research institute. PATIENT(S): Patients with either UE RPL (n = 10) or RPL due to AnE (n = 10) vs. a control group of patients who underwent EAb (n = 10). INTERVENTION(S): Immunohistochemistry of archived choriodecidual tissue samples. MAIN OUTCOME MEASURE(S): Histoscores of KISS1 and KISS1R immunoreactivity in the syncytiotrophoblast (SyT), cytotrophoblast (CyT), decidual glands (DeGs), and decidual stroma (DeS) across the 3 study groups. RESULT(S): There was no difference in both maternal and gestational ages among the 3 groups. Kisspeptin immunoreactivity was similar in the SyT, CyT, DeGs, and DeS of all groups. Similarly, KISS1R expression was not different in the DeGs or DeS among all study groups. In addition, there was no difference in KISS1R immunoreactivity in the SyTs and CyTs between patients with RPL due to AnE and those with UE RPL. However, KISS1R was significantly lower in the SyT and CyT of patients with RPL due to AnE and UE RPL than in those who underwent EAb. CONCLUSION(S): The expression of KISS1R is lower in the chorionic tissues of euploid (unexplained) and aneuploid RPLs than in the control group. The current results broaden our understanding of the role played by KISS1 and KISS1R in early placentation. Further investigation is necessary to determine whether KISS1 activity is the cause or a sequel of defective placentation.

LCZ696 (sacubitril/valsartan) protects against cyclophosphamide-induced nephrotoxicity in adult male rats: Up-regulation of Apelin-13/ACE2, miR-200, and down-regulation of TGF-ß/SMAD 2/3 and miR-192.

BACKGROUND: Cyclophosphamide (CP) is a widely used chemotherapeutic drug. However, the associated nephrotoxicity restricts its clinical use. AIM: The present research was designed to study the impact of LCZ696 (LCZ); which is a combination of Sacubitril/Valsartan compared to valsartan (VAL) on CP-induced nephrotoxicity. MAIN METHODS: Sixty adult male Wistar rats were randomly and equally assigned into 6 groups as follows: Control, LCZ (30 mg/kg, p.o.), VAL (15 mg/kg, p.o.), CP (200 mg/kg, single dose, i.p.), CP/LCZ, and CP/VAL groups. LCZ and VAL were given once daily for 6 days prior to CP (groups 5 & 6). At the end of the experiment, kidney functions, oxidants/antioxidants, inflammatory and fibrotic biomarkers in renal tissues were assessed. Further, immunohistochemical, and histomorphometric analyses were carried out. KEY FINDINGS: In comparison with CP-treated rats, LCZ resulted in a significant reduction in serum urea (26.6 %) and creatinine (63 %), moreover it decreased renal content of reactive oxygen species (ROS), zinc finger E-box-binding homeobox (ZEB)-1, SMAD2/3, plasminogen activator inhibitor (PAI)-1, fibronectin, histone deacetylase (HDAC)-4, nuclear factor-kappa B (NF-κB) and miR-192 expression by ~40-60 % as well as the immunohistological expressions of transforming growth factor-ß (TGF-ß) and anti-phospho Histone (H2AX) by ~75 % reduction. Whereas the renal total antioxidant capacity (TAC), apelin-13, miR-200 expression, and the immunoreactivity of angiotensin-converting enzyme 2 (ACE2) were enhanced by ~3-4-folds. Noteworthy, the prophylactic effect of LCZ was superior to VAL on the histomorphometric and immunohistological levels. SIGNIFICANCE: Prophylactic administration of LCZ protected against CP-induced nephrotoxicity via up-regulating apelin-13/ACE2, miR-200, and down-regulating TGF-ß/SMAD 2/3 and miR-192.

Combined microneedling with topical application of platelet-rich plasma versus microneedling alone in the treatment of stria distensae: clinicopathological analysis.

BACKGROUND: Striae distensae (SD) are common skin conditions. OBJECTIVES: This study was done to test the hypothesis that 'the use of microneedling (MN) before platelet-rich plasma (PRP) application will allow for deeper penetration and therefore, augment its efficacy in the treatment of SD.' PATIENTS AND METHODS: Forty patients with SD were divided into (i) Group I, the patients were treated with MN only, and (ii) Group II, the patients were treated with combined MN-PRP. The clinical improvement was evaluated by two dermatologists. Skin biopsies were obtained before and after therapy to examine immunohistological changes. RESULTS: As compared to the use of MN alone, therapy with combined MN-PRP was associated with: (i) a marked to the excellent improvement of the skin lesions of SD, (ii) a more significant deposition of collagen and elastic fibers, (iii) increased proliferative activity in the epidermis, and (iv) a decreased caspase-3 protein expression values in the epidermis. CONCLUSIONS: This study proved that the combined MN-PRP is more effective than MN alone for the treatment of the lesions of SD. The underlying molecular mechanisms are open for future studies.

Indomethacin can induce cell death in rat gastric parietal cells through alteration of some apoptosis- and autophagy-associated molecules.

In clinical medicine, indomethacin (IND, a non-steroidal anti-inflammatory drug) is used variously in the treatment of severe osteoarthritis, rheumatoid arthritis, gouty arthritis or ankylosing spondylitis. A common complication found alongside the therapeutic characteristics is gastric mucosal damage. This complication is mediated through apoptosis and autophagy of the gastrointestinal mucosal epithelium. Apoptosis and autophagy are critical homeostatic pathways catalysed by caspases downstream of the gastrointestinal mucosal epithelial injury. Both act through molecular signalling pathways characterized by the initiation, mediation, execution and regulation of the cell regulatory cycle. In this study we hypothesized that dysregulated apoptosis and autophagy are associated with IND-induced gastric damage. We examined the spectra of in vivo experimental gastric ulcers in male Sprague-Dawley rats through gastric gavage of IND. Following an 18-hour fast, IND was administered to experimental rats. They were sacrificed at 3-, 6- and 12-hour intervals. Parietal cells (H+ , K+ -ATPase ß-subunit assay) and apoptosis (TUNEL assay) were determined. The expression of apoptosis-signalling caspase (caspases 3, 8, 9 and 12), DNA damage (anti-phospho-histone H2A.X) and autophagy (MAP-LC3, LAMP-1 and cathepsin B)-related molecules in gastric mucosal cells was examined. The administration of IND was associated with gastric mucosal erosions and ulcerations mainly involving the gastric parietal cells (PCs) of the isthmic and upper neck regions and a time-dependent gradual increase in the number of apoptotic PCs with the induction of both apoptotic (upregulation of caspases 3 and 8) cell death and autophagic (MAP-LC3-II, LAMP-1 and cathepsin B) cell death. Autophagy induced by fasting and IND 3 hours initially prompted the degradation of caspase 8. After 6 and 12 hours, damping down of autophagic activity occurred, resulting in the upregulation of active caspase 8 and its nuclear translocation. In conclusion we report that IND can induce time-dependent apoptotic and autophagic cell death of PCs. Our study provides the first indication of the interactions between these two homeostatic pathways in this context.

Ultra-structural study of the indomethacin-induced apoptosis and autophagy in rat gastric parietal cells.

BACKGROUND AND AIM OF THE WORK: Indomethacin (IND), a non-steroidal anti-inflammatory drug, can induce gastric mucosal ulcerations. To date, the ultra-structural changes in the parietal cells (PCs) of the gastric mucosa following the intake of IND are mostly unknown. We carried out the current investigation to get insights into this issue. MATERIALS AND METHODS: We established an animal model consisting of 35 adult male Sprague Dawley rats. The animals were divided into three groups, including; control (normal feeding), fasting, and indomethacin-treated groups. After treatment of 18-h fasting rats with IND, they were sacrificed at 3, 6, and 12-h intervals. The morphological features, including the apoptotic, and autophagic changes in the gastric mucosa PCs were examined using transmission electron microscopy. RESULTS: In normal feeding animals (control group), the gastric PCs were present in various stages of activity. Fasting was associated with the predominance of the inactive parietal cells with features of up-regulated autophagy. In the IND -treated animals (at 3-h interval), PCs showed prominent autophagic changes, and subtle apoptotic cell death. In the IND -treated animals (at 6-12-h interval), PCs showed prominent apoptotic changes, and subtle autophagic features. CONCLUSIONS: Our study indicates that IND treatment could induce gastropathy through time-dependent alterations in the autophagic and apoptotic machinery of PCs. Further studies are needed to examine the underlying molecular mechanisms.