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Microorganisms May 2024Chagas Disease is a neglected tropical disease caused by the protozoan parasite affecting 6-8 million people, mainly in Latin America. The medical treatment is based on...
A Promising Amphotericin B Derivative Induces Morphological Alterations, Mitochondrial Damage, and Oxidative Stress In Vitro and Prevents Mice from Death Produced by a Virulent Strain of .
Chagas Disease is a neglected tropical disease caused by the protozoan parasite affecting 6-8 million people, mainly in Latin America. The medical treatment is based on two compounds, benznidazole and nifurtimox, with limited effectiveness and that produce severe side effects; consequently, there is an urgent need to develop new, safe, and effective drugs. Amphotericin B is the most potent antimycotic known to date. A21 is a derivative of this compound with the property of binding to ergosterol present in cell membranes of some organisms. In the search for a new therapeutic drug against , the objective of this work was to study the in vitro and in vivo effects of A21 derivative on . Our results show that the A21 increased the reactive oxygen species and reduced the mitochondrial membrane potential, affecting the morphology, metabolism, and cell membrane permeability of in vitro. Even more important was finding that in an in vivo murine model of infection, A21 in combination with benznidazole was able to reduce blood parasitemia, diminish the immune inflammatory infiltrate in skeletal muscle and rescue all the mice from death due to a virulent strain.
PubMed: 38930447
DOI: 10.3390/microorganisms12061064 -
Materials (Basel, Switzerland) Jun 2024In this study, the potential of silk fibroin biomaterials for enhancing wound healing is explored, focusing on their integration into a human 3D ex vivo wound model...
In this study, the potential of silk fibroin biomaterials for enhancing wound healing is explored, focusing on their integration into a human 3D ex vivo wound model derived from abdominoplasties. For this purpose, cast silk fibroin membranes and electrospun nonwoven matrices from silk cocoons were compared to untreated controls over 20 days. Keratinocyte behavior and wound healing were analyzed qualitatively and quantitatively by histomorphometric and immune histochemical methods (HE, Ki67, TUNEL). Findings reveal rapid keratinocyte proliferation on both silk fibroin membrane and nonwoven matrices, along with enhanced infiltration in the matrix, suggesting improved early wound closure. Silk fibroin membranes exhibited a significantly improved early regeneration, followed by nonwoven matrices ( < 0.05) compared to untreated wounds, resulting in the formation of multi-layered epidermal structures with complete regeneration. Overall, the materials demonstrated excellent biocompatibility, supporting cell activity with no signs of increased apoptosis or early degradation. These results underscore silk fibroin's potential in clinical wound care, particularly in tissue integration and re-epithelialization, offering valuable insights for advanced and-as a result of the electrospinning technique-individual wound care development. Furthermore, the use of an ex vivo wound model appears to be a viable option for pre-clinical testing.
PubMed: 38930373
DOI: 10.3390/ma17123004 -
Materials (Basel, Switzerland) Jun 2024The glycolysis process of flexible polyurethane foams containing styrene-acrylonitrile and calcium carbonate as fillers was explored in detail. The use of DABCO as a...
The glycolysis process of flexible polyurethane foams containing styrene-acrylonitrile and calcium carbonate as fillers was explored in detail. The use of DABCO as a catalyst allowed us to reduce the catalyst concentration and the polyurethane-to-glycol mass ratio to 0.1% and 1:1, respectively. The glycolysis process allowed us to obtain a high-purity polyol (99%), which can totally replace raw polyols in the synthesis of new flexible polyurethane foams, maintaining the standard mechanical properties of the original one and modifying the ratio of isocyanates employed to correct the closed cell structure caused by the impurities present in the recovered polyol. This isocyanate mixture was also optimized, resulting in a ratio of 30 and 70% of the isocyanates TDI80 and TDI65, respectively. Additionally, the fillers incorporated in the glycolyzed foams were recovered. Both recovered fillers, styrene-acrylonitrile and calcium carbonate, were fully characterized, showing a quality very similar to that of commercial compounds. Finally, the replacement of commercial fillers by the recovered ones in the synthesis of new polyurethane foams was studied, demonstrating the feasibility of using them in the synthesis of new foams without significantly altering their properties.
PubMed: 38930213
DOI: 10.3390/ma17122844 -
Life (Basel, Switzerland) Jun 2024Tracheal grafts have been investigated for over a century, aiming to replace various lesions. However, tracheal reconstruction surgery remains a challenge, primarily due...
BACKGROUND
Tracheal grafts have been investigated for over a century, aiming to replace various lesions. However, tracheal reconstruction surgery remains a challenge, primarily due to anatomical considerations, intraoperative airway management, the technical complexity of reconstruction, and the potential postoperative morbidity and mortality. Due to research development, the amniotic membrane (AM) and Wharton's Jelly (WJ) arise as alternatives within the new set of therapeutic alternatives. These structures hold significant therapeutic potential for tracheal defects. This study analyzed the capacity of tracheal tissue regeneration after 60 days of decellularized WJ and AM implantation in rabbits submitted to conventional tracheostomy.
METHODS
An in vivo experimental study was carried out using thirty rabbits separated into three groups (Control, AM, and WJ) (n = 10). The analyses were performed 60 days after surgery through immunohistochemistry.
RESULTS
Different immunomarkers related to scar regeneration, such as aggrecan, TGF-β1, and α-SMA, were analyzed. However, they highlighted no significant difference between the groups. Collagen type I, III, and Aggrecan also showed no significant difference between the groups.
CONCLUSIONS
Both scaffolds appeared to be excellent frameworks for tissue engineering, presenting biocompatibility and a desirable microenvironment for cell survival; however, they did not display histopathological benefits in trachea tissue regeneration.
PubMed: 38929764
DOI: 10.3390/life14060782 -
Medicina (Kaunas, Lithuania) Jun 2024Hepatitis E virus (HEV) infection is typically a self-limiting, acute illness that spreads through the gastrointestinal tract but replicates in the liver. However,... (Review)
Review
Hepatitis E virus (HEV) infection is typically a self-limiting, acute illness that spreads through the gastrointestinal tract but replicates in the liver. However, chronic infections are possible in immunocompromised individuals. The HEV virion has two shapes: exosome-like membrane-associated quasi-enveloped virions (eHEV) found in circulating blood or in the supernatant of infected cell cultures and non-enveloped virions ("naked") found in infected hosts' feces and bile to mediate inter-host transmission. Although HEV is mainly spread via enteric routes, it is unclear how it penetrates the gut wall to reach the portal bloodstream. Both virion types are infectious, but they infect cells in different ways. To develop personalized treatment/prevention strategies and reduce HEV impact on public health, it is necessary to decipher the entry mechanism for both virion types using robust cell culture and animal models. The contemporary knowledge of the cell entry mechanism for these two HEV virions as possible therapeutic target candidates is summarized in this narrative review.
Topics: Humans; Hepatitis E virus; Hepatitis E; Virion; Animals
PubMed: 38929615
DOI: 10.3390/medicina60060998 -
Medicina (Kaunas, Lithuania) Jun 2024: Dry Eye Disease (DED) is a chronic condition characterised by tear film instability and ocular surface disruption, significantly impacting patients' quality of life.... (Randomized Controlled Trial)
Randomized Controlled Trial
Sutureless Dehydrated Amniotic Membrane (Omnigen) Application Using a Specialised Bandage Contact Lens (OmniLenz) for the Treatment of Dry Eye Disease: A 6-Month Randomised Control Trial.
: Dry Eye Disease (DED) is a chronic condition characterised by tear film instability and ocular surface disruption, significantly impacting patients' quality of life. This study aimed to provide top-level clinical evidence for the long-term efficacy of dehydrated amniotic membrane (dAM, Omnigen) delivered via a specialised bandage contact lens (sBCL, OmniLenz) for managing moderate-to-severe DED. : This randomised controlled trial (NCT04553432) involved 93 participants with moderate-to-severe DED, randomised to receive a 1-week bilateral treatment of either dAM (17 mm diameter with 6 mm central 'window') applied under a sBCL or sBCL alone. Participants were assessed at baseline and followed up at 1, 3, and 6 months post-treatment. Outcomes included changes in symptomatology, tear film and ocular surface measurements, and in vivo confocal microscopy imaging of corneal nerve parameters and corneal dendritic cell (CDC) counts. : The dAM-sBCL group demonstrated a 65% reduction in OSDI scores at 6 months ( < 0.001), with 88% of participants showing improvement at 1 month. Corneal staining was significantly reduced in both groups. dAM-sBCL provided significant improvements in corneal nerve parameters at 1 month, with sustained positive trends at 3 months. Additionally, dAM-sBCL significantly reduced mature CDC counts, suggesting an anti-inflammatory effect. : Treatment with dAM-sBCL for just 1 week significantly and rapidly improved dry eye symptoms as well as ocular surface signs for at least 3 months. It also enhanced corneal nerve health while reducing activated/mature corneal inflammatory cell numbers, presenting a safe and promising new treatment for moderate-to-severe DED.
Topics: Humans; Dry Eye Syndromes; Male; Female; Amnion; Middle Aged; Adult; Contact Lenses; Treatment Outcome; Aged; Quality of Life; Bandages; Cornea
PubMed: 38929602
DOI: 10.3390/medicina60060985 -
Animals : An Open Access Journal From... Jun 2024Ringed seals are consumed in Greenland and are therefore included as a key biomonitoring species with the focus on pollution exposure and health effects. Ringed seals in...
Ringed seals are consumed in Greenland and are therefore included as a key biomonitoring species with the focus on pollution exposure and health effects. Ringed seals in Central West Greenland (Qeqertarsuaq) and in North West Greenland (Qaanaaq) were analyzed for metal concentrations in the liver and histological changes in the liver and kidney. The mean liver concentration of mercury in Qaanaaq was 3.73 ± 5.01 µg/g ww (range: 0.28-23.29 µg/g ww), and the mean cadmium concentration was 7.80 ± 8.95 µg/g ww (range: 0.013-38.79 µg/g ww). For Qeqertarsuaq, the liver concentration of mercury was 1.78 ± 1.70 µg/g ww (range: 0.45-8.00 µg/g ww) and the mean cadmium concentration was 11.58 ± 6.32 µg/g ww (range: 0.11-25.45 µg/g ww). Age had a positive effect on the liver concentrations of metals, while no effect was found for sex or histological changes. The prevalence of histological changes in liver tissue decreased in the following order: random pattern mononuclear cell infiltration (92.1%), portal cell infiltration (68.4%), hepatic intracellular fat (18.4%), portal fibrosis (7.9%), focal hepatic fibrosis (7.9%), bile duct hyperplasia/fibrosis (7.9%) and lipid granuloma (2.6%). For kidney tissue, the prevalence of histological changes decreased in the following order: glomerular mesangial deposits (54.1%) > glomerular basement membrane thickening (45.9%) > THD (40%) > tubular hyaline casts (14.0%) > glomerular atrophy (13.5%) > dilated tubules (13.5%) > glomerular hyper-cellularity (10.8%) > mononuclear cell infiltrations (8.1%).
PubMed: 38929358
DOI: 10.3390/ani14121739 -
Antioxidants (Basel, Switzerland) Jun 2024Oxidative stress (OS) and disrupted antioxidant defense mechanisms play a pivotal role in the etiology of male infertility. The alterations in reactive oxygen species...
Exogenous Oxidative Stress in Human Spermatozoa Induces Opening of the Mitochondrial Permeability Transition Pore: Effect on Mitochondrial Function, Sperm Motility and Induction of Cell Death.
Oxidative stress (OS) and disrupted antioxidant defense mechanisms play a pivotal role in the etiology of male infertility. The alterations in reactive oxygen species (ROS) production and calcium (Ca) homeostasis are the main activators for the mitochondrial permeability transition pore (mPTP) opening. The mPTP opening is one of the main mechanisms involved in mitochondrial dysfunction in spermatozoa. This alteration in mitochondrial function adversely affects energy supply, sperm motility, and fertilizing capacity and contributes to the development of male infertility. In human spermatozoa, the mPTP opening has been associated with ionomycin-induced endogenous oxidative stress and peroxynitrite-induced nitrosative stress; however, the effect of exogenous oxidative stress on mPTP opening in sperm has not been evaluated. The aim of this study was to determine the effect of exogenous oxidative stress induced by hydrogen peroxide (HO) on mPTP opening, mitochondrial function, motility, and cell death markers in human spermatozoa. Human spermatozoa were incubated with 3 mmol/L of HO for 60 min, and intracellular Ca concentration, mPTP opening, mitochondrial membrane potential (ΔΨm), ATP levels, mitochondrial reactive oxygen species (mROS) production, phosphatidylserine (PS) externalization, DNA fragmentation, viability, and sperm motility were evaluated. HO-induced exogenous oxidative stress caused increased intracellular Ca, leading to subsequent mPTP opening and alteration of mitochondrial function, characterized by ΔΨm dissipation, decreased ATP levels, increased mROS production, and the subsequent alteration of sperm motility. Furthermore, HO-induced opening of mPTP was associated with the expression of apoptotic cell death markers including PS externalization and DNA fragmentation. These results highlight the role of exogenous oxidative stress in causing mitochondrial dysfunction, deterioration of sperm motility, and an increase in apoptotic cell death markers, including PS externalization and DNA fragmentation, through the mPTP opening. This study yielded new knowledge regarding the effects of this type of stress on mitochondrial function and specifically on mPTP opening, factors that can contribute to the development of male infertility, considering that the role of mPTP in mitochondrial dysfunction in human sperm is not completely elucidated. Therefore, these findings are relevant to understanding male infertility and may provide an in vitro model for further research aimed at improving human sperm quality.
PubMed: 38929178
DOI: 10.3390/antiox13060739 -
Antioxidants (Basel, Switzerland) Jun 2024Cell death involving oxidative stress and mitochondrial dysfunction is a major cause of dopaminergic neuronal loss in the substantia nigra (SN) of Parkinson's disease...
Cell death involving oxidative stress and mitochondrial dysfunction is a major cause of dopaminergic neuronal loss in the substantia nigra (SN) of Parkinson's disease patients. Ergothioneine (ET), a natural dietary compound, has been shown to have cytoprotective functions, but neuroprotective actions against PD have not been well established. 6-Hydroxydopamine (6-OHDA) is a widely used neurotoxin to simulate the degeneration of dopaminergic (DA) neurons in Parkinson's disease. In this study, we investigated the protective effect of ET on 6-OHDA treated iPSC-derived dopaminergic neurons (iDAs) and further confirmed the protective effects in 6-OHDA-treated human neuroblastoma SH-SY5Y cells. In 6-OHDA-treated cells, decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial reactive oxygen species (mROS), reduced cellular ATP levels, and increased total protein carbonylation levels were observed. 6-OHDA treatment also significantly decreased tyrosine hydroxylase levels. These effects were significantly decreased when ET was present. Verapamil hydrochloride (VHCL), a non-specific inhibitor of the ET transporter OCTN1 abrogated ET's cytoprotective effects, indicative of an intracellular action. These results suggest that ET could be a potential therapeutic for Parkinson's disease.
PubMed: 38929132
DOI: 10.3390/antiox13060693 -
Antioxidants (Basel, Switzerland) May 2024Statins are 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors widely used in the treatment of hyperlipidemia. The inhibition of HMG-CoA reductase in...
Statins are 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors widely used in the treatment of hyperlipidemia. The inhibition of HMG-CoA reductase in the mevalonate pathway leads to the suppression of cell proliferation and induction of apoptosis. The cyclic GMP-AMP synthase (cGAS) stimulator of the interferon genes (STING) signaling pathway has been suggested to not only facilitate inflammatory responses and the production of type I interferons (IFN), but also activate other cellular processes, such as apoptosis. It has not been studied, however, whether cGAS-STING activation is involved in the apoptosis induced by statin treatment in human colorectal cancer cells. In this study, we reported that lovastatin impaired mitochondrial function, including the depolarization of mitochondrial membrane potential, reduction of oxygen consumption, mitochondrial DNA (mtDNA) integrity, and mtDNA abundance in human colorectal cancer HCT116 cells. The mitochondrial dysfunction markedly induced ROS production in mitochondria, whereas the defect in mitochondria respiration or depletion of mitochondria eliminated reactive oxygen species (ROS) production. The ROS-induced oxidative DNA damage by lovastatin treatment was attenuated by mitochondrial-targeted antioxidant mitoquinone (mitoQ). Upon DNA damage, mtDNA was released into the cytosol and bound to DNA sensor cGAS, thus activating the cGAS-STING signaling pathway to trigger a type I interferon response. This effect was not activated by nuclear DNA (nuDNA) or mitochondrial RNA, as the depletion of mitochondria compromised this effect, but not the knockdown of retinoic acid-inducible gene-1/melanoma differentiation-associated protein 5 (RIG-I/MDA5) adaptor or mitochondrial antiviral signaling protein (MAVS). Moreover, lovastatin-induced apoptosis was partly dependent on the cGAS-STING signaling pathway in HCT116 cells as the knockdown of cGAS or STING expression rescued cell viability and mitigated apoptosis. Similarly, the knockdown of cGAS or STING also attenuated the antitumor effect of lovastatin in the HCT116 xenograft model in vivo. Our findings suggest that lovastatin-induced apoptosis is at least partly mediated through the cGAS-STING signaling pathway by triggering mtDNA accumulation in the cytosol in human colorectal cancer HCT116 cells.
PubMed: 38929118
DOI: 10.3390/antiox13060679