Membrane Disintegration Research Articles

Immune‐stimulating properties of Wild Yam (Dioscorea villosa) root extract in triple‐negative breast cancer cells

Testing the roots of Wild yam (Dioscorea villosa extract (WYE) in vitroconsistently induced cell death at low IC50 concentrations in many types of cancers, including glioblastoma, melanoma, colon cancer, neuroblastoma, and breast cancer. However, reports also demonstrate that WYE contains detergent steroidal saponin surfactants, which act on contact to reduce oil‐water interfacial tensions causing disintegration of the bio‐lipid membranes. In the current investigation we separated cell death from saponins from its biological effects that occur at sub‐lethal doses, where lytic cell death is not an interfering variable in MDA‐MB‐231 triple‐negative breast cancer cells. Moreover, we confirmed the inverse relationship between rising saponin content with destruction to plasma and mitochondrial membranes, concurrent to toxicity in 2D and 3D cell cultures. Once appropriate sub‐lethal concentrations were established, we monitored the changes in whole transcriptomic (WT) mRNA miRNA. Also, the intergenic non‐coding RNAs concurrent to the biological cell proliferation studies, spot test of antibody‐protein arrays, and an ELISA were documented. The results indicate that at sub‐lethal concentrations of WYE, the microarray data show 346 differentially expressed genes (DEGs) of 48,226 transcripts tested; 166 upregulated and 180 downregulated. Upregulated DEGS reflected immune‐stimulating effects on TNF signaling, COX2, cytokine release, and elevated cholesterol/steroid biosynthesis. Downregulated DEGs reveal extensive damage to cell cycle processes, including loss of transcripts for cell division cycle (CDC) genes (25A,45,6,7, A2, A7, A7L,8) cyclins (CCN) (A2, B1, B2, E2, F), cyclin‐dependent kinases (CDKs), centromere proteins (CENP), kinesin family members (KIFs), and polo‐like kinases (PLKs) with exception to a corresponding up‐regulated DEG for p21 gene CDKN1A. The transcriptome data matches cytostatic effects observed in a 6‐day proliferation study. It was concluded that WYE mediates a saponin lytic effect by direct contact and this breast cancer cell model has two different biological consequences at lower concentrations and independent of cell death, including pro‐inflammatory and collapse of the cell cycle effects.

A Perfect Pair: Stabilized Black Phosphorous Nanosheets Engineering with Antimicrobial Peptides for Robust Multidrug Resistant Bacteria Eradication (Adv. Healthcare Mater. 10/2022)

Photothermal Therapy In article number 2101846, Xin Pan and co-workers establish a novel antibacterial platform that integrates antimicrobial peptides and photothermal agents to construct ε-poly-L-lysine (ε-PL)—stabilized black phosphorus (BP) nanosheets. The dual drug-delivery complex can closely anchor onto the surface of bacteria, leading to membrane disintegration. Subsequently, in situ hyperthermia generated by BP under NIR irradiation can effectively eradicate pathogenic bacteria.

Cardiac Remodeling in Heart Failure: Role of Pyroptosis and Its Therapeutic Implications.

Pyroptosis is a kind of programmed cell death closely related to inflammation. The pathways that mediate pyroptosis can be divided into the Caspase-1-dependent canonical pathway and the Caspase4/5/11-dependent non-canonical pathway. The most significant difference from other cell death is that pyroptosis rapidly causes rupture of the plasma membrane, cell expansion, dissolution and rupture of the cell membrane, the release of cell contents and a large number of inflammatory factors, and send pro-inflammatory signals to adjacent cells, recruit inflammatory cells and induce inflammatory responses. Cardiac remodeling is the basic mechanism of heart failure (HF) and the core of pathophysiological research on the underlying mechanism. A large number of studies have shown that pyroptosis can cause cardiac fibrosis, cardiac hypertrophy, cardiomyocytes death, myocardial dysfunction, excessive inflammation, and cardiac remodeling. Therefore, targeting pyroptosis has a good prospect in improving cardiac remodeling in HF. In this review, the basic molecular mechanism of pyroptosis is summarized, the relationship between pyroptosis and cardiac remodeling in HF is analyzed in-depth, and the potential therapy of targeting pyroptosis to improve adverse cardiac remodeling in HF is discussed, providing some ideas for improving the study of adverse cardiac remodeling in HF.

Functional role of a novel algicidal compound produced by Pseudoruegeria sp. M32A2M on the harmful algae Alexandrium catenella

A marine phytoplankton dinoflagellate, Alexandrium sp. is known to cause worldwide harmful algal blooms, resulting in paralytic shellfish poisoning. In this study, we isolated a novel compound secreted by the marine bacterium Pseudoruegeria sp. M32A2M, and showed that it displays algicidal activity against A. catenella (group I). The molecular structure of the compound was analyzed by using 1H nuclear magnetic resonance (NMR), 13C NMR, and gas chromatography-mass spectrometry, which revealed that the compound was a diketopiperazine, cyclo[Ala-Gly]. Cyclo[Ala-Gly] induced a rapid decrease in the active chlorophyll a content and maximal quantum yield of photosystem II, leading to membrane disintegration after 24 h of its treatment. It showed the highest algicidal effect against diketopiperazines and also showed specific algicidal activities against several dinoflagellate species, but not for diatom species. In particular, cyclo[Ala-Gly] caused the transcriptional downregulation of the photosynthesis-related membrane complex in A. catenella, but not in the diatom Chaetoceros simplex. Based on structural modeling, we elucidated that cyclo[Ala-Gly] has a structure similar to that of plastoquinone, which transfers electrons by binding to the photosystem II core proteins PsbA and PsbD. This suggests a novel role for cyclo[Ala-Gly] as a potential inhibitor of photosynthesis.

Evaluation of fresh, frozen, and lyophilized fecal samples by SPME and derivatization methods using GC×GC-TOFMS.

Feces is a highly complex matrix containing thousands of metabolites. It also contains live bacteria and enzymes, and does not have a static chemistry. Consequently, proper control of pre-analytical parameters is critical to minimize unwanted variations in the samples. However, no consensus currently exists on how fecal samples should be stored/processed prior to analysis. The effects of sample handling conditions on fecal metabolite profiles and abundances were examined using comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC×GC-TOFMS). Solid-phase microextraction (SPME) and derivatization via trimethylsilylation (TMS) were employed as complementary techniques to evaluate fresh, frozen, and lyophilized fecal samples with expanded coverage of the fecal metabolome. The total number of detected peaks and the signal intensities were compared among the different handling conditions. Our analysis revealed that the metabolic profiles of fecal samples depend greatly on sample handling and processing conditions, which had a more pronounced effect on results obtained by SPME than by TMS derivatization. Overall, lyophilization resulted in a greater amount of total and class-specific metabolites, which may be attributed to cell lysis and/or membrane disintegration. A comprehensive comparison of the sample handling conditions provides a deeper understanding of the physicochemical changes that occur within the samples during freezing and lyophilization. Based on our results, snap-freezing at -80°C would be preferred over lyophilization for handling samples in the field of fecal metabolomics as this imparts the least change from the fresh condition.

A Perfect Pair: Stabilized Black Phosphorous Nanosheets Engineering with Antimicrobial Peptides for Robust Multidrug Resistant Bacteria Eradication.

Black phosphorus (BP) nanosheets emerged as promising 2D nanomaterial that have been applied to eradicate antibiotic-resistant bacteria. However, their applications are limited by intrinsic ambient instability. Here, the ε-poly-l-lysine (ε-PL)-engineered BP nanosheets are constructed via simple electrostatic interaction to cater the demand for passivating BP with amplified antibacterial activity. The dual drug-delivery complex named BP@ε-PL can closely anchor onto the surface of bacteria, leading to membrane disintegration. Subsequently, in situ hyperthermia generated by BP under near-infrared (NIR) irradiation can precisely eradicate pathogenic bacteria. In vitro antibacterial studies verify the rapid disinfection ability of BP@ε-PL against Methicillin-resistant Staphylococcus aureus (MRSA) within 15min. Moreover, ε-PL can serve as an effective protector to avoid chemical degradation of bare BP. The in vivo antibacterial study shows that a 99.4% antibacterial rate in a MRSA skin infection model is achieved, which is accompanied by negligible toxicity. In conclusion, this work not merely provides a new conjecture for protecting the BP, but also opens a novel window for synergistic antibiotic-resistant bacteria therapy based on antimicrobial peptides and 2D photothermal nanomaterial.

Effect of symbiotic associations with Frankia and arbuscular mycorrhizal fungi on antioxidant activity and cell ultrastructure in C. equisetifolia and C. obesa under salt stress

ABSTRACT Plants of the Casuarinaceae family are widely known for their ability to tolerate salt stress. Casuarinaceae are able to develop symbiotic association with arbuscular mycorrhizal fungi and with the soil bacteria Frankia. The aim of this study was to evaluate adaptation mechanisms of Casuarina to tolerate salt stress when interacting Rhizophagus fasciculatus and Frankia. Two species showing different salt tolerance levels, i.e. C. equisetifolia and C. obesa, were grown in sandy sterile soil, inoculated with R. fasciculatus and/or Frankia and then watered gradually with increased concentrations of saline solutions. Total antioxidant activity, antioxidant enzyme concentration, and salt effects on cellular ultrastructure of shoots were evaluated. C. obesa has a better salt stress tolerance compared to C. equisetifolia. Co-inoculation (R. fasciculatus and Frankia) improved the performance of both plant species in saline. Higher antioxidant activity was observed in C. obesa. At 400 mM of NaCl C. obesa revealed a maintenance of cellular integrity whereas cell membrane rupture and disintegration of cellular contents were observed in C. equisetifolia tissues. Our results suggest that a selection of appropriate plant species is important to improve plant performance in saline soils.

Investigating the Environmental Survival of Marteilia refringens, a Marine Protozoan Parasite of the Flat Oyster Ostrea edulis, Through an Environmental DNA and Microscopy-Based Approach

Outside-host parasite survival is a key parameter to better understand disease mechanisms, especially for marine pathogens transmitted from one host to another through an environmental stage. For non-cultivable micro-parasites like Marteilia refringens, a protozoan parasite infecting the flat oyster Ostrea edulis, investigating this parameter requires innovative approaches. In the present study, we have developed an Environmental DNA (eDNA)-based method allowing detecting and quantifying up to 25 and 10 parasites DNA in seawater and sediment, respectively. This method was used in combination with light and transmission electron microscopy (TEM) to study experimentally parasite survival in seawater and flat oyster faeces after its release from naturally infected oysters. M. refringens DNA could be detected up to 20 days, in both seawater and oyster faeces with a more stable detection over time in the latter. Light and transmission microscopy confirm that parasites leaving flat oysters are sporangia. We also observed a membrane dissolution of the sporangia over time that could indicate the release of parasite spore. This study not only improves our understanding of M. refringens ecology but also highlights the interest to combine molecular and microscopical analysis to study non-cultivable micro-parasites life cycle outside their host.

Eradication of Fungi Using MoSe2/Chitosan Nanosheets

Antifungal drug resistance is an increasingly significant threat to humans, livestock, and crops. Recent studies have shown nanomaterials as promising alternatives in combating drug-resistant pathogens. Here, we show that molybdenum diselenide (MoSe2) nanosheets dispersed in the cationic polymer chitosan (CS) exhibit exceptional antifungal activity. The MoSe2/CS nanosheets provide minimum inhibitory concentrations (MICs) between 0.78 and 37.5 μg ml–1 against a variety of unicellular fungal strains and demonstrate minimum fungicidal concentrations (MFCs) from 0.5 to 75 μg ml–1 for diverse unicellular and filamentous strains. Furthermore, we demonstrate the ability of MoSe2/CS to eradicate increasingly prevalent and highly multi-drug-resistant (MDR) fungi Candida auris strains with MICs of 25 to 50 μm ml–1 and MFCs of 37.5 to 150 μm ml–1. The effective antifungal activity of MoSe2/CS was observed after an incubation time of 3 h, which is faster than the time needed for other nanomaterial-based antifungal agents incorporating graphene, two-dimensional (2D) nanomaterials, or silver nanoparticles. MoSe2/CS also showed high biocompatibility and was benign toward human red blood cells and human embryonic kidney cells. Electron microscopy and confocal optical microscopy show that fungal cells treated with MoSe2/CS nanosheets exhibit morphological deformities, ruptured cell walls and interior voids, and metabolic inactivation. Mechanistic investigations revealed that treatment with MoSe2/CS triggers complete membrane depolarization and membrane disintegration within 3 h. Hence, this work demonstrates that the biocompatible nanomaterial MoSe2/CS is a highly effective alternative antifungal agent against many kinds of pathogenic fungi including MDR strains.

Mechanistic Insight of the Antifungal Potential of Green Synthesized Zinc Oxide Nanoparticles against Alternaria brassicae

Alternaria brassicae is a necrotrophic fungus causes Alternaria blight disease in oilseed mustard crop. There is a 47% loss of the mustard crop due to the Alternaria blight disease. To control this disease, various chemical fungicides have been used till date which are harmful to our environment. Zinc oxide (ZnO) nanoparticles synthesized from Terminalia bellerica have been reported to have significant antifungal potential against A. brassicae at 200 ppm concentration. In the present study, the effect of green synthesized zinc oxide (Tb‐ZnO) nanoparticles, chemically synthesized ZnO nanoparticles, and chemical fungicides on A. brassicae has been anticipated by analysing changes in cytomorphology characteristics, biochemical constituent, and stress enzymes of A. brassicae. Cytomorphological studies by transmission electron microscopy and scanning electron microscopy have shown the complete disintegration of cell wall, cell membrane, and cytoplasmic content at 200 ppm concentration of Tb‐ZnO nanoparticles. Decrement in biochemical constituents and changes in activity of stress enzymes in Tb‐ZnO nanoparticles treated cell confirm the toxicity of nanoparticles at 200 ppm concentrations. Hence, on the basis of all these results, the mechanism of action of Tb‐ZnO nanofungicides on A. brassicae has been hypothesized in the present study. This study confirms how nanoparticles inhibit the growth of A. brassicae and suggested the use of nanofungicides.

Active P-Colonies

P-Systems are abstract machines inspired to the behaviour of cells which we can see like simple biological processing units. Many types of P-Systems have been developed considering different aspects of the cells working principles, obtaining different computational models. In this paper we introduce Active P-Colonies (APC), a variant of the model P-Colony systems. P-Colony systems are a model of computation based on the collaboration among different agents placed in a shared passive environment (i.e. a space where no computing operations take place). First of all, we show that using the P-Colony system basic model it is not possible to solve problems in the computational class NP (unless P=NP). Inspired by what has been done for the basic variant of P-Systems, we extend the original model by including new types of rules and new biological behaviours like duplication and membrane dissolution. In fact, in APC the agents are able to duplicate themselves obtaining new processing units having the same computational power as the original unit. The cells can also dissolve their membrane, releasing the contents into the environment. The obtained systems are able to solve in polynomial time (and exponential space) computationally hard problems. In particular, we focus on the development of systems able to solve problems in the classes NP (SAT), coNP (UNSAT) and #P (#SAT).

Changes in the contour of karyology and histoarchitecture of the primary respiratory organ in the fish Oreochromis mossambicus (Peters, 1852) inhabiting the polluted estuarine ecosystem

The wetland ecosystem (WE) is subject to pollution by many anthropogenic activities, including domestic and industrial effluents. These effluents may contain toxic heavy metals that can interact within the aquatic ecosystem and have a capacity to disturb the metabolic activities, histological profile, and genetic structure and functions in aquatic species inhabiting the environment. The present study observed the karyological and histological alterations in gills of the freshwater fish, Mozambique tilapia, Oreochromis mossambicus in two different sublethal concentrations (1% and 3%) of heavy metals in 7, 15, and 30 days of experimental periods. The heavy metals induced various structural damages such as ring chromosome, sister chromatid exchange, acrocentric association region, condensed chromosomal morphology, heterochromatin region, and nucleolar organizer region in the chromosomes of O. mossambicus treated with 1% and 3% sublethal concentrations of water sample collected from Pallikaranai wetland ecosystem. Gills exposed to 1% and 3% effluent exhibited several variations in the respiratory surfaces of gill arches or lamellae in the light and scanning microscopical study. The gills exposed to 1% concentration for 30 days showed marked necrosis, and the secondary lamellae showed the lamellar membrane's dissolution. Exposure of gills to raw effluent in the field condition was observed in the presence of Cd, Pb, Cr, Cu, and Zn. Thus, this present study shows the environmental deterioration by heavy metal pollution on the structure of the gills in tilapia.

Immunohistochemical Analysis of Myofibroblasts Using α- SMA in Oral Submucous Fibrosis Turning into Malignancy- A Case Report and Review

Oral submucous fibrosis is a premalignant condition, characterized by fibrosis in oral mucosa causing stiffness of mucosa and leading to reduced mouth opening. The malignant transformation of oral submucous fibrosis is very high among the rest of the premalignant conditions. Chronic chewing of arecanut causes production of myofibroblasts. These myofibroblasts plays an important role in neoangiogenesis as well as disintegration of the basement membrane at the tumor invasive front leading to carcinoma. Here, we are doing an Immunohistochemical study using alpha SMA for proper microscopic visulizations of myofibroblastic activity in an OSF patient, encompassing the pathogenesis and malignant potentiality of the disease.

Neutrophil and remnant clearance in immunity and inflammation

Neutrophil-centred inflammation and flawed clearance of neutrophils cause and exuberate multiple pathological conditions. These most abundant leukocytes exhibit very high daily turnover in steady-state and stress conditions. Various armours including oxidative burst, NETs and proteases function against pathogens, but also dispose neutrophils to spawn pro-inflammatory responses. Neutrophils undergo death through different pathways upon ageing, infection, executing the intruder's elimination. These include non-lytic apoptosis and other lytic deaths including NETosis, necroptosis and pyroptosis with distinct disintegration of the cellular membrane. This causes release and presence of different intracellular cytotoxic, and tissue-damaging content as cell remnants in the extracellular environment. The apoptotic cells and apoptotic bodies get cleared with non-inflammatory outcomes, while lytic deaths associated remnants including histones and cell-free DNA cause pro-inflammatory responses. Indeed, the enhanced frequencies of neutrophil-associated proteases, cell-free DNA and autoantibodies in diverse pathologies including sepsis, asthma, lupus and rheumatoid arthritis, imply disturbed neutrophil resolution programmes in inflammatory and autoimmune diseases. Thus, the clearance mechanisms of neutrophils and associated remnants are vital for therapeutics. Though studies focused on clearance mechanisms of senescent or apoptotic neutrophils so far generated a good understanding of the same, clearance of neutrophils undergoing distinct lytic deaths, including NETs, are being the subjects of intense investigations. Here, in this review, we are providing the current updates in the clearance mechanisms of apoptotic neutrophils and focusing on not so well-defined recognition, uptake and degradation of neutrophils undergoing lytic death and associated remnants that may provide new therapeutic approaches in inflammation and autoimmunity.

METHANOL LEAF EXTRACT OF Jatropha tanjorensis Ellis and Saroja POSSESS PHYTOCONSTITUENTS WITH FREE RADICAL SCAVENGING ACTIVITY

The body during normal metabolic function produces free radicals which are highly reactive species. Free radicals could also be introduced into the body from the environment. The oxidation induced by reactive oxygen species can result in DNA mutation, membrane protein damage and cell membrane disintegration. The present study assayed the preliminary phytochemicals, total phenolics and total flavonoids and free radicals scavenging ability of methanol extract of Jatropha tanjorensis leaf. Standard methods for determining phytochemicals, reducing power, nitric oxide scavenging, hydroxyl radical, and lipid peroxidation scavenging activity were employed. The phytochemical screening result revealed the presences of phenols, flavonoids, saponin, alkaloids, tannins, terpernoids and steroids. The total phenolic content of methanol extract of Jatropha tanjorensis leaf measured by Folin-Ciocalteau reagent in terms of gallic acid equivalent was 11.35±0.82mgGAE/g. The flavonoid content of the plant sample calculated as Quercetin equivalent was 15.91±1.60mgQCE/g. GC-MS results revealed relevant pharmacological bioactive compounds. The antioxidative activity of the plant’s extract correlated with total phenolic content. The radical scavenging activity showed a dose dependent increase in the reducing power. The minimum NO inhibitory activity was 8.88±0.63 at 200µg/ml and the maximum activity was 32.70±2.71 at 800µg/ml. The minimum percentage H2O2 radical inhibitory activity was 8.30±0.88 at 200µg/ml and a maximum activity was 22.80±2.28 at 800µg/ml. There was also an increase scavenging effect of lipid peroxide radical in concentration dependent manner. The results of this study indicate that the leaf of Jatropha tanjorensis possess antioxidant properties and could serve as free radical inhibitor

Basement membrane proteins improve human islet survival in hypoxia: Implications for islet inflammation

Enzymatic digestion of the pancreas during islet isolation is associated with disintegration of the islet basement membrane (IBM) that can cause reduction of functional and morphological islet integrity. Attempts to re-establish IBM by coating the surface of culture vessels with various IBM proteins (IBMP) have resulted in loss of islet phenotype and function. This study investigated the capability of Collagen-IV, Laminin-521 and Nidogen-1, utilised as single or combined media supplements, to protect human islets cultured in hypoxia.When individually supplemented to media, all IBMP significantly improved islet survival and in-vitro function, finally resulting in as much as a two-fold increase of islet overall survival. In contrast, combining IBMP enhanced the production of chemokines and reactive oxygen species diminishing all positive effects of individually added IBMP. This impact was concentration-dependent and concerned nearly all parameters of islet integrity.Predictive extrapolation of these findings to data from 116 processed human pancreases suggests that more than 90% of suboptimal pancreases could be rescued for clinical islet transplantation increasing the number of transplantable preparations from actual 25 to 40 when adding Nidogen-1 to pretransplant culture.This study suggests that media supplementation with essential IBMP protects human islets from hypoxia. Amongst those, certain IBMP may be incompatible when combined or applied at higher concentrations. Statement of significancePancreatic islet transplantation is a minimally-invasive treatment that can reverse type 1 diabetes in certain patients. It involves infusing of insulin-producing cell-clusters (islets) from donor pancreases. Unfortunately, islet extraction is associated with damage of the islet basement membrane (IBM) causing reduced islet function and cell death. Attempts to re-establish the IBM by coating the surface of culture vessels with IBM proteins (IBMP) have been unsuccessful. Instead, we dissolved the most relevant IBM components Collagen-IV, Laminin-521 and Nidogen-1 in media routinely used for clinical islet culture and transplantation. We found human islet survival and function was substantially improved by IBMP, particularly Nidogen-1, when exposed to a hypoxic environment as found in vivo. We also investigated IBMP combinations. Our present findings have important clinical implications.

Histological alterations, oxidative stress, and inflammatory response in the liver of swamp eel (Monopterus albus) acutely exposed to copper.

Copper (Cu) is widely used as an essential trace element in diets as well as a therapeutic chemical. However, excessive Cu has deleterious effects on organisms, including teleosts. Although numerous toxic effects of Cu have been reported, the effects of Cu exposure on the swamp eel (Monopterus albus) as well as the underlying mechanisms have not yet been elucidated. In this study, swamp eels were acutely exposed to 100, 200, and 400μg/L of Cu for 96h to evaluate liver histopathology, oxidative stress, and inflammation. Dissolution of hepatocyte membrane, vacuolar degeneration, and inflammatory cell infiltration were detected in the livers of the Cu-treated swamp eels, especially in the 400μg Cu/L group. Cu-induced hepatic dysfunction was further verified by the elevated activities of glutamate oxaloacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT) and transcript levels of GOT and GPT genes. In addition, Cu exposure decreased the activities of total superoxide dismutase T-SOD and catalase (CAT) and the contents of glutathione (GSH) and total antioxidant capacity (T-AOC) and increased the levels of malondialdehyde (MDA). Cu exposure also significantly decreased the transcript levels of glutathione synthetase (GSS) and increased the transcript levels of SOD1, SOD2, CAT, and heme oxygenase-1 (HO-1) genes. Furthermore, pro-inflammatory genes such as interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), and IL-8 were significantly upregulated. These results indicate that Cu induces oxidative stress and inflammatory response and causes pathological changes in the liver of the swamp eel.

Targeted delivery of a phosphoinositide 3‐kinase γ inhibitor to restore organ function in sepsis

Jaundice, the clinical hallmark of infection‐associated liver dysfunction, reflects altered membrane organization of the canalicular pole of hepatocytes and portends poor outcomes. Mice lacking phosphoinositide 3‐kinase‐γ (PI3Kγ) are protected against membrane disintegration and hepatic excretory dysfunction. However, they exhibit a severe immune defect that hinders neutrophil recruitment to sites of infection. To exploit the therapeutic potential of PI3Kγ inhibition in sepsis, a targeted approach to deliver drugs to hepatic parenchymal cells without compromising other cells, in particular immune cells, seems warranted. Here, we demonstrate that nanocarriers functionalized through DY‐635, a fluorescent polymethine dye, and a ligand of organic anion transporters can selectively deliver therapeutics to hepatic parenchymal cells. Applying this strategy to a murine model of sepsis, we observed the PI3Kγ‐dependent restoration of biliary canalicular architecture, maintained excretory liver function, and improved survival without impairing host defense mechanisms. This strategy carries the potential to expand targeted nanomedicines to disease entities with systemic inflammation and concomitantly impaired barrier functionality.

Macromolecular assembly and membrane activity of antimicrobial D,L-α-Cyclic peptides

Antimicrobial peptides are viewed as a promising alternative to conventional antibiotics, as their activity through membrane targeting makes them less prone to resistance development. Among them, antimicrobial D,L-α-cyclic peptides (CPs) have been proposed as an alternative, specially due to their cyclic nature and to the presence of D-α-amino acids that increases their resistance to proteases. In present work, second generation D,L-α-cyclic peptides with proven antimicrobial activity are shown to form complex macromolecular assemblies in the presence of membranes. We addressed the CPs:membrane interactions through a combination of experimental techniques (DSC and ATR-FTIR) with coarse-grained molecular dynamics (CG-MD) simulations, aiming at understanding their interactions, macromolecular assemblies and eventually unveil their mechanism of action. DSC shows that the interaction depends heavily on the negatively charge content of the membrane and on lipid/peptide ratio, suggesting different mechanisms for the different peptides and lipid systems. CG-MD proved that CPs can self-assemble at the lipid surface as nanotubes or micellar aggregates, depending on the peptide, in agreement with ATR-FTIR results. Finally, our results shed light into possible mechanisms of action of the peptides with pending hydrocarbon tail, namely membrane extensive segregation and/or membrane disintegration through the formation of disk-like lipid/peptide aggregates.

Sol-Gel Synthesis of Dy-Substituted Ni0.4Cu0.2Zn0.4(Fe2-xDyx)O4 Nano Spinel Ferrites and Evaluation of Their Antibacterial, Antifungal, Antibiofilm and Anticancer Potentialities for Biomedical Application.

BackgroundThe constant rise of microbial biofilm formation and drug resistance to existing antimicrobial drugs poses a significant threat to community health around the world because it reduces the efficacy and efficiency of treatments, increasing morbidity, mortality, and health-care expenditures. As a result, there is an urgent need to develop novel antimicrobial agents that inhibit microbial biofilm formation.MethodsThe [Ni0.4Cu0.2Zn0.4](Fe2-xDyx)O4(x≤0.04) (Ni-Cu-Zn) nano spinel ferrites (NSFs) have been synthesized by the sol–gel auto-combustion process and were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive x-ray (EDX) and transmission electron microscopy (TEM). The antimicrobial, antibiofilm and antiproliferative activities of Ni-Cu-Zn NSFs were also examined.ResultsThe XRD pattern confirms the secondary phase DyFeO3 and Fe2O3 for substituted Dy3+ samples, and the crystallite size ranged from 10 to 19 nm. TEM analysis of NSFs revealed that the particles were cube-shaped and 15nm in size. NSFs exhibited significant antimicrobial, antibiofilm and antiproliferative activity. At concentration of 1 mg/mL, it was found that the NSFs (ie, x=0.0, x=0.01, x=0.02, x=0.03 and x=0.04) inhibit biofilm formation by 27.6, 26.2, 58.5, 33.3 and 25% for methicillin-resistant Staphylococcus aureus (MRSA) and 47.5, 43.5, 48.6, 58.3 and 26.6% for Candida albicans, respectively. SEM images demonstrate that treating MRSA and C. albicans biofilms with NSFs significantly reduces cell adhesion, colonization and destruction of biofilm architecture and extracellular polymeric substances matrices. Additionally, SEM and TEM examination revealed that NSFs extensively damaged the cell walls and membranes of MRSA and C. albicans. Huge ultrastructural alteration such as deformation, disintegration and separation of cell wall and membrane from the cells was observed, indicating significant loss of membrane integrity, which eventually led to cell death. Furthermore, it was observed that NSF inhibited the cancer cell growth and proliferation of HCT-116 in a dose-dependent manner.ConclusionThe current study demonstrated that the synthesized Ni-Cu-Zn NSFs could be used to develop potential antimicrobial surface coatings agents for a varieties of biomedical-related materials and devices in order to prevent the biofilms formation and their colonization. Furthermore, the enhanced antiproliferative properties of manufactured SNFs suggest a wide range of biomedical applications.