Concurrent strangulated obturator hernia and femoral hernia repair via TAPP approach: A case report.

An obturator hernia is a rare pelvic hernia with high mortality. Early diagnosis and treatment are essential to reduce postoperative complications. The treatment of choice for obturator hernias is surgery. In an emergency, laparotomy to resolve herniated viscera and complications is often the choice. However, some researchers have shown the feasibility of laparoscopy. The laparoscopic approach has several benefits over the open approach, including reduced postoperative pain, early mobilization, shorter length of stay, and lower postoperative morbidity rates. We report the case of an 81-year-old woman with a right-side obstructed obturator hernia. The patient was hospitalized with an acute onset of inner thigh pain and bowel obstruction. The obturator hernia was diagnosed preoperatively by an abdominopelvic CT scan with the image of protrusion of an ileal loop in the right obturator foramen. The patient was treated by an emergency laparoscopy. The right obturator hernia and a concurrent right femoral hernia were confirmed during the operation. The hernia defect was repaired with a mesh large enough to cover all hernia foramen. The patient recovered without any complications. Emergency laparoscopic repair for obstructed obturator hernia was safe and effective.

Orange G degradation by heterogeneous peroxymonosulfate activation based on magnetic MnFe2O4/α-MnO2 hybrid.

Wastewater containing an azo dye Orange G (OG) causes massive environmental pollution, thus it is critical to develop a highly effective, environmental-friendly, and reusable catalyst in peroxymonosulfate (PMS) activation for OG degradation. In this work, we successfully applied a magnetic MnFe2O4/α-MnO2 hybrid fabricated by a simple hydrothermal method for OG removal in water. The characteristics of the hybrid were investigated by X-ray diffraction, scanning electron microscopy, energy-dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, Brunauer-Emmett-Teller method, vibrating sample magnetometry, electron paramagnetic resonance, thermogravimetric analysis, and X-ray photoelectron spectroscopy. The effects of operational parameters (i.e., catalytic system, catalytic dose, solution pH, and temperature) were investigated. The results exhibited that 96.8% of OG degradation was obtained with MnFe2O4/α-MnO2(1:9)/PMS system in 30 min regardless of solution pH changes. Furthermore, the possible reaction mechanism of the coupling system was proposed, and the degradation intermediates of OG were identified by mass spectroscopy. The radical quenching experiments and EPR tests demonstrated that SO4•̶, O2•̶, and 1O2 were the primary reactive oxygen species responsible for the OG degradation. The hybrid also displayed unusual stability with less than 30% loss in the OG removal after four sequential cycles. Overall, magnetic MnFe2O4/α-MnO2 hybrid could be used as a high potential activator of PMS to remove orange G and maybe other dyes from wastewater.

Recent progress in nitric oxide-generating nanomedicine for cancer therapy.

Nitric oxide (NO) is an endogenous, multipotent biological signaling molecule that participates in several physiological processes. Recently, exogenous supplementation of tumor tissues with NO has emerged as a potential anticancer therapy. In particular, it induces synergistic effects with other conventional therapies (such as chemo-, radio-, and photodynamic therapies) by regulating the activity of P-glycoprotein, acting as a vascular relaxant to relieve tumor hypoxia, and participating in the metabolism of reactive oxygen species. However, NO is highly reactive, and its half-life is relatively short after generation. Meanwhile, NO-induced anticancer activity is dose-dependent. Therefore, the targeted delivery of NO to the tumor is required for better therapeutic effects. In the past decade, NO-generating nanomedicines (NONs), which enable sustained and specific NO release in tumor tissues, have been developed for enhanced cancer therapy. This review describes the recent efforts and preclinical achievements in the development of NON-based cancer therapies. The chemical structures employed in the fabrication of NONs are summarized, and the strategies involved in NON-based cancer therapies are elaborated.

Dissolving microneedles for long-term storage and transdermal delivery of extracellular vesicles.

Extracellular vesicles (EVs) have shown great potential in disease diagnosis and treatment; however, their clinical applications remain challenging due to their unsatisfactory long-term stability and the lack of effective delivery strategies. In this study, we prepared human adipose stem cell-derived EV (hASC-EV)-loaded hyaluronic acid dissolving microneedles (EV@MN) to investigate the feasibility of EVs for their clinical applications. The biological activities of the EVs in this formulation were maintained for more than six months under mild storage conditions, especially at temperatures lower than 4 °C. Moreover, the EV@MN enabled precise and convenient intradermal delivery for sustained release of EVs in the dermis layer. Therefore, EV@MN significantly improved the biological functions of hASC-EVs on dermal fibroblasts by promoting syntheses of proteins for the extracellular matrix such as collagen and elastin, enhancing fibroblast proliferation, and regulating the phenotype of fibroblast, compared with other administration methods. This research revealed a possible and feasible formulation for the clinical application of EVs.

Polymeric Hydrogels for Controlled Drug Delivery to Treat Arthritis.

Rheumatoid arthritis (RA) and osteoarthritis (OA) are disabling musculoskeletal disorders that affect joints and cartilage and may lead to bone degeneration. Conventional delivery of anti-arthritic agents is limited due to short intra-articular half-life and toxicities. Innovations in polymer chemistry have led to advancements in hydrogel technology, offering a versatile drug delivery platform exhibiting tissue-like properties with tunable drug loading and high residence time properties This review discusses the advantages and drawbacks of polymeric materials along with their modifications as well as their applications for fabricating hydrogels loaded with therapeutic agents (small molecule drugs, immunotherapeutic agents, and cells). Emphasis is given to the biological potentialities of hydrogel hybrid systems/micro-and nanotechnology-integrated hydrogels as promising tools. Applications for facile tuning of therapeutic drug loading, maintaining long-term release, and consequently improving therapeutic outcome and patient compliance in arthritis are detailed. This review also suggests the advantages, challenges, and future perspectives of hydrogels loaded with anti-arthritic agents with high therapeutic potential that may alter the landscape of currently available arthritis treatment modalities.

Stem Cell-Derived Extracellular Vesicle-Bearing Dermal Filler Ameliorates the Dermis Microenvironment by Supporting CD301b-Expressing Macrophages.

Hyaluronic acid-based hydrogels (Hyal-Gels) have the potential to reduce wrinkles by physically volumizing the skin. However, they have limited ability to stimulate collagen generation, thus warranting repeated treatments to maintain their volumizing effect. In this study, stem cell-derived extracellular vesicle (EV)-bearing Hyal-Gels (EVHyal-Gels) were prepared as a potential dermal filler, ameliorating the dermis microenvironment. No significant differences were observed in rheological properties and injection force between Hyal-Gels and EVHyal-Gels. When locally administered to mouse skin, Hyal-Gels significantly extended the biological half-life of EVs from 1.37 d to 3.75 d. In the dermis region, EVHyal-Gels induced the overexpression of CD301b on macrophages, resulting in enhanced proliferation of fibroblasts. It was found that miRNAs, such as let-7b-5p and miR-24-3p, were significantly involved in the change of macrophages toward the CD301bhi phenotype. The area of the collagen layer in EVHyal-Gel-treated dermis was 2.4-fold higher than that in Hyal-Gel-treated dermis 4 weeks after a single treatment, and the collagen generated by EVHyal-Gels was maintained for 24 weeks in the dermis. Overall, EVHyal-Gels have the potential as an antiaging dermal filler for reprogramming the dermis microenvironment.

An anti-DR5 antibody-curcumin conjugate for the enhanced clearance of activated hepatic stellate cells.

Anti-death receptor 5 (DR5) antibody is a potential therapeutic agent for liver fibrosis because it exhibits anti-fibrotic effects by inducing the apoptosis of activated hepatic stellate cells (HSCs), which are responsible for hepatic fibrogenesis. However, the clinical applications of anti-DR5 antibodies have been limited by their low agonistic activity against DR5. In this study, an anti-DR5 antibody-curcumin conjugate (DCC) was prepared to investigate its effect on the clearance of activated HSCs. The DCC was synthesized through a coupling reaction between a maleimide-functionalized curcumin derivative and a thiolated anti-DR5 antibody. No significant differences were observed in the uptake behaviors of activated HSCs between the bare anti-DR5 antibodies and DCC. Owing to the antioxidant and anti-inflammatory effects of curcumin, DCC-treated HSCs produced much lower levels of reactive oxygen species and inducible nitric oxide synthase than the bare anti-DR5 antibody-treated HSCs. Additionally, the anti-fibrotic effects of DCC on activated HSCs were more prominent than those of the bare anti-DR5 antibodies, as demonstrated by the immunocytochemical analysis of α-smooth muscle actin. DCC preferentially accumulated in the liver after its systemic administration to mice with liver fibrosis. Thus, DCC may serve as a potential therapeutic agent for treating liver fibrosis.

Insight into the Influence of Analyte Molecular Structure Targeted on MoS2-GO-Coated Electrochemical Nanosensors.

MoS2-GO composites were fabricated by an ultrasonication method at room temperature. Raman spectra, emission scanning electron microscopy (SEM), and transmission electron microscopy (TEM) images were used to study the structural characteristics, morphologies, and sizes of the synthesized materials. An MoS2-GO/SPE (screen-printed electrode) was prepared by a facile dropping method and acted as an effective electrochemical sensor toward clenbuterol (CLB) and 4-nitrophenol (4-NP) detection. Based on the obtained results, the influence of analyte molecular structure on the adsorption ability and electronic interoperability between the targeted analyte and electrode surface were investigated in detail and discussed as well, through some electrochemical kinetic parameters (electron/proton-transfer number, electron transfer rate constant (ks), charge transfer coefficient, and adsorption capacity (Γ)). In particular, it should be stressed that 4-NP molecules possess a simple molecular structure with many positive effects (electronic, conjugation, and small steric effects) and flexible functional groups, resulting in fast electron transport/charge diffusion and effective adsorption process as well as strong interactions with the electrode surface. Therefore, 4-NP molecules have been facilitated better in electrochemical reactions at the electrode surface and electrode-electrolyte interfaces, leading to improved current response and electrochemical sensing performance, compared with those of CLB.

Vitamin A-coupled stem cell-derived extracellular vesicles regulate the fibrotic cascade by targeting activated hepatic stellate cells in vivo.

Allogeneic transplantation of mesenchymal stem cell-derived extracellular vesicles (EVs) offers great potential for treating liver fibrosis. However, owing to their intrinsic surface characteristics, bare EVs are non-specifically distributed in the liver tissue after systemic administration, leading to limited therapeutic efficacy. To target activated hepatic stellate cells (HSCs), which are responsible for hepatic fibrogenesis, vitamin A-coupled small EVs (V-EVs) were prepared by incorporating vitamin A derivative into the membrane of bare EVs. No significant differences were found in the particle size and morphology between bare and V-EVs. In addition, surface engineering of EVs did not affect the expression of surface marker proteins (e.g., CD63 and CD9), as demonstrated by flow cytometry. Owing to the surface incorporation of vitamin A, V-EVs were selectively taken up by activated HSCs via receptor-mediated endocytosis. When systemically administered to mice with liver fibrosis, V-EVs effectively targeted activated HSCs in the liver tissue, resulting in reversal of the fibrotic cascade. Consequently, even at a 10-fold lower dose, V-EVs exhibited comparable anti-fibrotic effects to those of bare EVs, substantiating their therapeutic potential for liver fibrosis.

Flavones from Combretum quadrangulare Growing in Vietnam and Their Alpha-Glucosidase Inhibitory Activity.

Combretum quadrangulare Kurz is widely used in folk medicine in Eastern Asia and is associated with various ethnopharmacological properties including hepatoprotective, antipyretic, analgesic, antidysenteric, and anthelmintic activities. Previous phytochemical investigations reported the presence of numerous triterpenes (mostly cycloartanes, ursanes, lupanes, and oleananes) along with dozens of flavonoids. However, the extracts of C. quadrangulare and isolated flavonoids have not been evaluated for their alpha-glucosidase inhibition. In the frame of our efforts dedicated to the chemical investigation of Vietnamese medicinal plants and their biological activities, a phytochemical study of the MeOH extract of the leaves of C. quadrangulare using bioactive guided isolation was undertaken. In this paper, the isolation and structure elucidation of twelve known compounds, 5-hydroxy-3,7,4'-trimethoxyflavone (1), ayanin (2), kumatakenin (3), rhamnocitrin (4), ombuin (5), myricetin-3,7,3',5'-tetramethyl ether (6), gardenin D (7), luteolin (12), apigenin (13), mearnsetin (14), isoorientin (15), and vitexin (16) were reported. Bromination was applied to compounds 2 and 3 to provide four new synthetic analogues 8-11. All isolated and synthesized compounds were evaluated for alpha-glucosidase inhibition and antibacterial activity. Compounds 4 and 5 showed moderate antibacterial activity against methicillin-resistant Staphylococcus aureus while others were inactive. All compounds failed to reveal any activity toward extended spectrum beta-lactamase-producing Escherichia coli. Compounds 2, 4, 6-9, and 11-14 showed good alpha-glucosidase inhibition with IC50 values in the range of 30.5-282.0 µM. The kinetic of enzyme inhibition showed that 8 and 11 were noncompetitive type inhibition against alpha-glucosidase. In silico molecular docking model indicated that compounds 8 and 11 were potential inhibitors against enzyme α-glucosidase.

Hyaluronic Acid Nanoparticles as Nanomedicine for Treatment of Inflammatory Diseases.

Owing to their unique biological functions, hyaluronic acid (HA) and its derivatives have been explored extensively for biomedical applications such as tissue engineering, drug delivery, and molecular imaging. In particular, self-assembled HA nanoparticles (HA-NPs) have been used widely as target-specific and long-acting nanocarriers for the delivery of a wide range of therapeutic or diagnostic agents. Recently, it has been demonstrated that empty HA-NPs without bearing any therapeutic agent can be used therapeutically for the treatment of inflammatory diseases via modulating inflammatory responses. In this review, we aim to provide an overview of the significant achievements in this field and highlight the potential of HA-NPs for the treatment of inflammatory diseases.

Self-assembled hyaluronic acid nanoparticle suppresses fat accumulation via CD44 in diet-induced obese mice.

Obesity, a major risk factor for type 2 diabetes and cardiovascular diseases, is characterized by an abnormal expansion of adipose tissue. Herein, we investigated the potential of hyaluronic acid nanoparticles (HA-NPs) as therapeutics to treat obesity-related diseases by assessing the in vitro and in vivo effects of HA-NPs on adipogenesis and lipogenesis. Treatment of 3T3-L1 preadipocytes with HA-NPs resulted in a dose-dependent suppression of adipogenesis and lipid accumulation, and decreased the expression of key adipogenic and lipogenic regulators. However, these HA-NPs mediated effects were not observed in 3T3-L1 cells transfected with siRNAs against CD44, a major HA receptor. Further, HA-NP treatment of diet-induced obese (DIO) mice reduced the epididymal fat mass and suppressed the induction of adipogenic and lipogenic regulators, while these effects were attenuated in the CD44-null mice. Thus, our study provides a better understanding of how HA-NP modulates fat accumulation and presents a potential anti-obesity strategy targeting CD44.

Human adipose stem cell-derived extracellular nanovesicles for treatment of chronic liver fibrosis.

Liver fibrosis is an excessive wound healing process that occurs in response to liver damage depending on underlying aetiologies. Currently, there are no effective therapies and FDA-approved therapeutics for the treatment of liver fibrosis except liver transplantation. Multipotent adipose-derived stem cells (ADSCs) have received significant attention as regenerative medicine for liver fibrosis owing to their advantages over stem cells with other origins. However, intrinsic limitations of stem cell therapies, such as cellular rejection and tumor formation, have impeded clinical applications of the ADSC-based liver therapeutics. To overcome these problems, the extracellular nanovesicles (ENVs) responsible for the therapeutic effect of ADSCs (A-ENVs) have shown considerable promise as cell-free therapeutics for liver diseases. However, A-ENVs have not been used for the treatment of intractable chronic liver diseases including liver fibrosis and cirrhosis. Therefore, in this study, we investigated the in vitro and in vivo antifibrotic efficacy of A-ENVs in thioacetamide-induced liver fibrosis models. A-ENVs significantly downregulated the expression of fibrogenic markers, such as matrix metalloproteinase-2, collagen-1, and alpha-smooth muscle actin. The systemic administration of A-ENVs led to high accumulation in fibrotic liver tissue and the restoration of liver functionality in liver fibrosis models through a marked reduction in α-SMA and collagen deposition. These results demonstrate the significant potential of A-ENVs for use as extracellular nanovesicles-based therapeutics in the treatment of liver fibrosis and possibly other intractable chronic liver diseases.

ROS-responsive mesoporous silica nanoparticles for MR imaging-guided photodynamically maneuvered chemotherapy.

Mesoporous silica nanoparticles (MSNs) with stimuli-responsive gatekeepers have been extensively investigated for controlled drug delivery at the target sites. Herein, we developed reactive oxygen species (ROS)-responsive MSNs (R-MSNs), consisting of a gadolinium (Gd)-DOTA complex as the ROS-responsive gatekeeper and polyethylene glycol (PEG)-conjugated chlorin e6 as the ROS generator, for magnetic resonance (MR) imaging-guided photodynamic chemotherapy. Doxorubicin (DOX), chosen as an anticancer drug, was physically encapsulated into DOTA-conjugated MSNs, followed by chemical crosslinking via the addition of GdCl3. DOX-R-MSNs could effectively maintain their structural integrity in a physiological environment for 7 days and show an enhanced in vitro T1-MR imaging signal for the Gd-DOTA complex. Upon 660 nm laser irradiation, the release rate of DOX from DOX-R-MSNs remarkably increased along with the disintegration of the gatekeeper, whereas DOX release was significantly retarded without irradiation. When DOX-R-MSNs were intravenously injected into tumor-bearing mice, they were effectively accumulated in tumor tissue, which was demonstrated using MR imaging. In addition, tumor growth was significantly suppressed by DOX-R-MSNs, allowing for site-specific release of DOX in a photodynamically maneuvered manner. Overall, these results suggest that R-MSNs have potential as drug carriers for MR imaging-guided photodynamic chemotherapy.

Self-assembled hyaluronic acid nanoparticles: Implications as a nanomedicine for treatment of type 2 diabetes.

Self-assembled hyaluronic acid nanoparticles (HA-NPs) have been extensively investigated for biomedical and pharmaceutical applications owing to their biocompatibility and receptor-binding properties. Here, we report that an empty HA-NP itself not bearing any drug has therapeutic effects on adipose tissue inflammation and insulin resistance. HA-NPs inhibited not only the receptor-mediated internalization of low-molecular-weight (LMW) free HA but also LMW free HA-induced pro-inflammatory gene expression in mouse primary bone marrow-derived macrophages (BMDMs) isolated from wild-type mice, but not in CD44-null (CD44-/-) BMDMs. An in vivo biodistribution study showed the distribution of HA-NPs and their co-localization with CD44 in adipose tissues including epididymal white adipose tissues (eWATs), but these were rarely observed in the eWATs of CD44-/- mice. In addition, CD44 expression and HA-NP accumulation in the eWATs were increased in mice with diet-induced obesity (DIO) compared to lean mice. Interestingly, treatment with HA-NPs in DIO mice suppressed adipose tissue inflammation as indicated by reduced macrophage content, the production of proinflammatory cytokines and NLRP3 inflammasome activity in eWATs, leading to improved insulin sensitivity and normalized blood glucose levels. Collectively, these results suggest that an empty HA-NP itself can be a therapeutic agent for the treatment of type 2 diabetes.

Carboxymethyl dextran-based hypoxia-responsive nanoparticles for doxorubicin delivery.

In an attempt to develop the hypoxia-responsive nanoparticles for cancer therapy, a polymer conjugate, consisting of carboxymethyl dextran (CMD) and black hole quencher 3 (BHQ3), was prepared. The polymer conjugate can self-assemble into nanoparticles (CMD-BHQ3 NPs) under aqueous conditions. The anticancer drug, doxorubicin (DOX), was loaded in CMD-BHQ3 NPs to prepare DOX@CMD-BHQ3 NPs. The CMD-BHQ3 NPs released DOX in a sustained manner under physiological conditions, whereas the release rate of DOX remarkably increased under hypoxic conditions throughout the cleavage of the azo bond in BHQ3. In vitro cytotoxicity study revealed that DOX@CMD-BHQ3 NPs showed higher toxicity under hypoxic conditions than normoxic conditions. Confocal microscopic images indicated oxygen-dependent intracellular release of DOX from DOX@CMD-BHQ3. In vivo biodistribution study demonstrated that CMD-BHQ3 NPs were preferentially accumulated in the tumor after systemic administration into tumor-bearing mice. Overall, CMD-BHQ3 might be a promising carrier for selective drug release in the hypoxic tumor.

In situ diselenide-crosslinked polymeric micelles for ROS-mediated anticancer drug delivery.

Stimuli-responsive micelles have emerged as the drug carrier for cancer therapy since they can exclusively release the drug via their structural changes in response to the specific stimuli of the target site. Herein, we developed the in situ diselenide-crosslinked micelles (DCMs), which are responsive to the abnormal ROS levels of tumoral region, as anticancer drug carriers. The DCMs were spontaneously derived from selenol-bearing triblock copolymers consisting of polyethylene glycol (PEG) and polypeptide derivatives. During micelle formation, doxorubicine (DOX) was effectively encapsulated in the hydrophobic core, and diselenide crosslinks were formed in the shell. The DCMs maintained their structural integrity, at least for 6 days in physiological conditions, even in the presence of destabilizing agents. However, ROS-rich conditions triggered rapid release of DOX from the DOX-encapsulating DCMs (DOX-DCMs) because the hydrophobic diselenide bond was cleaved into hydrophilic selenic acid derivatives. Interestingly, after their systemic administration into the tumor-bearing mice, DOX-DCMs delivered significantly more drug to tumors (1.69-fold and 3.73-fold higher amount compared with their non-crosslinked counterparts and free drug, respectively) and effectively suppressed tumor growth. Overall, our data indicate that DCMs have great potential as drug carriers for anticancer therapy.