Premature senescence and cardiovascular disease following cancer treatments: mechanistic insights.

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality, especially among the aging population. The "response-to-injury" model proposed by Dr. Russell Ross in 1999 emphasizes inflammation as a critical factor in atherosclerosis development, with atherosclerotic plaques forming due to endothelial cell (EC) injury, followed by myeloid cell adhesion and invasion into the blood vessel walls. Recent evidence indicates that cancer and its treatments can lead to long-term complications, including CVD. Cellular senescence, a hallmark of aging, is implicated in CVD pathogenesis, particularly in cancer survivors. However, the precise mechanisms linking premature senescence to CVD in cancer survivors remain poorly understood. This article aims to provide mechanistic insights into this association and propose future directions to better comprehend this complex interplay.

Verubulin (Azixa) Analogues with Increased Saturation: Synthesis, SAR and Encapsulation in Biocompatible Nanocontainers Based on Ca2+ or Mg2+ Cross-Linked Alginate.

Tubulin-targeting agents attract undiminished attention as promising compounds for the design of anti-cancer drugs. Verubulin is a potent tubulin polymerization inhibitor, binding to colchicine-binding sites. In the present work, a series of verubulin analogues containing a cyclohexane or cycloheptane ring 1,2-annulated with pyrimidine moiety and various substituents in positions 2 and 4 of pyrimidine were obtained and their cytotoxicity towards cancer and non-cancerous cell lines was estimated. The investigated compounds revealed activity against various cancer cell lines with IC50 down to 1-4 nM. According to fluorescent microscopy data, compounds that showed cytotoxicity in the MTT test disrupt the normal cytoskeleton of the cell in a pattern similar to that for combretastatin A-4. The hit compound (N-(4-methoxyphenyl)-N,2-dimethyl-5,6,7,8-tetrahydroquinazolin-4-amine) was encapsulated in biocompatible nanocontainers based on Ca2+ or Mg2+ cross-linked alginate and it was demonstrated that its cytotoxic activity was preserved after encapsulation.

Endothelial activation and fibrotic changes are impeded by laminar flow-induced CHK1-SENP2 activity through mechanisms distinct from endothelial-to-mesenchymal cell transition.

Background: The deSUMOylase sentrin-specific isopeptidase 2 (SENP2) plays a crucial role in atheroprotection. However, the phosphorylation of SENP2 at T368 under disturbed flow (D-flow) conditions hinders its nuclear function and promotes endothelial cell (EC) activation. SUMOylation has been implicated in D-flow-induced endothelial-to-mesenchymal transition (endoMT), but the precise role of SENP2 in counteracting this process remains unclear. Method: We developed a phospho-specific SENP2 S344 antibody and generated knock-in (KI) mice with a phospho-site mutation of SENP2 S344A using CRISPR/Cas9 technology. We then investigated the effects of SENP2 S344 phosphorylation under two distinct flow patterns and during hypercholesteremia (HC)-mediated EC activation. Result: Our findings demonstrate that laminar flow (L-flow) induces phosphorylation of SENP2 at S344 through the activation of checkpoint kinase 1 (CHK1), leading to the inhibition of ERK5 and p53 SUMOylation and subsequent suppression of EC activation. We observed a significant increase in lipid-laden lesions in both the aortic arch (under D-flow) and descending aorta (under L-flow) of female hypercholesterolemic SENP2 S344A KI mice. In male hypercholesterolemic SENP2 S344A KI mice, larger lipid-laden lesions were only observed in the aortic arch area, suggesting a weaker HC-mediated atherogenesis in male mice compared to females. Ionizing radiation (IR) reduced CHK1 expression and SENP2 S344 phosphorylation, attenuating the pro-atherosclerotic effects observed in female SENP2 S344A KI mice after bone marrow transplantation (BMT), particularly in L-flow areas. The phospho-site mutation SENP2 S344A upregulates processes associated with EC activation, including inflammation, migration, and proliferation. Additionally, fibrotic changes and up-regulated expression of EC marker genes were observed. Apoptosis was augmented in ECs derived from the lungs of SENP2 S344A KI mice, primarily through the inhibition of ERK5-mediated expression of DNA damage-induced apoptosis suppressor (DDIAS). Summary: In this study, we have revealed a novel mechanism underlying the suppressive effects of L-flow on EC inflammation, migration, proliferation, apoptosis, and fibrotic changes through promoting CHK1-induced SENP2 S344 phosphorylation. The phospho-site mutation SENP2 S344A responds to L-flow through a distinct mechanism, which involves the upregulation of both mesenchymal and EC marker genes.

Possible molecular mechanisms underlying the development of atherosclerosis in cancer survivors.

Cancer survivors undergone treatment face an increased risk of developing atherosclerotic cardiovascular disease (CVD), yet the underlying mechanisms remain elusive. Recent studies have revealed that chemotherapy can drive senescent cancer cells to acquire a proliferative phenotype known as senescence-associated stemness (SAS). These SAS cells exhibit enhanced growth and resistance to cancer treatment, thereby contributing to disease progression. Endothelial cell (EC) senescence has been implicated in atherosclerosis and cancer, including among cancer survivors. Treatment modalities for cancer can induce EC senescence, leading to the development of SAS phenotype and subsequent atherosclerosis in cancer survivors. Consequently, targeting senescent ECs displaying the SAS phenotype hold promise as a therapeutic approach for managing atherosclerotic CVD in this population. This review aims to provide a mechanistic understanding of SAS induction in ECs and its contribution to atherosclerosis among cancer survivors. We delve into the mechanisms underlying EC senescence in response to disturbed flow and ionizing radiation, which play pivotal role in atherosclerosis and cancer. Key pathways, including p90RSK/TERF2IP, TGFßR1/SMAD, and BH4 signaling are explored as potential targets for cancer treatment. By comprehending the similarities and distinctions between different types of senescence and the associated pathways, we can pave the way for targeted interventions aim at enhancing the cardiovascular health of this vulnerable population. The insights gained from this review may facilitate the development of novel therapeutic strategies for managing atherosclerotic CVD in cancer survivors.

Isolated Ocular Mpox without Skin Lesions, United States.

We report a case of a 53-year-old HIV-negative patient in San Francisco, California, USA, with no classic mpox prodromal symptoms or skin lesions who experienced fulminant, vision-threatening scleritis, keratitis, and uveitis. Deep sequence analysis identified monkeypox virus RNA in the aqueous humor. We confirmed the virus on the cornea and sclera by PCR.

Postoperative Endophthalmitis after Combined Cataract Extraction and iStent Inject Implantation.

Purpose. To report a case of postoperative endophthalmitis after combined cataract extraction and iStent inject implantation. Observation. A 70-year-old male with a nuclear sclerotic cataract and primary open-angle glaucoma underwent an uneventful phacoemulsification cataract extraction with implantation of an intraocular lens and an iStent inject trabecular bypass stent. The patient was prescribed a postoperative regimen of ofloxacin 0.3% and prednisolone acetate 1%, 1 drop four times a day each. On postoperative day five, he presented to the emergency room for eye pain and had 4+ mixed cells in the anterior chamber (AC) without hypopyon or vitritis on exam. Prednisolone 1% eye drops were increased from four times a day to every two hours while awake. Overnight, he developed worsening vision and severe eye pain. The next morning, he was found to have increased AC cells, vitritis, and intraretinal hemorrhages and was diagnosed with endophthalmitis. The patient underwent a vitreous tap and intravitreal injections of vancomycin (1 mg/0.1 mL) and amikacin (0.4 mg/0.1 mL). Cultures grew Staphylococcus epidermidis. Lab work-up revealed underlying neutropenia. Visual acuity eventually recovered to 20/20. Conclusion and Importance. This report highlights a case of endophthalmitis associated with placement of the iStent inject. The infection was well-controlled after administration of intravitreal antibiotics without removal of the iStent inject, and visual acuity eventually recovered to 20/20. Surgeons should be aware of endophthalmitis risk following combined iStent inject placement, and good recovery is possible without removal of the implant.

TNIK regulation of interferon signaling and endothelial cell response to virus infection.

Background: Traf2 and Nck-interacting kinase (TNIK) is known for its regulatory role in various processes within cancer cells. However, its role within endothelial cells (ECs) has remained relatively unexplored. Methods: Leveraging RNA-seq data and Ingenuity Pathway Analysis (IPA), we probed the potential impact of TNIK depletion on ECs. Results: Examination of RNA-seq data uncovered more than 450 Differentially Expressed Genes (DEGs) in TNIK-depleted ECs, displaying a fold change exceeding 2 with a false discovery rate (FDR) below 0.05. IPA analysis unveiled that TNIK depletion leads to the inhibition of the interferon (IFN) pathway [-log (p-value) >11], downregulation of IFN-related genes, and inhibition of Hypercytokinemia/Hyperchemokinemia [-log (p-value) >8]. The validation process encompassed qRT-PCR to evaluate mRNA expression of crucial IFN-related genes, immunoblotting to gauge STAT1 and STAT2 protein levels, and ELISA for the quantification of IFN and cytokine secretion in siTNIK-depleted ECs. These assessments consistently revealed substantial reductions upon TNIK depletion. When transducing HUVECs with replication incompetent E1-E4 deleted adenovirus expressing green fluorescent protein (Ad-GFP), it was demonstrated that TNIK depletion did not affect the uptake of Ad-GFP. Nonetheless, TNIK depletion induced cytopathic effects (CPE) in ECs transduced with wild-type human adenovirus serotype 5 (Ad-WT). Summary: Our findings suggest that TNIK plays a crucial role in regulating the EC response to virus infections through modulation of the IFN pathway.

ß-sitosterol from Clinacanthus nutans Lindau enhances osteoblastogenic activity via upregulation of differentiation related genes and proteins.

ß-sitosterol derived from Clinacanthus nutans Lindau was tested for its in vitro osteogenic activity using MC3T3-E1 pre-osteoblasts. Our results indicated that ß-sitosterol was non-toxic to the cells cultured at a concentration <20 µg/mL. Treatment of the cells with ß-sitosterol significantly enhanced the alkaline phosphatase activity up to 210 and 204.6% at 5 and 10 µg/mL, respectively (P < .05). Similarly, the mineralization activity of the ß-sitosterol treated cells was elevated up to 134, 168, 118% at a concentration of 2.5, 5, and 10 µg/mL, respectively (P < .05). In addition, this compound up-regulated several marker genes for osteoblast differentiation, including runx2, osx and col I to 2, 2.5 and 5.6 folds at 10 µg/mL, respectively (P < .05). The expression of p38 and ERK proteins involved in the MAPK signal pathway related to mineralization and differentiation was also enhanced. Thus, the osteoblastogenic activity of ß-sitosterol was fully illustrated for the first time.

Irreversible Bilateral Cicatricial Keratoconjunctivitis after Dupilumab Therapy.

This report highlights a case of irreversible bilateral cicatricial keratoconjunctivitis related to dupilumab therapy for the treatment of severe atopic dermatitis (AD). After 38 years of AD, the patient began dupilumab therapy and achieved disease control. Two years into treatment, his ophthalmic examination was significant for bilateral cicatricial keratoconjunctivitis with severe foreshortening of the inferior conjunctival fornices, symblepharon, and ankyloblepharon, which persisted even after topical steroid eye drops and discontinuation of dupilumab. Treating dermatologists should be aware of this potential irreversible adverse effect, and we recommend that patients are monitored for ocular complications while on dupilumab therapy.

MAGI1 inhibits interferon signaling to promote influenza A infection.

We have shown that membrane-associated guanylate kinase with inverted domain structure-1 (MAGI1), a scaffold protein with six PSD95/DiscLarge/ZO-1 (PDZ) domains, is involved in the regulation of endothelial cell (EC) activation and atherogenesis in mice. In addition to causing acute respiratory disease, influenza A virus (IAV) infection plays an important role in atherogenesis and triggers acute coronary syndromes and fatal myocardial infarction. Therefore, the aim of this study is to investigate the function and regulation of MAGI1 in IAV-induced EC activation. Whereas, EC infection by IAV increases MAGI1 expression, MAGI1 depletion suppresses IAV infection, suggesting that the induction of MAGI1 may promote IAV infection. Treatment of ECs with oxidized low-density lipoprotein (OxLDL) increases MAGI1 expression and IAV infection, suggesting that MAGI1 is part of the mechanistic link between serum lipid levels and patient prognosis following IAV infection. Our microarray studies suggest that MAGI1-depleted ECs increase protein expression and signaling networks involve in interferon (IFN) production. Specifically, infection of MAGI1-null ECs with IAV upregulates expression of signal transducer and activator of transcription 1 (STAT1), interferon b1 (IFNb1), myxovirus resistance protein 1 (MX1) and 2'-5'-oligoadenylate synthetase 2 (OAS2), and activate STAT5. By contrast, MAGI1 overexpression inhibits Ifnb1 mRNA and MX1 expression, again supporting the pro-viral response mediated by MAGI1. MAGI1 depletion induces the expression of MX1 and virus suppression. The data suggests that IAV suppression by MAGI1 depletion may, in part, be due to MX1 induction. Lastly, interferon regulatory factor 3 (IRF3) translocates to the nucleus in the absence of IRF3 phosphorylation, and IRF3 SUMOylation is abolished in MAGI1-depleted ECs. The data suggests that MAGI1 inhibits IRF3 activation by maintaining IRF3 SUMOylation. In summary, IAV infection occurs in ECs in a MAGI1 expression-dependent manner by inhibiting anti-viral responses including STATs and IRF3 activation and subsequent MX1 induction, and MAGI1 plays a role in EC activation, and in upregulating a pro-viral response. Therefore, the inhibition of MAGI1 is a potential therapeutic target for IAV-induced cardiovascular disease.

Identification of Metastatic Conjunctival Squamous Cell Carcinoma through Neck Palpation.

An 80-year-old male with a distant 10 pack-years smoking history and squamous cell carcinoma (SCCA) of the scalp diagnosed 15 years ago presented with a new right nasal bulbar conjunctival lesion found to be invasive SCCA. The patient was started on interferon alfa-2b for 5 months until there was no evidence of residual disease. During a follow-up visit 10 months after diagnosis and during routine ophthalmic follow-up, an enlarged right submandibular lymph node was found through neck palpation and revealed to be SCCA without extranodal extension. The lesion was likely to have metastasized from his right conjunctival squamous cell carcinoma (CSCCA). Regional lymph nodes are a commonplace of metastasis for CSCCA making neck palpation a reasonable and recommended part of clinical examination to monitor for metastasis. This is the first known case of identifying regional metastasis of CSCCA through neck palpation.

PHOTODYNAMIC THERAPY FOR THE TREATMENT OF CHOROIDAL METASTASES: A Case Series and Meta-analysis.

PURPOSE: To investigate the efficacy and safety of photodynamic therapy (PDT) in the treatment of choroidal metastasis. METHODS: We conducted a systematic review of all reported cases of choroidal metastases treated with PDT in literature, and included the cases from our institution, for a comprehensive meta-analysis. RESULTS: We identified 52 tumors in 40 eyes of 34 patients. The mean age was 60 years (range 28-77). The mean tumor thickness was 1.9 mm (range 0-4.8 mm), whereas the mean largest basal diameter was 8.2 mm (range 1.5-30 mm) on presentation. After an average of 1.4 treatment visit, PDT resulted in decreased tumor thickness (mean 1.9 mm before vs. 1.0 mm after PDT, P < 0.0001) and decreased central macular thickness (mean 454 µm before vs. 289 µm after PDT, P = 0.03). After PDT, 82% of tumors had reduced thickness, and subretinal fluid resolved in 75% of eyes. Photodynamic therapy also resulted in stable or improved vision in 78% of treated eyes (logMAR 0.50 before vs. 0.56 after PDT, P = 0.54). No adverse events were reported, and PDT was effective in treating the most common choroidal metastases (tumor control rate of 94% in 16 lung adenocarcinoma and 92% in 26 breast carcinoma metastasis cases). CONCLUSION: Photodynamic therapy is effective at controlling tumors and preserving vision in patients with some choroidal metastases. Because of its minimal time commitment and good safety profile, PDT should be considered as a potential first-line treatment for small choroidal metastases.

Free Cholesterol Bioavailability and Atherosclerosis.

PURPOSE OF REVIEW: As both a cholesterol acceptor and carrier in the reverse cholesterol transport (RCT) pathway, high-density lipoprotein (HDL) is putatively atheroprotective. However, current pharmacological therapies to increase plasma HDL cholesterol (HDL-c) concentration have paradoxically failed to prevent or reduce atherosclerosis and cardiovascular disease (CVD). Given that free cholesterol (FC) transfer between surfaces of lipoproteins and cells is reversible, excess plasma FC can be transferred to the cells of peripheral tissue sites resulting in atherosclerosis. Here, we summarize potential mechanisms contributing to this paradox and highlight the role of excess free cholesterol (FC) bioavailability in atherosclerosis vs. atheroprotection. RECENT FINDINGS: Recent findings have established a complex relationship between HDL-c concentration and atherosclerosis. Systemic scavenger receptor class B type 1 (SR-B1) knock out (KO) mice exhibit with increased diet-induced atherosclerosis despite having an elevated plasma HDL-c concentration compared to wild type (WT) mice. The greater bioavailability of HDL-FC in SR-B1 vs. WT mice is associated with a higher FC content in multiple cell types and tissue sites. These results suggest that dysfunctional HDL with high FC bioavailability is atheroprone despite high HDL-c concentration. Past oversimplification of HDL-c involvement in cholesterol transport has led to the failures in HDL targeted therapy. Evidence suggests that FC-mediated functionality of HDL is of higher importance than its quantity; as a result, deciphering the regulatory mechanisms by which HDL-FC bioavailability can induce atherosclerosis can have far-reaching clinical implications.

Cyclodialysis cleft formation following Yamane secondary intraocular lens implantation.

PURPOSE: To report two cases of hypotony with maculopathy related to cyclodialysis cleft after Yamane intraocular lens (IOL) implantation, and the use of localized transscleral cyclophotocoagulation (TSCPC) to successfully treat this condition. OBSERVATION: 1. 37 year-old man with childhood BB-gun related injury in the left eye (OS) and traumatic iridodialysis and angle recession underwent pars plana vitrectomy and Yamane IOL placement for subluxed traumatic cataract OS. Postoperative hypotony [intraocular pressure (IOP) 5-6 mmHg] and maculopathy with best corrected vision acuity (BCVA) of 20/200 at 1 month postoperative prompted referral, and localized TSCPC was performed. Nine days later sudden elevation of IOP occurred, responsive to treatment, and the hypotony and maculopathy resolved. 2. 87 year-old man with prior OS retinal detachments treated with scleral buckling, pars plana vitrectomy x 2, and cataract extraction with sulcus IOL ranging from 8 to 37 years prior presented with temporal sulcus IOL haptic penetration through the iris and dense vitreous hemorrhage. He underwent pars plana vitrectomy, IOL explantation and Yamane IOL placement OS. Postoperative hypotony (IOP 1-4 mmHg) and maculopathy with evidence of cyclodialysis cleft on ultrasonography at 1 month postoperative prompted referral. The patient underwent 2 rounds of localized TSCPC; after his second treatment, IOP ranged from 9 to 14 mmHg over the next 8 months and maculopathy resolved. CONCLUSION AND IMPORTANCE: We highlight the risk of development of cyclodialysis cleft after Yamane IOL placement in highly traumatized eyes, and the benefit of localized TSCPC in such cases for cleft closure.

The Impact of NAFLD on Hospitalization Outcomes in Patients With Inflammatory Bowel Diseases: Nationwide Analysis.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in patients with inflammatory bowel diseases (IBD). Yet, the impact of NAFLD on outcomes, along with the contribution of nonmetabolic factors to NAFLD development, is unclear. To investigate these topics, we conducted a nationwide study examining the impact of NAFLD on hospitalization outcomes in IBD patients after adjusting for metabolic factors. METHODS: Patients with IBD-related hospitalizations were identified using the Nationwide Readmissions Database from 2016 to 2018. Inflammatory bowel disease patients with and without NAFLD were matched based on IBD type, age, sex, metabolic syndrome, and diabetes mellitus. Primary outcomes were IBD-related readmission, IBD-related surgery, and death. Secondary outcomes were length of stay (LOS) and cost of care (COC). The primary multivariable model adjusted for obesity, dyslipidemia, Charlson-Deyo comorbidity index, hospital characteristics, payer, patient income, and elective status of admissions. RESULTS: Nonalcoholic fatty liver disease was associated with a higher risk of IBD-related readmission (adjusted hazard ratio, 1.90; P < .01) and death (adjusted hazard ratio, 2.73; P < .01), 0.71-day longer LOS (P < .01), and $7312 higher COC (P < .01) in those with Crohn's disease. Nonalcoholic fatty liver disease was also associated with a higher risk of IBD-related readmission (adjusted hazard ratio, 1.65; P < .01), 0.64-day longer LOS (P < .01), and $9392 (P < .01) higher COC, but there was no difference in death in those with UC. No differences in risk of IBD-related surgery were observed. CONCLUSIONS: Nonalcoholic fatty liver disease is associated with worse hospitalization outcomes in IBD patients after adjusting for metabolic factors. These data suggest nonmetabolic factors may be implicated in the pathogenesis of NAFLD in IBD patients and may contribute to worsened clinical outcomes.

Isolation of bioactive compounds from medicinal plants used in traditional medicine: Rautandiol B, a potential lead compound against Plasmodium falciparum.

BACKGROUND: Neorautanenia mitis, Hydnora abyssinica, and Senna surattensis are medicinal plants with a variety of traditional uses. In this study, we sought to isolate the bioactive compounds responsible for some of these activities, and to uncover their other potential medicinal properties. METHODS: The DCM and ethanol extracts of the roots of N. mitis and H. abyssinica, and the leaves of S. surattensis were prepared and their phytochemical components were isolated and purified using chromatographic methods. These extracts and their pure phytochemical components were evaluated in in-vitro models for their inhibitory activities against Plasmodium falciparum, Trypanosoma brucei rhodesiense, Mycobacterium tuberculosis, α-amylase (AA), and α-glucosidase (AG). RESULTS: Rautandiol B had significant inhibitory activities against two strains of Plasmodium falciparum showing a high safety ratio (SR) and IC50 values of 0.40 ± 0.07 µM (SR - 108) and 0.74 ± 0.29 µM (SR - 133) against TM4/8.2 and K1CB1, respectively. While (-)-2-isopentenyl-3-hydroxy-8-9-methylenedioxypterocarpan showed the highest inhibitory activity against T. brucei rhodesiense with an IC50 value of 4.87 ± 0.49 µM (SR > 5.83). All crude extracts showed inhibitory activities against AA and AG, with three of the most active phytochemical components; rautandiol A, catechin, and dolineon, having only modest activities against AG with IC50 values of 0.28 mM, 0.36 mM and 0.66 mM, respectively. CONCLUSION: These studies have led to the identification of lead compounds with potential for future drug development, including Rautandiol B, as a potential lead compound against Plasmodium falciparum. The relatively higher inhibitory activities of the crude extracts against AG and AA over their isolated components could be due to the synergistic effects between their phytochemical components. These crude extracts could potentially serve as alternative inhibitors of AG and AA and as therapeutics for diabetes.

Video Surveillance Processing Algorithms utilizing Artificial Intelligent (AI) for Unmanned Autonomous Vehicles (UAVs).

With the advancement of science and technology, the combination of the unmanned aerial vehicle (UAV) and camera surveillance systems (CSS) is currently a promising solution for practical applications related to security and surveillance operations. However, one of the biggest risks and challenges for the UAV-CSS is analysis, process, and transmission data, especially, the limitations of computational capacity, storage and overloading the transmission bandwidth. Regard to conventional methods, almost the data collected from UAVs is processed and transmitted that cost huge energy. A certain amount of data is redundant and not necessary to be processed or transmitted. This paper proposes an efficient algorithm to optimize the transmission and reception of data in UAV-CSS systems, based on the platforms of artificial intelligence (AI) for data processing. The algorithm creates an initial background frame and update to the complete background which is sent to server. It splits the region of interest (moving objects) in the scene and then sends only the changes. This supports the CSS to reduce significantly either data storage or data transmission. In addition, the complexity of the systems could be significantly reduced. The main contributions of the algorithm can be listed as follows;-The developed solution can reduce data transmission significantly.-The solution can empower smart manufacturing via camera surveillance.-Simulation results have validated practical viability of this approach.The experimental method results show that reducing up to 80% of storage capacity and transmission data.

Inhibition of biofilm formation by alpha-mangostin loaded nanoparticles against Staphylococcus aureus.

This study aimed to investigate the antibiofilm activity of alpha-mangostin (AMG) loaded nanoparticles (nanoAMG) against Staphylococcus aureus, including the methicillin-resistant strain MRSA252. The results indicated that treatment with 24 µmol/L nanoAMG inhibited the formation of biofilm biomass by 53-62%, compared to 40-44% for free AMG (p < 0.05). At 48 µmol/L, biofilms in all nanoAMG treated samples were nearly fully disrupted for the two tested strains, MRSA252 and the methicillin-sensitive strain NCTC6571. That concentration resulted in killing of biofilm cells. A lower concentration of 12 µmol/L nanoAMG inhibited initial adherence of the two bacterial strains by > 50%. In contrast, activity of nanoAMG was limited on preformed mature biofilms, which at a concentration of 48 µmol/L were reduced only by 27% and 22% for NCTC6571 and MRSA252, respectively. The effects of AMG or nanoAMG on the expression of biofilm-related genes showed some noticeable differences between the two strains. For instance, the expression level of ebpS was downregulated in MRSA252 and upregulated in NCTC6571 when those strains were treated with either AMG or nanoAMG. In contrast, the expression of fnbB was down regulated in NCTC6571, while it was up-regulated in the MRSA252. The expression of other biofilm-related genes (icaC, clfB and fnbA) was down regulated in both strains. In conclusion, our results suggest that AMG coated nanoparticles had enhanced biological activity as compared to free AMG, indicating that nanoAMG could be a new and promising inhibitor of biofilm formation to tackle S. aureus, including strains that are resistant to multiple antibiotics.

Discrete Open-Shell Tris(bipyridinium radical cationic) Inclusion Complexes in the Solid State.

The solid-state properties of organic radicals depend on radical-radical interactions that are influenced by the superstructure of the crystalline phase. Here, we report the synthesis and characterization of a substituted tetracationic cyclophane, cyclobis(paraquat-p-1,4-dimethoxyphenylene), which associates in its bisradical dicationic redox state with the methyl viologen radical cation (MV•+) to give a 1:1 inclusion complex. The (super)structures of the reduced cyclophane and this 1:1 complex in the solid state deviate from the analogous (super)structures observed for the reduced state of cyclobis(paraquat-p-phenylene) and that of its trisradical tricationic complex. Titration experiments reveal that the methoxy substituents on the p-phenylene linkers do not influence binding of the cyclophane toward small neutral guests-such as dimethoxybenzene and tetrathiafulvalene-whereas binding of larger radical cationic guests such as MV•+ by the reduced cyclophane decreases 10-fold. X-ray diffraction analysis reveals that the solid-state superstructure of the 1:1 complex constitutes a discrete entity with weak intermolecular orbital overlap between neighboring complexes. Transient nutation EPR experiments and DFT calculations confirm that the complex has a doublet spin configuration in the ground state as a result of the strong orbital overlap, while the quartet-state spin configuration is higher in energy and inaccessible at ambient temperature. Superconducting quantum interference device (SQUID) measurements reveal that the trisradical tricationic complexes interact antiferromagnetically and form a one-dimensional Heisenberg antiferromagnetic chain along the a-axis of the crystal. These results offer insights into the design and synthesis of organic magnetic materials based on host-guest complexes.

Host-Guest Complexation-Mediated Supramolecular Photon Upconversion.

The phenomenon of photon upconversion, in which a system absorbs two or more photons of lower energy and emits a photon of higher energy, has been used in numerous applications, including non-destructive bioimaging, deep-penetrating photodynamic therapy, catalysis, and photovoltaic devices. To date, photon upconversion has been observed typically in inorganic nanocrystals, nanoparticles, metal-organic frameworks, supramolecular assemblies, and organic dyads. Herein, we demonstrate a new strategy for harnessing photon upconversion-supramolecular upconversion-based on host-guest chemistry. We have identified a box-like fluorescent tetracationic host incorporating a thiazolothiazole emitter, which can accommodate a guest-sensitizer, 5,15-diphenylporphyrin, inside its cavity, and demonstrated that the host-guest inclusion complex displays triplet-fusion upconversion when the guest is excited with low-energy light. The strategy of supramolecular upconversion has been employed successfully in two other host-guest complexes-with hosts comprised of anthracene emitters and a 5,15-diphenylporphyrin guest-corroborating the fact that this strategy is a general one and can be applied to the design of a new family of host-guest complexes for photon upconversion. More importantly, supramolecular upconversion is accessible in solution under dilute conditions (µM) compared to most of the existing approaches that require significantly higher concentrations (mM) of emitters and/or sensitizers. Transient absorption spectroscopy and density functional theory have been employed in order to confirm a triplet-fusion upconversion mechanism. Host-guest complexation-mediated supramolecular photon upconversion eliminates multiple issues in the existing systems related to high working concentrations, high incident laser power, and low optical penetration depths.