Aspergillus fumigatus-induced biogenic silver nanoparticles' efficacy as antimicrobial and antibiofilm agents with potential anticancer activity: an in vitro investigation.

A worldwide hazard to human health is posed by the growth of toxic bacteria that have contaminated fresh, processed, cereal, and seed products in storage facilities. As the number of multidrug-resistant pathogenic microorganisms rises, we must find safe, and effective antimicrobials. The use of green synthesis nanoparticles to combat microbial pathogens has gained a rising interest. The current study showed Aspergillus fumigatus was applied as a promising biomass for the green synthesis of biogenic silver nanoparticles (Ag NPs). The UV-visible spectra of biosynthesized Ag NPs appeared characteristic surface plasmon absorption at 475 nm, round-shaped with sizes ranging from 17.11 to 75.54 nm and an average size of 50.37 ± 2.3 nm. In vitro tests were conducted to evaluate the antibacterial, antioxidant, and anticancer effects of various treatment procedures for Ag NP applications. The synthesized Ag NPs was revealed biological activity against Aspergillus flauvas, A. niger, Bacillus cereus, Candida albicans, Esherichia coli, Pseudomonas aerugonosa, and Staphylococcus aureus under optimum conditions. The test bacteria were sensitive to low Ag NPs concentrations. (5, 10, 11, 8, 7, 10, and 7 mg/mL) was observed for the mentioned-before tested microorganisms, respectively. The bacterial pathogens described above experienced their biofilm formation effectively suppressed by Ag NPs at sub-inhibitory doses. Ag NPs were tested using scanning electron microscopy (SEM) to verify their antibacterial efficacy towards S. aureus and P. aeruginosa. These findings clearly show how harmful Ag NPs are to pathogenic bacteria. The Ag NPs showed antitumor activity with IC50 at 5 µg/mL against human HepG-2 and MCF-7 cellular carcinoma cells, while 50 mg/mL was required to induce 70% of normal Vero cell mortality. These findings imply that green synthetic Ag NPs can be used on cancer cell lines in vitro for anticancer effect beside their potential as a lethal factor against some pathogenic microbes.

Synthesis, anticancer activity, docking and computational studies of new pyridyl-glycosyl hybrids and acyclic analogs.

New pyridine-O-glycosides and their acyclic nucleoside analogues were prepared by heterocyclization and glycosylation. The anticancer activity against HCT-116, HepG2 and MCF-7 human cancer cells and BJ-1 cell revealed that the galacto- and xylopyranosyl glycosides possessing 4-bromophenyl have superior cytotoxic activities against HepG2 cell while glycosides 7-9 resulted in superior cytotoxic activities regarding MCF-7 breast cell. In case of HCT-116 colorectal carcinoma cells, two products and the derived glycosides and acyclic analogues showed potent activities. The most potent compounds were investigated for their possible binding affinities to the active site of CDK2 enzyme via in silico molecular docking simulation in addition to computational studies. The results support the antiproliferative effect and elucidate the interactions of 3a and 8 with catalytic sites.

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Turkish coffee has an antitumor effect on breast cancer cells in vitro and in vivo.

BACKGROUND: Breast cancer is the most diagnosed cancer in women. Its pathogenesis includes several pathways in cancer proliferation, apoptosis, and metastasis. Some clinical data have indicated the association between coffee consumption and decreased cancer risk. However, little data is available on the effect of coffee on breast cancer cells in vitro and in vivo. METHODS: In our study, we assessed the effect of Turkish coffee and Fridamycin-H on different pathways in breast cancer, including apoptosis, proliferation, and oxidative stress. A human breast cancer cell line (MCF-7) was treated for 48 h with either coffee extract (5% or 10 v/v) or Fridamycin-H (10 ng/ml). Ehrlich solid tumors were induced in mice for in vivo modeling of breast cancer. Mice with Ehrlich solid tumors were treated orally with coffee extract in drinking water at a final concentration (v/v) of either 3%, 5%, or 10% daily for 21 days. Protein expression levels of Caspase-8 were determined in both in vitro and in vivo models using ELISA assay. Moreover, P-glycoprotein and peroxisome proliferator-activated receptor gamma (PPAR-γ) protein expression levels were analyzed in the in vitro model. ß-catenin protein expression was analyzed in tumor sections using immunohistochemical analysis. In addition, malondialdehyde (MDA) serum levels were analyzed using colorimetry. RESULTS: Both coffee extract and Fridamycin-H significantly increased Caspase-8, P-glycoprotein, and PPAR-γ protein levels in MCF-7 cells. Consistently, all doses of in vivo coffee treatment induced a significant increase in Caspase-8 and necrotic zones and a significant decrease in ß- catenin, MDA, tumor volume, tumor weight, and viable tumor cell density. CONCLUSION: These findings suggest that coffee extract and Fridamycin-H warrant further exploration as potential therapies for breast cancer.

Silicon Clathrate-Supported Catalysts with Low Work Functions for Ammonia Synthesis.

Diamond-type silicon has a work function of ≈4.8 eV, and conventional n- or p-type doping modifies the value only between 4.6 and 5.05 eV. Here, it is shown that the alkali clathrates AxSi46 have substantially lower work functions approaching 2.6 eV, with clear trends between alkali electropositivity and clathrate cage size. The low work function enables alkali clathrates such as K8Si46 to be effective Haber-Bosch catalyst supports for NH3 synthesis. The catalytic properties of Si, Ge, and Sn-based clathrates are investigated while supporting Fe and Ru on the surface. The activity largely scales with the work function, and low activation energies below 60 kJ mol-1 are observed due to strong electron donation effects from the support. Ru metal and Sn clathrates seem to be unsuitable for stability issues. Compared to other similar hydride/electride catalysts, the simple structure and composition combined with stability in air/water make a systematic study of these clathrates possible and open the door to other electron-rich Zintl phases and related intermetallics as low-work function materials suitable for catalysis. The observed low work function may also have implications for other existing electronic applications.

Novel combinatorial approach: Harnessing HIV protease inhibitors to enhance amphotericin B's antifungal efficacy in cryptococcosis.

Cryptococcosis is a fungal infection that is becoming increasingly prevalent worldwide, particularly among individuals with compromised immune systems, such as HIV patients. Amphotericin B (AmB) is the first-line treatment mainly combined with flucytosine. The scarcity and the prohibitive cost of this regimen urge the use of fluconazole as an alternative, leading to increased rates of treatment failure and relapses. Therefore, there is a critical need for efficient and cost-effective therapy to enhance the efficacy of AmB. In this study, we evaluated the efficacy of the HIV protease inhibitors (PIs) to synergize the activity of AmB in the treatment of cryptococcosis. Five PIs (ritonavir, atazanavir, saquinavir, lopinavir, and nelfinavir) were found to synergistically potentiate the killing activity of AmB against Cryptococcus strains with Æ©FICI ranging between 0.09 and 0.5 against 20 clinical isolates. This synergistic activity was further confirmed in a time-kill assay, where different AmB/PIs combinations exhibited fungicidal activity within 24 hrs. Additionally, PIs in combination with AmB exhibited an extended post-antifungal effect on treated cryptococcal cells for approximately 10 hrs compared to 4 hours with AmB alone. This promising activity against cryptococcal cells did not exhibit increased cytotoxicity towards treated kidney cells, ruling out the risk of drug combination-induced nephrotoxicity. Finally, we evaluated the efficacy of AmB/PIs combinations in the Caenorhabditis elegans model of cryptococcosis, where these combinations significantly reduced the fungal burden of the treated nematodes by approximately 2.44 Log10 CFU (92.4%) compared to the untreated worms and 1.40 Log10 ((39.4%) compared to AmB alone. The cost-effectiveness and accessibility of PIs in resource-limited geographical areas compared to other antifungal agents, such as flucytosine, make them an appealing choice for combination therapy.

Medicinal Plants Cultivated in Egypt with Antiviral Potential: A Systematic Review.

Background: Viral diseases are a worldwide concern as some of them are associated with unexpectedly high mortality rates. Common viruses include e.g., Influenza virus, HIV, hepatitis viruses, and recently COVID-19. Many viral diseases are still incurable by conventional antiviral drugs. Moreover, the emergence of resistant viral strains has reinforced the search for other alternatives. In ancient times, herbal therapy was commonly used where medicinal formulations were created from various plants. In recent times, in vitro, in vivo, animal studies, and clinical trials have revealed the antiviral properties of these plants, sparking hope for the treatment of serious viral diseases. The present review aims to summarize studies that focus on medicinal plants available in Egypt with antiviral properties. Methods: The articles published in English between 1988 and 2022 and available in PubMed and Scopus databases with the relevant keywords were included. Results: Thirty-two plants in Egypt have met the criteria and possess in vitro or in vivo antiviral activity via different mechanisms. Only five of them; Camellia sinensis, Marine algae, Zizyphus spina-christi L., Trachyspermum Ammi, and Aloe Vera have been proven to be effective in vivo. For COVID-19, thirteen plants have shown efficacy against SARS-Cov-2 via different mechanisms including Camellia sinensis, Cinnamomum Verum, Punica granatum, Glycyrrhiza glabra, Zingiber officinale, Curcuma longa, Marine algae, Phlomis aurea oil, Solanum nigrum, Trachyspermum Ammi, Arum palaestinum, Aloe Vera, and Cyperus rotundus. Conclusion: This review summarizes the current scientific evidence on 32 medicinal plant species cultivated in Egypt that have demonstrated antiviral properties against various DNA and RNA viruses through in vitro and in vivo studies, highlighting their potential as prospective sources for the development of novel antiviral therapies. Further clinical research is still warranted to validate the effectiveness and safety of these plants as complementary treatment options for viral infections.

Optimization of Ethoxzolamide Analogs with Improved Pharmacokinetic Properties for In Vivo Efficacy against Neisseria gonorrhoeae.

Drug-resistant gonorrhea is caused by the bacterial pathogen Neisseria gonorrhoeae, for which there is no recommended oral treatment. We have demonstrated that the FDA-approved human carbonic anhydrase inhibitor ethoxzolamide potently inhibits N. gonorrhoeae; however, is not effective at reducing N. gonorrhoeae bioburden in a mouse model. Thus, we sought to optimize the pharmacokinetic properties of the ethoxzolamide scaffold. These efforts resulted in analogs with improved activity against N. gonorrhoeae, increased metabolic stability in mouse liver microsomes, and improved Caco-2 permeability compared to ethoxzolamide. Improvement in these properties resulted in increased plasma exposure in vivo after oral dosing. Top compounds were investigated for in vivo efficacy in a vaginal mouse model of gonococcal genital tract infection, and they significantly decreased the gonococcal burden compared to vehicle and ethoxzolamide controls. Altogether, results from this study provide evidence that ethoxzolamide-based compounds have the potential to be effective oral therapeutics against gonococcal infection.

Autophagy modulation attenuates sorafenib resistance in HCC induced in rats.

Hepatocellular carcinoma (HCC) has risen as the villain of cancer-related death globally, with a usual cruel forecasting. Sorafenib was officially approved by the FDA as first-line treatment for advanced HCC. Despite the brilliant promise revealed in research, actual clinical results are limited due to the widespread appearance of drug resistance. The tumor microenvironment (TME) has been correlated to pharmacological resistance, implying that existing cellular level strategies may be insufficient to improve therapy success. The role of autophagy in cancer is a two-edged sword. On one hand, autophagy permits malignant cells to overcome stress, such as hypoxic TME and therapy-induced starvation. Autophagy, on the other hand, plays an important role in damage suppression, which can reduce carcinogenesis. As a result, controlling autophagy is certainly a viable technique in cancer therapy. The goal of this study was to investigate at the impact of autophagy manipulation with sorafenib therapy by analyzing autophagy induction and inhibition to sorafenib monotherapy in rats with HCC. Western blot, ELISA, immunohistochemistry, flow cytometry, and quantitative-PCR were used to investigate autophagy, apoptosis, and the cell cycle. Routine biochemical and pathological testing was performed. Ultracellular features and autophagic entities were observed using a transmission electron microscope (TEM). Both regimens demonstrated significant reductions in chemotherapeutic resistance and hepatoprotective effects. According to the findings, both autophagic inhibitors and inducers are attractive candidates for combating sorafenib-induced resistance in HCC.

Role of the type 3 cytokines IL-17 and IL-22 in modulating metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises a spectrum of liver diseases that span simple steatosis, metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis and may progress to cirrhosis and cancer. The pathogenesis of MASLD is multifactorial and is driven by environmental, genetic, metabolic and immune factors. This review will focus on the role of the type 3 cytokines IL-17 and IL-22 in MASLD pathogenesis and progression. IL-17 and IL-22 are produced by similar adaptive and innate immune cells such as Th17 and innate lymphoid cells, respectively. IL-17-related signaling is upregulated during MASLD resulting in increased chemokines and proinflammatory cytokines in the liver microenvironment, enhanced recruitment of myeloid cells and T cells leading to exacerbation of inflammation and liver disease progression. IL-17 may also act directly by activating hepatic stellate cells resulting in increased fibrosis. In contrast, IL-22 is a pleiotropic cytokine with a dominantly protective signature in MASLD and is currently being tested as a therapeutic strategy. IL-22 also exhibits beneficial metabolic effects and abrogates MASH-related inflammation and fibrosis development via inducing the production of anti-oxidants and anti-apoptotic factors. A sex-dependent effect has been attributed to both cytokines, most importantly to IL-22 in MASLD or related conditions. Altogether, IL-17 and IL-22 are key effectors in MASLD pathogenesis and progression. We will review the role of these two cytokines and cells that produce them in the development of MASLD, their interaction with host factors driving MASLD including sexual dimorphism, and their potential therapeutic benefits.

Novel Approaches to Mortierella alpina Identification and Arachidonic Acid Production Optimization.

Arachidonic acid (ARA) is an integral constituent of cell structures and is instrumental for the nervous, muscular, and immune systems' functions. The sore need for this nutrient may be fulfilled via production based on the fungus Mortierella alpina. The identity of the M. alpina culture obtained from Assiut University, Egypt, was confirmed based on internal transcribed spacer DNA barcoding and elongation enzyme RNA sequencing. Liquid media glucose and peptone as carbon and nitrogen sources, respectively, and diverse micronutritional factors were adjusted for optimal biomass and ARA production. Shake flask cultivation at 25 °C for 7 days produced around 0.570 g of ARA per liter of culture. M. alpina treatment using mutagen 5-fluorouracil and octyl gallate-supplemented glucose-yeast-agar screening plates and shake-flask incubation at 25 °C, then at 20 °C, followed by aging at 10 °C, led to >3 g ARA/liter culture, a yield considered suitable for potential commercial production.

Advancing clinical understanding of surface electromyography biofeedback: bridging research, teaching, and commercial applications.

INTRODUCTION: Expanding the use of surface electromyography-biofeedback (EMG-BF) devices in different therapeutic settings highlights the gradually evolving role of visualizing muscle activity in the rehabilitation process. This review evaluates their concepts, uses, and trends, combining evidence-based research. AREAS COVERED: This review dissects the anatomy of EMG-BF systems, emphasizing their transformative integration with machine-learning (ML) and deep-learning (DL) paradigms. Advances such as the application of sophisticated DL architectures for high-density EMG data interpretation, optimization techniques for heightened DL model performance, and the fusion of EMG with electroencephalogram (EEG) signals have been spotlighted for enhancing biomechanical analyses in rehabilitation. The literature survey also categorizes EMG-BF devices based on functionality and clinical usage, supported by insights from commercial sectors. EXPERT OPINION: The current landscape of EMG-BF is rapidly evolving, chiefly propelled by innovations in artificial intelligence (AI). The incorporation of ML and DL into EMG-BF systems augments their accuracy, reliability, and scope, marking a leap in patient care. Despite challenges in model interpretability and signal noise, ongoing research promises to address these complexities, refining biofeedback modalities. The integration of AI not only predicts patient-specific recovery timelines but also tailors therapeutic interventions, heralding a new era of personalized medicine in rehabilitation and emotional detection.

Predictors of methotrexate adherence and patient's awareness of it in rheumatoid arthritis and its effect on quality of life.

Introduction: Adherence studies among rheumatoid arthritis (RA) patients, in Egypt and throughout the Middle East region, are lacking. This study aimed to evaluate methotrexate (MTX) adherence in Rheumatoid arthritis (RA) patients and to identify specific non-adherence predictors. Methods: A cross-sectional observational study included 300 RA patients who were administered MTX for at least one year. The survey was completed through direct interviews. The demographic patient data were collected (age, education, sex, work status, disease duration, duration of MTX administration and current dose). Patients' adherence to MTX predictors for non-adherence, MTX side effects and functional disability were assessed in the study. Results: Majority of respondents showed good MTX adherence, and more than 50% of patient's experienced MTX side effects. A large percentage of participants showed low knowledge about MTX nature and side effects. Most participants reported no or some difficulty in quality of life-related activities and functional disability. Conclusion: MTX adherence and awareness were positively correlated to many variables, including, age, educational level and disease duration, which in turn has its positive impact on the patient's quality of life. Still, more research is needed to determine the impact of non-adherence on the patient's health outcomes.

Transcriptome-Wide Association Study Reveals New Molecular Interactions Associated with Melanoma Pathogenesis.

A transcriptome-wide association study (TWAS) was conducted on genome-wide association study (GWAS) summary statistics of malignant melanoma of skin (UK Biobank dataset) and The Cancer Genome Atlas-Skin Cutaneous Melanoma (TCGA-SKCM) gene expression weights to identify melanoma susceptibility genes. The GWAS included 2465 cases and 449,799 controls, while the gene expression testing was conducted on 103 cases. Afterward, a gene enrichment analysis was applied to identify significant TWAS associations. The melanoma's gene-microRNA (miRNA) regulatory network was constructed from the TWAS genes and their corresponding miRNAs. At last, a disease enrichment analysis was conducted on the corresponding miRNAs. The TWAS detected 27 genes associated with melanoma with p-values less than 0.05 (the top three genes are LOC389458 (RBAK), C16orf73 (MEIOB), and EIF3CL). After the joint/conditional test, one gene (AMIGO1) was dropped, resulting in 26 significant genes. The Gene Ontology (GO) biological process associated the extended gene set (76 genes) with protein K11-linked ubiquitination and regulation of cell cycle phase transition. K11-linked ubiquitin chains regulate cell division. Interestingly, the extended gene set was related to different skin cancer subtypes. Moreover, the enriched pathways were nsp1 from SARS-CoV-2 that inhibit translation initiation in the host cell, cell cycle, translation factors, and DNA repair pathways full network. The gene-miRNA regulatory network identified 10 hotspot genes with the top three: TP53, BRCA1, and MDM2; and four hotspot miRNAs: mir-16, mir-15a, mir-125b, and mir-146a. Melanoma was among the top ten diseases associated with the corresponding (106) miRNAs. Our results shed light on melanoma pathogenesis and biologically significant molecular interactions.

Fighting Emerging Caspofungin-Resistant Candida Species: Mitigating Fks1-Mediated Resistance and Enhancing Caspofungin Efficacy by Chitosan.

Invasive candidiasis poses a worldwide threat because of the rising prevalence of antifungal resistance, resulting in higher rates of morbidity and mortality. Additionally, Candida species, which are opportunistic infections, have significant medical and economic consequences for immunocompromised individuals. This study explores the antifungal potential of chitosan to mitigate caspofungin resistance in caspofungin-resistant Candida albicans, C. krusei, and C. tropicalis isolates originating from human and animal sources using agar well diffusion, broth microdilution tests, and transmission electron microscope (TEM) analysis of treated Candida cells. Reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) was performed to assess the expression of SAGA complex genes (GCN5 and ADA2) and the caspofungin resistance gene (FKS) in Candida species isolates after chitosan treatment. The highest resistance rate was observed to ketoconazole (80%) followed by clotrimazole (62.7%), fluconazole (60%), terbinafine (58%), itraconazole (57%), miconazole (54.2%), amphotericin B (51.4%), voriconazole (34.28%), and caspofungin (25.7%). Nine unique FKS mutations were detected, including S645P (n = 3 isolates), S645F, L644F, S645Y, L688M, E663G, and F641S (one isolate in each). The caspofungin minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) values before chitosan treatment ranged from 2 to 8 µg/mL and 4 to 16 µg/mL, respectively. However, the MIC and MFC values were decreased after chitosan treatment (0.0625-1 µg/mL) and (0.125-2 µg/mL), respectively. Caspofungin MIC was significantly decreased (p = 0.0007) threefold following chitosan treatment compared with the MIC values before treatment. TEM analysis revealed that 0.5% chitosan disrupted the integrity of the cell surface, causing irregular morphologies and obvious aberrant changes in cell wall thickness in caspofungin-resistant and sensitive Candida isolates. The cell wall thickness of untreated isolates was 0.145 µm in caspofungin-resistant isolate and 0.125 µm in sensitive isolate, while it was significantly lower in chitosan-treated isolates, ranging from 0.05 to 0.08 µm when compared with the cell wall thickness of sensitive isolate (0.03 to 0.06 µm). Moreover, RT-qPCR demonstrated a significant (p < 0.05) decrease in the expression levels of histone acetyltransferase genes (GCN5 and ADA2) and FKS gene of caspofungin-resistant Candida species isolates treated with 0.5% chitosan when compared with before treatment (fold change values ranged from 0.001 to 0.0473 for GCN5, 1.028 to 4.856 for ADA2, and 2.713 to 12.38 for FKS gene). A comparison of the expression levels of cell wall-related genes (ADA2 and GCN5) between caspofungin-resistant and -sensitive isolates demonstrated a significant decrease following chitosan treatment (p < 0.001). The antifungal potential of chitosan enhances the efficacy of caspofungin against various caspofungin-resistant Candida species isolates and prevents the development of further antifungal resistance. The results of this study contribute to the progress in repurposing caspofungin and inform a development strategy to enhance its efficacy, appropriate antifungal activity against Candida species, and mitigate resistance. Consequently, chitosan could be used in combination with caspofungin for the treatment of candidiasis.

Infantile Hemangioma in Infancy: A Case Study on the Natural Course and Therapeutic Management.

Infantile hemangiomas (IHs) are common benign vascular tumors that affect infants. In this case report, we detail the natural course of an IH in an infant monitored over four months without medical intervention, illustrating the benign progression and potential for spontaneous stabilization of such lesions. The aim was to observe changes in the size and morphology of the hemangioma, alongside the infant's overall health and developmental milestones, through regular clinical assessments. This case presented a challenge as the patient's parents lacked English fluency, lacked healthcare access, and had low socioeconomic status. It highlights the importance of individualized patient care, advocating for careful observation and restraint in the application of pharmacological treatments when clinically unnecessary. The report contributes to existing pediatric dermatology knowledge by emphasizing the natural benign behavior of IH and the need for a balanced approach to treatment decisions, ensuring safe and favorable long-term outcomes for patients.

Renoprotective effect of a novel combination of 6-gingerol and metformin in high-fat diet/streptozotocin-induced diabetic nephropathy in rats via targeting miRNA-146a, miRNA-223, TLR4/TRAF6/NLRP3 inflammasome pathway and HIF-1α.

BACKGROUND: MiRNA-146a and miRNA-223 are key epigenetic regulators of toll-like receptor 4 (TLR4)/tumor necrosis factor-receptor-associated factor 6 (TRAF6)/NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome pathway, which is involved in diabetic nephropathy (DN) pathogenesis. The currently available oral anti-diabetic treatments have been insufficient to halt DN development and progression. Therefore, this work aimed to assess the renoprotective effect of the natural compound 6-gingerol (GR) either alone or in combination with metformin (MET) in high-fat diet/streptozotocin-induced DN in rats. The proposed molecular mechanisms were also investigated. METHODS: Oral gavage of 6-gingerol (100 mg/kg) and metformin (300 mg/kg) were administered to rats daily for eight weeks. MiRNA-146a, miRNA-223, TLR4, TRAF6, nuclear factor-kappa B (NF-κB) (p65), NLRP3, caspase-1, and hypoxia-inducible factor-1 alpha (HIF-1α) mRNA expressions were measured using real-time PCR. ELISA was used to measure TLR4, TRAF6, NLRP3, caspase-1, tumor necrosis factor-alpha (TNF-α), and interleukin-1-beta (IL-1ß) renal tissue levels. Renal tissue histopathology and immunohistochemical examination of fibronectin and NF-κB (p65) were performed. RESULTS: 6-Gingerol treatment significantly reduced kidney tissue damage and fibrosis. 6-Gingerol up-regulated miRNA-146a and miRNA-223 and reduced TLR4, TRAF6, NF-κB (p65), NLRP3, caspase-1, TNF-α, IL-1ß, HIF-1α and fibronectin renal expressions. 6-Gingerol improved lipid profile and renal functions, attenuated renal hypertrophy, increased reduced glutathione, and decreased blood glucose and malondialdehyde levels. 6-Gingerol and metformin combination showed superior renoprotective effects than either alone. CONCLUSION: 6-Gingerol demonstrated a key protective role in DN by induction of miRNA-146a and miRNA-223 expression and inhibition of TLR4/TRAF6/NLRP3 inflammasome signaling. 6-Gingerol, a safe, affordable, and abundant natural compound, holds promise for use as an adjuvant therapy with metformin in diabetic patients to attenuate renal damage and stop the progression of DN.

Effects of Rigidity and Configuration of Charged Moieties within Cationic Amphiphilic Polyproline Helices on Cell Penetration and Antibiotic Activity.

Effective molecular strategies are needed to target pathogenic bacteria that thrive and proliferate within mammalian cells, a sanctuary inaccessible to many therapeutics. Herein, we present a class of cationic amphiphilic polyproline helices (CAPHs) with a rigid placement of the cationic moiety on the polyproline helix and assess the role of configuration of the unnatural proline residues making up the CAPHs. By shortening the distance between the guanidinium side chain and the proline backbone of the agents, a notable increase in cellular uptake and antibacterial activity was observed, whereas changing the configuration of the moieties on the pyrrolidine ring from cis to trans resulted in more modest increases. When the combination of these two activities was evaluated, the more rigid CAPHs were exceptionally effective at eradicating intracellular methicillin-resistant Staphylococcus aureus (MRSA) and Salmonella infections within macrophages, significantly exceeding the clearance with the parent CAPH.

Impact of preoperative intra-aortic balloon pump on outcomes in coronary artery bypass grafting for unprotected left-main coronary artery disease.

Background: Preoperative intra-aortic balloon pump (IABP) before coronary artery bypass grafting (CABG) could improve operative outcomes by augmenting the diastolic coronary blood flow. Data on preoperative IABP use in patients with left-main coronary artery (LMCA) disease are limited. This study aimed to characterize patients who received preoperative IABP before CABG for LMCA and evaluate its effect on postoperative outcomes. Methods: This multicenter retrospective cohort study that included consecutive 914 patients who underwent CABG for unprotected LMCA disease from January 2015 to December 2019 in 14 tertiary referral centers. Patients were grouped according to the preoperative IABP insertion into patients with IABP (n=101) and without IABP (n=813). Propensity score matching adjusting for preoperative variables, with 1:1 match and a caliber of 0.03 identified 80 matched pairs. The primary outcomes used in propensity score matching were cardiac mortality and major adverse cardiac and cerebrovascular events (MACCE). Results: IABP was commonly inserted in patients with previous myocardial infarction (MI), chronic kidney disease, peripheral arterial disease, and congestive heart failure. IABP patients had higher EuroSCORE [ES >8%: 95 (11.86%) vs. 40 (39.60%), P<0.001] and SYNTAX {29 [interquartile range (IQR) 25-35] vs. 33 (IQR 26-36); P=0.02} scores. Preoperative cardiogenic shock and arrhythmia were more prevalent in patients with IABP, while acute coronary syndrome was more prevalent in patients without IABP. After matching, there was no difference in vasoactive inotropic score between groups [3.5 (IQR 1-7.5) vs. 6 (IQR 1-13.5), P=0.06], and lactate levels were nonsignificantly higher in patients with IABP [2.4 (IQR 1.4-4.5) vs. 3.1 (IQR 1.05-7.75), P=0.05]. There were no differences between groups in acute kidney injury [20 (25%) vs. 26 (32.5%), P=0.34], cerebrovascular accidents [3 (3.75%) vs. 4 (5%), P>0.99], heart failure [5 (6.25%) vs. 7 (8.75%), P=0.75], MI [7 (8.75%) vs. 8 (10%), P>0.99], major adverse cardiac and cerebrovascular events [10 (12.5%) vs. 17 (21.25%), P=0.21], and cardiac mortality [6 (7.50%) vs. 14 (17.50%), P=0.09]. Patients who received IABP had longer ventilation times [8.5 (IQR 6-23) vs. 15.5 (IQR 5-50.5) h, P=0.03] and intensive care unit (ICU) stays [3 (IQR 2-5) vs. 4 (IQR 2-7.5) days, P=0.01]. Conclusions: Preoperative IABP in patients with LMCA might not be associated with reduced cardiac mortality or hospital complications. IABP could increase the duration of mechanical ventilation and ICU stay, and its use should be individualized for each patient.

Lipoprotein(a) and Long-term In-stent Restenosis after Percutaneous Coronary Intervention.

AIM: Lipoprotein(a) [Lp(a)] has demonstrated its association with atherosclerosis and myocardial infarction. However, its role in the development of in-stent restenosis (ISR) after percutaneous coronary intervention (PCI) is not clearly established. The aim of this study is to investigate the association between Lp(a) and ISR. METHODS: A retrospective study of adult patients who underwent successful PCI between January 2006 and December 2017 at the three Mayo Clinic sites and had a preprocedural Lp(a) measurement was conducted. Patients were divided into two groups according to the serum Lp(a) concentration (high Lp(a) ≥50 mg/dl and low Lp(a) <50 mg/dl). Univariable and multivariable analyses were performed to compare risk of ISR between patients with high Lp(a) versus those with low Lp(a). RESULTS: A total of 1209 patients were included, with mean age 65.9 ±11.7 years and 71.8% were male. Median follow-up after baseline PCI was 8.8 (IQR 7.4) years. Restenosis was observed in 162 (13.4%) patients. Median serum levels of Lp(a) were significantly higher in patients affected by ISR versus non-affected cases: 27 (IQR 73.8) vs. 20 (IQR 57.5) mg/dL, p=0.008. The rate of ISR was significantly higher among patients with high Lp(a) versus patients with low Lp(a) values (17.0% vs 11.6%, p=0.010). High Lp(a) values were independently associated with ISR events (HR 1.67, 95%CI 1.18 to 2.37, p=0.004), and this association was more prominent after the first year following the PCI. CONCLUSION: Lipoprotein(a) is an independent predictor for long-term in-stent restenosis and should be considered in the evaluation of patients undergoing PCI.

The role of Lp(a) in the development of in-stent restenosis is not clearly established. In this study including 1209 patients who underwent successful percutaneous coronary intervention and had a preprocedural Lp(a) measurement between 2006 and 2017, the rates of restenosis were significantly higher among patients with high Lp(a) versus patients with low Lp(a) values and high Lp(a) concentrations were independently associated with restenosis events. Lp(a) should be considered as a risk factor for long term in-stent restenosis in the evaluation of patients undergoing percutaneous coronary intervention and assessed as a potential therapeutic target for reducing residual cardiovascular risk in this population.