Phytonanotherapy for the Treatment of Metabolic Dysfunction-Associated Steatotic Liver Disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease, is a steatotic liver disease associated with metabolic syndrome (MetS), especially obesity, hypertension, diabetes, hyperlipidemia, and hypertriglyceridemia. MASLD in 43-44% of patients can progress to metabolic dysfunction-associated steatohepatitis (MASH), and 7-30% of these cases will progress to liver scarring (cirrhosis). To date, the mechanism of MASLD and its progression is not completely understood and there were no therapeutic strategies specifically tailored for MASLD/MASH until March 2024. The conventional antiobesity and antidiabetic pharmacological approaches used to reduce the progression of MASLD demonstrated favorable peripheral outcomes but insignificant effects on liver histology. Alternatively, phyto-synthesized metal-based nanoparticles (MNPs) are now being explored in the treatment of various liver diseases due to their unique bioactivities and reduced bystander effects. Although phytonanotherapy has not been explored in the clinical treatment of MASLD/MASH, MNPs such as gold NPs (AuNPs) and silver NPs (AgNPs) have been reported to improve metabolic processes by reducing blood glucose levels, body fat, and inflammation. Therefore, these actions suggest that MNPs can potentially be used in the treatment of MASLD/MASH and related metabolic diseases. Further studies are warranted to investigate the feasibility and efficacy of phytonanomedicine before clinical application.

Methylated DNA markers for plasma detection of ovarian cancer: Discovery, validation, and clinical feasibility.

OBJECTIVE: Aberrant DNA methylation is an early event in carcinogenesis which could be leveraged to detect ovarian cancer (OC) in plasma. METHODS: DNA from frozen OC tissues, benign fallopian tube epithelium (FTE), and buffy coats from cancer-free women underwent reduced representation bisulfite sequencing (RRBS) to identify OC MDMs. Candidate MDM selection was based on receiver operating characteristic (ROC) discrimination, methylation fold change, and low background methylation among controls. Blinded biological validation was performed using methylated specific PCR on DNA extracted from independent OC and FTE FFPE tissues. MDMs were tested using Target Enrichment Long-probe Quantitative Amplified Signal (TELQAS) assays in pre-treatment plasma from women newly diagnosed with OC and population-sampled healthy women. A random forest modeling analysis was performed to generate predictive probability of disease; results were 500-fold in silico cross-validated. RESULTS: Thirty-three MDMs showed marked methylation fold changes (10 to >1000) across all OC subtypes vs FTE. Eleven MDMs (GPRIN1, CDO1, SRC, SIM2, AGRN, FAIM2, CELF2, RIPPLY3, GYPC, CAPN2, BCAT1) were tested on plasma from 91 women with OC (73 (80%) high-grade serous (HGS)) and 91 without OC; the cross-validated 11-MDM panel highly discriminated OC from controls (96% (95% CI, 89-99%) specificity; 79% (69-87%) sensitivity, and AUC 0.91 (0.86-0.96)). Among the 5 stage I/II HGS OCs included, all were correctly identified. CONCLUSIONS: Whole methylome sequencing, stringent filtering criteria, and biological validation yielded candidate MDMs for OC that performed with high sensitivity and specificity in plasma. Larger plasma-based OC MDM studies, including testing of pre-diagnostic specimens, are warranted.

Advances in Nanotechnology towards Development of Silver Nanoparticle-Based Wound-Healing Agents.

Since antiquity, silver-based therapies have been used in wound healing, wound care and management of infections to provide adequate healing. These therapies are associated with certain limitations, such as toxicity, skin discolouration and bacterial resistance, which have limited their use. As a result, new and innovative wound therapies, or strategies to improve the existing therapies, are sought after. Silver nanoparticles (AgNPs) have shown the potential to circumvent the limitations associated with conventional silver-based therapies as described above. AgNPs are effective against a broad spectrum of microorganisms and are less toxic, effective at lower concentrations and produce no skin discolouration. Furthermore, AgNPs can be decorated or coupled with other healing-promoting materials to provide optimum healing. This review details the history and impact of silver-based therapies leading up to AgNPs and AgNP-based nanoformulations in wound healing. It also highlights the properties of AgNPs that aid in wound healing and that make them superior to conventional silver-based wound treatment therapies.

Antitumor activity of phenylene bridged binuclear bis(imino-quinolyl)palladium(II) and platinum(II) complexes.

Antitumor effects of a known bis(imino-quinolyl)palladium(II) complex 1 and its newly synthesized platinum(II) analogue 2 were evaluated against human breast (MCF-7) and human colon (HT-29) cancer cell lines. The complexes gave cytotoxicity profiles that were better than the reference drug cisplatin. The highest cytotoxic activities were pronounced in complex 2 across the two examined cancer cell lines. Both compounds represent potential active drugs based on bimetallic complexes.

Mechanisms of remembering the past and imagining the future--new data from autobiographical memory tasks in a lifespan approach.

We investigated the episodic/semantic distinction in remembering the past and imagining the future and explored cognitive mechanisms predicting events' specificity throughout the lifespan. Eighty-three 6- to 81-year-old participants, divided into 5 age groups, underwent past, present and future episodic (events' evocation) and semantic (self-descriptions) autobiographical tasks and a complementary cognitive test battery (executive functions, working and episodic memory). The main results showed age effects on episodic events' evocation indicating an inverted U function (i.e., developmental progression from 6 to 21years and aging decline). By contrast, age effects were slighter on self-descriptions while self-defining events' evocation increased with age. Furthermore, age effects on episodic events' evocation were mainly mediated by age effects on cognitive functions and personal semantics. These new findings indicate a developmental and aging episodic/semantic distinction for both remembering the past and imagining the future, and suggest that above similarities, these abilities could have a fundamentally different basis.

Wound healing effects of biogenic gold nanoparticles synthesized using red wine extracts.

Gold nanoparticles (AuNPs) were synthesized using three red wine extracts (RW-Es); by varying temperature, pH, concentrations of RW-Es and gold salt. The RW-AuNPs were characterized by UV-vis, transmission electron microscopy (TEM), dynamic light scattering (DLS), and the Fourier Transform Infra-red Spectroscopy (FT-IR). Their stability was evaluated in water, foetal bovine serum (FBS), phosphate-buffered saline (PBS), and Dulbecco's Modified Eagle Medium (DMEM) by UV-Vis. The effect of the RW-Es and RW-AuNPs on KMST-6 cell cell viability was evaluated by MTT assay; and their wound healing effects were monitored by scratch assay. RW-AuNPs synthesis was observed by colour change, and confirmed by UV-Vis spectrum, with an absorption peak around 550 nm. The hydrodynamic sizes of the RW-AuNPs ranged between 10 and 100 nm. Polyphenols, carboxylic acids, and amino acids are some of functional groups in the RW-Es that were involved in the reduction of RW-AuNPs. The RW-AuNPs were stable in test solutions and showed no cytotoxicity to the KMST-6 cells up to 72 h. AuNPs synthesized from Pinotage and Cabernet Sauvignon enhanced proliferation of KMST-6 cells and showed potential as wound healing agents. Further studies are required to investigate the molecular mechanisms involved in the potential wound-healing effect of the RW-AuNPs.

The role and potential of computer-aided drug discovery strategies in the discovery of novel antimicrobials.

Antimicrobial resistance (AMR) has become more of a concern in recent decades, particularly in infections associated with global public health threats. The development of new antibiotics is crucial to ensuring infection control and eradicating AMR. Although drug discovery and development are essential processes in the transformation of a drug candidate from the laboratory to the bedside, they are often very complicated, expensive, and time-consuming. The pharmaceutical sector is continuously innovating strategies to reduce research costs and accelerate the development of new drug candidates. Computer-aided drug discovery (CADD) has emerged as a powerful and promising technology that renews the hope of researchers for the faster identification, design, and development of cheaper, less resource-intensive, and more efficient drug candidates. In this review, we discuss an overview of AMR, the potential, and limitations of CADD in AMR drug discovery, and case studies of the successful application of this technique in the rapid identification of various drug candidates. This review will aid in achieving a better understanding of available CADD techniques in the discovery of novel drug candidates against resistant pathogens and other infectious agents.

Salmonella enterica arthritis in a patient with rheumatoid arthritis receiving anti-tumour necrosis factor therapy.

Anti-tumour necrosis factor (TNF) monoclonal antibodies have become an invaluable treatment against chronic inflammatory diseases such as rheumatoid arthritis (RA). However, due to increased risk of opportunistic infections, patients receiving anti-TNF therapy should be closely monitored for serious infections. Here, we describe a case of acute Salmonella_enteritidis infection of a joint arthroplasty that previously was functioning well, in a patient receiving infliximab treatment for RA. After prolonged antimicrobial chemotherapy and interrupted infliximab treatment, reimplantation of a new prosthesis was successfully performed two years after Salmonella septic arthritis. Therefore, because of the possibility of extraintestinal salmonellosis, screening for fecal colonization could be advisable in patients undergoing anti-TNF treatment. Moreover we emphasize the importance of appropriate counselling of these patients concerning food hygiene.

National Data and the Applicability to Understanding Rural and Remote Substance Use.

Responding to increases in overdose, addiction, and substance misuse, local public health experts need accurate data to plan and implement evidence-based prevention and treatment programs. In many countries, national data are the tool most readily available for these efforts. In the United States, the National Study on Drug Use and Health and the Treatment Episode Data Set are data sources used by states to determine the extent of addiction. This project sought to determine if these national data sources are applicable for local use in addiction prevention and program planning. NSDUH prevalence estimates from 2015 to 2019 were applied to the state population to determine the number of persons estimated to be substance users. The prevalence estimates were compared over time with the population data and substance use treatment admissions to assess the covariance and population change as an indicator of efficacy. The primary drivers of fatal overdose in Alaska are fentanyl, heroin, and methamphetamine. Fentanyl use was not assessed in either dataset. When applying the estimated use prevalence to the population, heroin users varied annually by 1777 persons and methamphetamine varied up to 2143 persons. These observed variances did not correspond with state population changes nor any trend in the persons seeking treatment for these substances. Our analyses do not support the use of NSDUH data for planning in rural and remote areas. The methods used in NSDUH data collection exclude ~ 20% of the state population, mostly Native persons, based on location and language. The annual prevalence estimates applied to the population did not correspond with changes in population nor changes in treatment. Fentanyl, which causes the most overdoses in Alaska and is of primary concern locally, was not assessed.

Ehretia Species Phytoconstituents as Potential Lead Compounds against Klebsiella pneumoniae Carbapenemase: A Computational Approach.

The evolution of antibiotic-resistant carbapenemase has negatively impacted the management of critical healthcare-associated infections. K. pneumoniae carbapenemase-2- (KPC-2-) expressing bacteria have developed resistance to conventional therapeutic options, including those used as a last resort for life-threatening diseases. In this study, Ehretia species phytoconstituents were screened for their potential to inhibit KPC-2 protein using in silico approaches. Molecular docking was used to identify strong KPC-2 protein binding phytoconstituents retrieved from the literature. The best-docked conformation of the ligands was selected based on their glide energy and binding interactions. To determine their binding free energies, these hit compounds were subjected to molecular mechanics with generalized born and surface area (MM-GBSA) in the PRIME module. Pharmacological assessments of the ligands were performed to evaluate their drug-likeness. Molecular dynamic (MD) simulations were used to analyze the conformational stability of the selected druglike compounds within the active site of the KPC-2 protein. Overall, a total of 69 phytoconstituents were compiled from the literature. Fourteen of these compounds exhibited a stronger binding affinity for the protein target than the reference drugs. Four of these top hit compounds, DB09, DB12, DB28, and DB66, revealed the highest efficacy in terms of drug-likeness properties. The MD simulation established that among the druglike compounds, DB66 attained stable conformations after 150 ns simulation in the active site of the protein. We concluded that DB66 from Ehretia species could play a significant role in therapeutic efforts against KPC-2-expressing bacteria.

Anticancer, Antioxidant, and Catalytic Activities of Green Synthesized Gold Nanoparticles Using Avocado Seed Aqueous Extract.

Disposal of agricultural waste has a negative impact on the environment and human health and may contribute to the greenhouse effect. The field of nanotechnology could provide alternative solutions to upcycle agricultural wastes in a safer manner into high-end value products. Organic waste from plants contain biomaterials that could serve as reducing and capping agents in the synthesis of nanomaterials with enhanced activities for use in biomedical and environmental applications. Persea americana (avocado) is a fruit with a high nutritional value; however, despite its rich phytochemical profile, its seed is often discarded as waste. Therefore, this study aimed to upcycle avocado seeds through the synthesis of gold nanoparticles (AuNPs) and evaluate their anticancer, antioxidant, and catalytic activities. The biosynthesis of avocado seed extract (AvoSE)-mediated AuNPs (AvoSE-AuNPs) was achieved following the optimization of various reaction parameters, including pH, temperature, extract, and gold salt concentrations. The AvoSE-AuNPs were poly-dispersed and anisotropic, with average core and hydrodynamic sizes of 14 ± 3.7 and 101.39 ± 1.4 nm, respectively. The AvoSE-AuNPs showed excellent antioxidant potential in terms of ferric reducing antioxidant power (343.88 ± 0.001 µmolAAE/L), 2,2-diphenyl-1-picrylhydrazyl (128.80 ± 0.0159 µmolTE/L), and oxygen radical absorbance capacity (1822.02 ± 12.6338 µmolTE/L); significantly reduced the viability of Caco-2 and PC-3 cells in a dose-dependent manner; and efficiently reduced 4-nitrophenol (4-NP) to 4-aminophenol. This study demonstrated how avocado seeds, an agricultural waste, can be used as sources of new bioactive materials for the synthesis of AuNPs, which have excellent antioxidant, anticancer, and catalytic activities, showing AvoSE-AuNPs' versatility in various applications. In addition, the AvoSE-AuNPs exhibited good stability and recyclability during the catalytic activity, which is significant because some of the primary issues with the use of metallic NPs as catalysts are around the cost-effectiveness, recovery, and reusability of the catalyst.

Dichlorido[2-(phenyl-imino-meth-yl)quinoline-N,N']palladium(II).

In the title complex, [PdCl(2)(C(16)H(12)N(2))], the Pd(II) ion is coordinated by two N atoms [Pd-N 2.039 (2), 2.073 (2) Å] from a bidentate ligand and two chloride anions [Pd-Cl 2.2655 (7), 2.2991 (7) Å] in a distorted square-planar geometry. In the crystal, π-π inter-actions between the six-membered rings of the quinoline fragments [centroid-centroid distances = 3.815 (5), 3.824 (5) Å] link two mol-ecules into centrosymmetric dimers.

Epidemiology of oral squamous cell carcinoma.

The National Cancer Registry (NCR) of South Africa publishes the pathology-based cancer incidence in the country and is the main cancer data source. The data published by the NCR have been used extensively in the development of the draft national guidelines for cancer prevention and control as well as for cancer research. The list of contributing pathology laboratories is fairly inclusive. Data from the NCR and the University of Limpopo, Department of Oral Pathology for the five years 1997-2001 were combined and then filtered for sites in the oral and oropharyngeal region. Age-Standardised Incidence Rates (ASIR) and the Cumulative Lifetime Risk (LR) for males and females in the different population groups were determined. Comprehensive reporting of oral and oropharyngeal cancer incidence will influence the allocation of government resources for prevention and treatment of oral cancers.

Antimicrobial Effects of Gum Arabic-Silver Nanoparticles against Oral Pathogens.

Dental caries is considered one of the most prevalent oral diseases worldwide, with a high rate of morbidity among populations. It is a chronic infectious disease with a multifactorial etiology that leads to the destruction of the dental tissues. Due to their antimicrobial, anti-inflammatory, antifungal, and antioxidant properties; silver nanoparticles (AgNPs) are incorporated in dental products to help prevent infectious oral diseases. In this study, the antimicrobial effects of AgNPs synthesized using Gum Arabic extracts (GAE) were examined. The GA-AgNPs were synthesized and characterized using ultraviolet-visible (UV-Vis) spectrophotometer, dynamic light scattering (DLS), transmission electron microscopy (TEM), and Fourier transform infrared (FTIR) spectroscopy. The antimicrobial activity of the GA-AgNPs was evaluated on Streptococcus sanguinis (S. sanguinis), Streptococcus mutans (S. mutans), Lactobacillus acidophilus (L. acidophilus), and Candida albicans (C. albicans) using agar disc diffusion and microdilution assays. The antibiofilm of GA-AgNPs was evaluated on the surface of human tooth enamel that had been exposed to S. mutans with and without the GA-AgNPs using scanning electron microscopy (SEM). GA-AgNPs were spherical in shape with a particle size distribution between 4 and 26 nm. The GA-AgNPs exhibited antimicrobial activity against all the tested oral microbes, with GA-AgNPs_0.4g having higher antimicrobial activity. The GA-AgNPs_0.4g inhibited S. mutans adhesion and biofilm formation on the surface of the tooth enamel. Therefore, this study supports the prospective implementation of the plant extract-mediated AgNPs in dental healthcare.

A Label-Free Gold Nanoparticles-Based Optical Aptasensor for the Detection of Retinol Binding Protein 4.

Retinol-binding protein 4 (RBP4) has been implicated in insulin resistance in rodents and humans with obesity and T2DM, making it a potential biomarker for the early diagnosis of T2DM. However, diagnostic tools for low-level detection of RBP4 are still lagging behind. Therefore, there is an urgent need for the development of T2DM diagnostics that are rapid, cost-effective and that can be used at the point-of-care (POC). Recently, nano-enabled biosensors integrating highly selective optical detection techniques and specificity of aptamers have been widely developed for the rapid detection of various targets. This study reports on the development of a rapid gold nanoparticles (AuNPs)-based aptasensor for the detection of RBP4. The retinol-binding protein aptamer (RBP-A) is adsorbed on the surface of the AuNPs through van der Waals and hydrophobic interactions, stabilizing the AuNPs against sodium chloride (NaCl)-induced aggregation. Upon the addition of RBP4, the RBP-A binds to RBP4 and detaches from the surface of the AuNPs, leaving the AuNPs unprotected. Addition of NaCl causes aggregation of AuNPs, leading to a visible colour change of the AuNPs solution from ruby red to purple/blue. The test result was available within 5 min and the assay had a limit of detection of 90.76 ± 2.81 nM. This study demonstrates the successful development of a simple yet effective, specific, and colorimetric rapid assay for RBP4 detection.

Endogenous gas gangrene after laparoscopic cholecystectomy.

Clostridial gas gangrene of the abdominal wall is rare, and it is usually associated with organ perforation, immunosuppression or gastrointestinal malignancies. In this paper we present a case of fulminant, endogenous gas gangrene in a 58-year old diabetic female with arterial hypertension and atherosclerosis, following uneventful laparoscopic cholecystectomy. She developed gas gangrene of the abdominal wall 12-hours after cholecystectomy and died 24-hours after the onset of the first symptoms, in spite of treatment.

Nanotechnology-Based Strategies for Effective and Rapid Detection of SARS-CoV-2.

The coronavirus disease 2019 (COVID-19) pandemic has gained worldwide attention and has prompted the development of innovative diagnostics, therapeutics, and vaccines to mitigate the pandemic. Diagnostic methods based on reverse transcriptase-polymerase chain reaction (RT-PCR) technology are the gold standard in the fight against COVID-19. However, this test might not be easily accessible in low-resource settings for the early detection and diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The lack of access to well-equipped clinical laboratories, requirement for the high level of technical competence, and the cost of the RT-PCR test are the major limitations. Moreover, RT-PCR is unsuitable for application at the point-of-care testing (PoCT) as it is time-consuming and lab-based. Due to emerging mutations of the virus and the burden it has placed on the health care systems, there is a growing urgency to develop sensitive, selective, and rapid diagnostic devices for COVID-19. Nanotechnology has emerged as a versatile technology in the production of reliable diagnostic tools for various diseases and offers new opportunities for the development of COVID-19 diagnostic systems. This review summarizes some of the nano-enabled diagnostic systems that were explored for the detection of SARS-CoV-2. It highlights how the unique physicochemical properties of nanoparticles were exploited in the development of novel colorimetric assays and biosensors for COVID-19 at the PoCT. The potential to improve the efficiency of the current assays, as well as the challenges associated with the development of these innovative diagnostic tools, are also discussed.

Simplified structure of a new model to describe urinary excretion of plutonium after systemic, liver or pulmonary contamination of rats associated with Ca-DTPA treatments.

This study validates, by targeted experiments, several modeling hypotheses for interpretation of urinary excretion of plutonium after Ca-DTPA treatments. Different formulations and doses of Ca-DTPA were administered to rats before or after systemic, liver or lung contamination with various chemical forms of plutonium. The biokinetics of plutonium was also characterized after i.v. injection of Pu-DTPA. Once formed, Pu-DTPA complexes are stable in most biological environments. Pu-DTPA present in circulating fluids is rapidly excreted in the urine, but 2-3% is retained, mainly in soft tissues, and is then excreted slowly in the urine after transfer to blood. Potentially, all intracellular monoatomic forms of plutonium could be decorporated after DTPA internalization involving slow urinary excretion of Pu-DTPA with half-lives varying from 2.5 to 6 days as a function of tissue retention. The ratio of fast to slow urinary excretion of Pu-DTPA depends on both plutonium contamination and Ca-DTPA treatment. Fast urinary excretion of Pu-DTPA corresponds to extracellular decorporation that occurs beyond a threshold of the free DTPA concentration in circulating fluids. Slow excretion corresponds mostly to intracellular decorporation and depends on the amount of intracellular DTPA. From these results, the structure of a simplified model is proposed for interpretation of data obtained with Ca-DTPA treatments after systemic, wound or pulmonary contamination by plutonium.

Inactivation of glycogen synthase kinase-3beta, a downstream target of the raf-1 pathway, is associated with growth suppression in medullary thyroid cancer cells.

Glycogen synthase kinase-3beta (GSK-3beta) is an important regulator of cell proliferation and survival. Conflicting observations have been reported regarding the regulation of GSK-3beta and extracellular signal-regulated kinase (ERK1/2) in cancer cells. In this study, we found that raf-1 activation in human medullary thyroid cancer cells, TT cells, resulted in phosphorylation of GSK-3beta. Inactivation of GSK-3beta in TT cells with well-known GSK-3beta inhibitors such as lithium chloride (LiCl) and SB216763 is associated with both growth suppression and a significant decrease in neuroendocrine markers such as human achaete-scute complex-like 1 and chromogranin A. Growth inhibition by GSK-3beta inactivation was found to be associated with cell cycle arrest due to an increase in the levels of cyclin-dependent kinase inhibitors such as p21, p27, and p15. Additionally, LiCl-treated TT xenograft mice had a significant reduction in tumor volume compared with those treated with control. For the first time, we show that GSK-3beta is a key downstream target of the raf-1 pathway in TT cells. Also, our results show that inactivation of GSK-3beta alone is sufficient to inhibit the growth of TT cells both in vitro and in vivo.

Antimicrobial use at a university hospital: appropriate or misused? A qualitative study.

OBJECTIVE: To evaluate the quality of antimicrobial drug use in a university hospital medical department (Department of Medicine, University Hospital Rijeka, Croatia) with 279 hospital-beds in wards containing patients from endocrinology, gastroenterology, hematology, clinical immunology, cardiology and coronary care unit, nephrology and pulmonology sections of the hospital. METHODS: The appropriateness of antimicrobial treatment for all in-patients in the Department of Medicine was assessed in a prospective, longitudinal survey carried out during a 21-week period using Kunin's criteria where Categories I and II indicate "appropriate therapy", Categories III and IV indicate major deficiency in the choice or use of antimicrobials. Category V indicates unjustified antimicrobial administration. RESULTS: During the study period, a total of 438 patients were treated with antimicrobials in the Department of Medicine. Of these, 159 (36%) received antimicrobials appropriately (Category I and II), 180 (41%) needed antimicrobials (Category III and IV) but they should have been prescribed differently. The main reason for inappropriate antimicrobial treatment was the wrong choice of antimicrobials (broad-spectrum where a narrow spectrum antibiotic would have been sufficient). In the case of 99 patients (23%) an indication for antimicrobial therapy did not exist (Category V). CONCLUSION: The main reason for suboptimal use of antimicrobials was the over-prescribing of broad-spectrum antimicrobials. This situation should be corrected e.g. by changes in the post-graduate medical teaching program.