Artificial Intelligence (AI) and Internet of Medical Things (IoMT) Assisted Biomedical Systems for Intelligent Healthcare.

Artificial intelligence (AI) is a modern approach based on computer science that develops programs and algorithms to make devices intelligent and efficient for performing tasks that usually require skilled human intelligence. AI involves various subsets, including machine learning (ML), deep learning (DL), conventional neural networks, fuzzy logic, and speech recognition, with unique capabilities and functionalities that can improve the performances of modern medical sciences. Such intelligent systems simplify human intervention in clinical diagnosis, medical imaging, and decision-making ability. In the same era, the Internet of Medical Things (IoMT) emerges as a next-generation bio-analytical tool that combines network-linked biomedical devices with a software application for advancing human health. In this review, we discuss the importance of AI in improving the capabilities of IoMT and point-of-care (POC) devices used in advanced healthcare sectors such as cardiac measurement, cancer diagnosis, and diabetes management. The role of AI in supporting advanced robotic surgeries developed for advanced biomedical applications is also discussed in this article. The position and importance of AI in improving the functionality, detection accuracy, decision-making ability of IoMT devices, and evaluation of associated risks assessment is discussed carefully and critically in this review. This review also encompasses the technological and engineering challenges and prospects for AI-based cloud-integrated personalized IoMT devices for designing efficient POC biomedical systems suitable for next-generation intelligent healthcare.

Non-antifungal drugs inhibit growth, morphogenesis and biofilm formation in Candida albicans.

The increased resistance/tolerance of Candida infections to antimicrobial treatment can be attributed to biofilm-associated cells. A way to overcome this situation is to re-purpose non-anti-fungal drugs that could be active against fungi. We have explored the potential of a small library of eighteen non-antifungal drugs used in different human diseases. Candida albicans was cultured in the presence and absence of different concentrations of these drugs. Subsequently, inhibition of growth, germ tube formation, adhesion, and biofilm development were studied. Out of eighteen drug molecules, six showed a reduction in planktonic and biofilm growth in a dose-dependent manner and three drugs inhibited germ tube formation. This study shows the potential of non-antifungal drugs for the development of new anti-Candida agents.

State-of-Art Bio-Assay Systems and Electrochemical Approaches for Nanotoxicity Assessment.

Innovations in the field of nanotechnology, material science and engineering has rendered fruitful utilities in energy, environment and healthcare. Particularly, emergence of surface engineered nanomaterials offered novel varieties in the daily consumables and healthcare products including therapeutics and diagnostics. However, the nanotoxicity and bioactivity of the nanomaterials upon interaction with biological system has raised critical concerns to individual as well as to the environment. Several biological models including plant and animal sources have been identified to study the toxicity of novel nanomaterials, correlating the physio-chemical properties. Biological interaction of nanomaterials and its mediated physiological functions are studied using conventional cell/molecular biological assays to understand the expression levels of genetic information specific to intra/extra cellular enzymes, cell viability, proliferation and function. However, modern research still demands advanced bioassay methods to screen the acute and chronic effects of nanomaterials at the real-time. In this regard, bioelectrochemical techniques, with the recent advancements in the microelectronics, proved to be capable of providing non-invasive measurement of the nanotoxicity effects (in vivo and in vitro) both at single cellular and multicellular levels. This review attempted to provide a detailed information on the recent advancements made in development of bioassay models and systems for assessing the nanotoxicology. With a short background information on engineered nanomaterials and physiochemical properties specific to consumer application, present review highlights the multiple bioassay models evolved for toxicological studies. Emphasize on multiple mechanisms involved in the cell toxicity and electrochemical probing of the biological interactions, revealing the cytotoxicity were also provided. Limitations in the existing electrochemical techniques and opportunities for the future research focusing the advancement in single molecular and whole cell bioassay has been discussed.

Comparative Cytotoxicity of Inorganic Arsenite and Methylarsenite in Human Brain Cells.

The overall goal of this study is to elucidate the potential effect(s) of arsenic on a variety of human brain cells. Arsenic is the most pervasive Group A human environmental carcinogen. Long-term exposure to arsenic is associated with human diseases including cancer, cardiovascular disease, and diabetes. More immediate are the health effects on neurological development and associated disorders in infants and children exposed to arsenic in utero. Arsenic is metabolized in various organs and tissues into more toxic methylated species, including methylarsenite (MAs(III)), so the question arises whether the methylate species are responsible for the neurological effects of arsenic. Arsenic enters the brain through the blood-brain barrier and produces toxicity in the brain microvascular endothelial cells, glia (astrocytes and microglia), and neurons. In this study, we first assessed the toxicity in different types of brain cells exposed to either inorganic trivalent As(III) or MAs(III) using both morphological and cytotoxicity cell-based analysis. Second, we determined the methylation of arsenicals and the expression levels of the methylation enzyme, As(III) S-adenosylmethionine (SAM) methyltransferase (AS3MT), in several types of brain cells. We showed that the toxicity to neurons of MAs(III) was significantly higher than that of As(III). Interestingly, the differences in cytotoxicity between cell types was not due to expression of AS3MT, as this was expressed in neurons and glia but not in endothelial cells. These results support our hypothesis that MAs(III) is the likely physiological neurotoxin rather than inorganic arsenic species.

Antiepileptic Drugs Inhibit Growth, Dimorphism, and Biofilm Mode of Growth in Human Pathogen Candida albicans.

Exploring the potential of existing drugs for their unknown properties may offer advantages over conventional drug development by saving time and money. Candida albicans, an important human opportunist, shares many genetic properties with humans. This has encouraged us to study drugs that are not originally antifungals against C. albicans. In the present study, we have tested six antiepileptic drugs for their activities against C. albicans. Their effects on growth, time-dependent killing, yeast-to-hyphal form switching, and biofilms formation by C. albicans were studied. Out of the drugs studied, four drugs, which are γ-aminobutyric acid (GABA) receptor agonists in humans, inhibited growth, yeast-to-hyphal form switching, and biofilm formation in C. albicans. Lorazepam inhibited growth of C. albicans at 25 µg/ml, followed by midazolam and diazepam (minimum inhibitory concentrations 100 and 400 µg/ml, respectively). Members from other group voltage-gated sodium channel blockers failed to inhibit C. albicans. Our study has identified GABA receptor agonists used in epileptic therapy as potential candidates for antifungal drug development against the human pathogen C. albicans.

Phenylpropanoids of plant origin as inhibitors of biofilm formation by Candida albicans.

Biofilm-related infections of Candida albicans are a frequent cause of morbidity and mortality in hospitalized patients, especially those with immunocompromised status. Options of the antifungal drugs available for successful treatment of drug-resistant biofilms are very few, and as such, new strategies need to be explored against them. The aim of this study was to evaluate the efficacy of phenylpropanoids of plant origin against planktonic cells, important virulence factors, and biofilm forms of C. albicans. Standard susceptibility testing protocol was used to evaluate the activities of 13 phenylpropanoids against planktonic growth. Their effects on adhesion and yeast-to-hyphae morphogenesis were studied in microplate-based methodologies. An in vitro biofilm model analyzed the phenylpropanoid-mediated prevention of biofilm development and mature biofilms using XTT-metabolic assay, crystal violet assay, and light microscopy. Six molecules exhibited fungistatic activity at ≤0.5 mg/ml, of which four were fungicidal at low concentrations. Seven phenylpropanoids inhibited yeast-to-hyphae transition at low concentrations (0.031-0.5 mg/ml), whereas adhesion to the solid substrate was prevented in the range of 0.5-2 mg/ml. Treatment with ≤0.5 mg/ml concentrations of at least six small molecules resulted in significant (p < 0.05) inhibition of biofilm formation by C. albicans. Mature biofilms that are highly resistant to antifungal drugs were susceptible to low concentrations of 4 of the 13 molecules. This study revealed phenylpropanoids of plant origin as promising candidates to devise preventive strategies against drug-resistant biofilms of C. albicans.

Effect of alcohols on filamentation, growth, viability and biofilm development in Candida albicans

In this study we report the potential of alcohols as morphogenetic regulators in Candida albicans. All the alcohols tested influenced various modes of growth like planktonic as well as biofilm forms. Viability was affected at high concentrations. Among the alcohols, the response of C. albicans to amyl alcohol (pentanol) was noteworthy. Amyl alcohol at a concentration 0.5% which was not inhibitory to growth and viability specifically inhibited morphogenetic switching from yeast to hyphal forms. It also inhibited normal biofilm development favoring yeast dominated biofilms. Based on this study we hypothesize that alcohols produced under anaerobic conditions may not favor biofilm development and support dissemination of yeast cells. Since anaerobic conditions are not found to favor production of quorum sensing molecules like farnesol, the alcohols may play a role in morphogenetic regulation.

Anti-Candida properties of asaronaldehyde of Acorus gramineus rhizome and three structural isomers.

BACKGROUND: Asaronaldehyde (2, 4, 5-trimethoxybeznaldehyde) is an active component of Acorus gramineus rhizome. This study aims to evaluate the anti-Candida efficacy of asaronaldehyde and its three structural isomers, namely, 2, 3, 4-trimethoxybenzaldehyde, 3, 4, 5-trimethoxybenzaldehyde, and 2, 4, 6- trimethoxybenzaldehyde. METHODS: Susceptibility testing of test compounds was carried out using standard methodology (M27-A2) as per clinical and laboratory standards institute guidelines. Minimum fungicidal concentration (MFC) was determined as the lowest concentration of drug killing 99.9% of Candida cells. The effect on sterol profile was evaluated using the ergosterol quantitation method. Effects on morphogenesis, adhesion and biofilm formation in C. albicans were studied using germ-tube, adherence and biofilm formation assays respectively. Cytotoxicity of test compounds to human RBCs was determined by hemolysis assay. RESULTS: 2, 4, 6-Trimethoxybenzaldehyde exhibited significant anti-Candida activity (P = 0.0412). Minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) were established as 0.25 and 0.5 mg/mL, respectively. All of the test compounds showed significant inhibition of hyphal form transition in yeast at MIC/2 and MIC/4 values. 3, 4, 5-Trimethoxybenzaldehyde and 2, 4, 6-trimethoxybenzaldehyde inhibited adhesion and biofilms. A hemolytic assay of these compounds revealed that they were non-toxic at MIC values. Asaronaldehyde reduced sterol content. CONCLUSION: Asaronaldehyde and 2, 4, 6-trimethoxybenzaldehyde showed anti-Candida efficacy.

Chloroquine sensitizes biofilms of Candida albicans to antifungal azoles

Biofilms formed by Candida albicans, a human pathogen, are known to be resistant to different antifungal agents. Novel strategies to combat the biofilm associated Candida infections like multiple drug therapy are being explored. In this study, potential of chloroquine to be a partner drug in combination with four antifungal agents, namely fluconazole, voriconazole, amphotericin B, and caspofungin, was explored against biofilms of C. albicans. Activity of various concentrations of chloroquine in combination with a particular antifungal drug was analyzed in a checkerboard format. Growth of biofilm in presence of drugs was analyzed by XTT-assay, in terms of relative metabolic activity compared to that of drug free control. Results obtained by XTT-metabolic assay were confirmed by scanning electron microscopy. The interactions between chloroquine and four antifungal drugs were determined by calculating fractional inhibitory concentration indices. Azole resistance in biofilms was reverted significantly (p < 0.05) in presence of 250 µg/mL of chloroquine, which resulted in inhibition of biofilms at very low concentrations of antifungal drugs. No significant alteration in the sensitivity of biofilms to caspofungin and amphotericin B was evident in combination with chloroquine. This study for the first time indicates that chloroquine potentiates anti-biofilm activity of fluconazole and voriconazole.

Chloroquine sensitizes biofilms of Candida albicans to antifungal azoles.

Biofilms formed by Candida albicans, a human pathogen, are known to be resistant to different antifungal agents. Novel strategies to combat the biofilm associated Candida infections like multiple drug therapy are being explored. In this study, potential of chloroquine to be a partner drug in combination with four antifungal agents, namely fluconazole, voriconazole, amphotericin B, and caspofungin, was explored against biofilms of C. albicans. Activity of various concentrations of chloroquine in combination with a particular antifungal drug was analyzed in a checkerboard format. Growth of biofilm in presence of drugs was analyzed by XTT-assay, in terms of relative metabolic activity compared to that of drug free control. Results obtained by XTT-metabolic assay were confirmed by scanning electron microscopy. The interactions between chloroquine and four antifungal drugs were determined by calculating fractional inhibitory concentration indices. Azole resistance in biofilms was reverted significantly (p<0.05) in presence of 250µg/mL of chloroquine, which resulted in inhibition of biofilms at very low concentrations of antifungal drugs. No significant alteration in the sensitivity of biofilms to caspofungin and amphotericin B was evident in combination with chloroquine. This study for the first time indicates that chloroquine potentiates anti-biofilm activity of fluconazole and voriconazole.

Effect of alcohols on filamentation, growth, viability and biofilm development in Candida albicans.

In this study we report the potential of alcohols as morphogenetic regulators in Candida albicans. All the alcohols tested influenced various modes of growth like planktonic as well as biofilm forms. Viability was affected at high concentrations. Among the alcohols, the response of C. albicans to amyl alcohol (pentanol) was noteworthy. Amyl alcohol at a concentration 0.5% which was not inhibitory to growth and viability specifically inhibited morphogenetic switching from yeast to hyphal forms. It also inhibited normal biofilm development favoring yeast dominated biofilms. Based on this study we hypothesize that alcohols produced under anaerobic conditions may not favor biofilm development and support dissemination of yeast cells. Since anaerobic conditions are not found to favor production of quorum sensing molecules like farnesol, the alcohols may play a role in morphogenetic regulation.

Terpenoids of plant origin inhibit morphogenesis, adhesion, and biofilm formation by Candida albicans.

Biofilm-related infections caused by Candida albicans and associated drug resistant micro-organisms are serious problems for immunocompromised populations. Molecules which can prevent or remove biofilms are needed. Twenty-eight terpenoids of plant origin were analysed for their activity against growth, virulence attributes, and biofilms of C. albicans. Eighteen molecules exhibited minimum inhibitory concentrations of <2 mg ml(-1) for planktonic growth. Selected molecules inhibited yeast to hyphal dimorphism at low concentrations (0.031-0.5 mg ml(-1)), while adhesion to a solid surface was prevented at 0.5-2 mg ml(-1). Treatment with 14 terpenoids resulted in significant (p < 0.05) inhibition of biofilm formation, and of these, linalool, nerol, isopulegol, menthol, carvone, α-thujone, and farnesol exhibited biofilm-specific activity. Eight terpenoids were identified as inhibitors of mature biofilms. This study demonstrated the antibiofilm potential of terpenoids, which need to be further explored as therapeutic strategy against biofilm associated infections of C. albicans.

Sensitization of Candida albicans biofilms to various antifungal drugs by cyclosporine A.

BACKGROUND: Biofilms formed by Candida albicans are resistant towards most of the available antifungal drugs. Therefore, infections associated with Candida biofilms are considered as a threat to immunocompromised patients. Combinatorial drug therapy may be a good strategy to combat C. albicans biofilms. METHODS: Combinations of five antifungal drugs- fluconazole (FLC), voriconazole (VOR), caspofungin (CSP), amphotericin B (AmB) and nystatin (NYT) with cyclosporine A (CSA) were tested in vitro against planktonic and biofilm growth of C. albicans. Standard broth micro dilution method was used to study planktonic growth, while biofilms were studied in an in vitro biofilm model. A chequerboard format was used to determine fractional inhibitory concentration indices (FICI) of combination effects. Biofilm growth was analyzed using XTT-metabolic assay. RESULTS: MICs of various antifungal drugs for planktonic growth of C. albicans were lowered in combination with CSA by 2 to 16 fold. Activity against biofilm development with FIC indices of 0.26, 0.28, 0.31 and 0.25 indicated synergistic interactions between FLC-CSA, VOR-CSA, CSP-CSA and AmB-CSA, respectively. Increase in efficacy of the drugs FLC, VOR and CSP against mature biofilms after addition of 62.5 µg/ml of CSA was evident with FIC indices 0.06, 0.14 and 0.37, respectively. CONCLUSIONS: The combinations with CSA resulted in increased susceptibility of biofilms to antifungal drugs. Combination of antifungal drugs with CSA would be an effective prophylactic and therapeutic strategy against biofilm associated C. albicans infections.