Telomerase: a nexus between cancer nanotherapy and circadian rhythm.

Cancer represents a complex disease category defined by the unregulated proliferation and dissemination of anomalous cells within the human body. According to the GLOBOCAN 2020 report, the year 2020 witnessed the diagnosis of approximately 19.3 million new cases of cancer and 10.0 million individuals succumbed to the disease. A typical cell eventually becomes cancerous because of a long-term buildup of genetic instability and replicative immortality. Telomerase is a crucial regulator of cancer progression as it induces replicative immortality. In cancer cells, telomerase inhibits apoptosis by elongating the length of the telomeric region, which usually protects the genome from shortening. Many nanoparticles are documented as being available for detecting the presence of telomerase, and many were used as delivery systems to transport drugs. Furthermore, telomere homeostasis is regulated by the circadian time-keeping machinery, leading to 24-hour rhythms in telomerase activity and TERT mRNA expression in mammals. This review provides a comprehensive discussion of various kinds of nanoparticles used in telomerase detection, inhibition, and multiple drug-related pathways, as well as enlightens an imperative association between circadian rhythm and telomerase activity from the perspective of nanoparticle-based anticancer therapeutics.

Recent Trends in Bio-nanomaterials and Non-invasive Combinatorial Approaches of Photothermal Therapy against Cancer.

In 2020, approximately 10 million deaths worldwide were attributed to cancer, making it the primary cause of death globally. Photothermal therapy (PTT) is one of the novel ways to treat and abolish cancer. PTT significantly impacts cancer theranostics compared to other therapies like surgery, chemotherapy, and radiotherapy due to its remarkable binding capability to tumor sites and lower invasiveness into normal healthy tissues. PTT relies on photothermal agents (PTAs), which generate heat by absorbing the near-infrared (NIR) light and destroying cancer cells. Several PTT agents remain longer in the reticuloendothelial system (RES) and induce toxicity, restricting their use in the biomedical field. To overcome this problem, the usage of biodegradable nano-photothermal agents is required. This review has discussed the PTT mechanism of action and different types of novel bio-nanomaterials used for PTT. We also focussed on the combinatorial effects of PTT with other cancer therapies and their effect on human health. The role of LED lights and mild hypothermia in PTT has been discussed briefly in this review.

Development, systematic optimisation and biofilm disruption activity of eugenol-based nanosized emulsions stabilised with Tween 80.

The aims of this study were to systematically optimise a formula for eugenol emulsions via face-centered central composite design and to assess the activity against two-different bacterial strains (Staphylococcus aureus and Propionibacterium acnes) present at planktonic and biofilm forms. The molecular interaction of excipients, mean particle size (MPS) including zeta potential (ZP), drug entrapment efficiency (DEE) and in vitro drug release of optimised emulsions was done using FT-IR, Malvern Zetasizer, ultracentrifugation technique and membrane-free dissolution model, respectively. The emulsions consisted of 151.3 ± 1.45 nm MPS, -21.3 ± 1.25 mV ZP and 93.98 ± 1.41% DEE values. On storage of emulsions at 25 °C for 3 months, the value of DEE was found to be 72.12 ± 2.82%. The Tween 80 emulsifier film coverage onto the dispersed eugenol droplets of emulsions delayed significantly the drug release (12%-19%) compared to the drug release occurred from pure eugenol. The treatment of planktonic S. aureus and P. acnes with diluted eugenol emulsions showed the minimum inhibitory concentration and minimum bactericidal concentration values at 1.25-2.5 mg/ml whereas it occurred at 10 mg/ml for pure eugenol. Treating the biofilms with eugenol emulsions (1-2 mg/ml) yielded 59-70% minimum biofilm eradication concentration but 10 mg/ml pure eugenol showed 60%. Hence, the eugenol emulsions displayed antibacterial activity and could be projected as an antibiofilm or biofilm disruption agent.

Investigating the role of Candida albicans as a universal substrate for oral bacteria using a transcriptomic approach: implications for interkingdom biofilm control?

Candida albicans is frequently identified as a colonizer of the oral cavity in health and has recently been termed a "keystone" commensal due to its role on the bacterial communities. However, the role that C. albicans plays in such interactions is not fully understood. Therefore, this study aimed to identify the relationship between C. albicans and bacteria associated with oral symbiosis and dysbiosis. To do this, we evaluated the ability of C. albicans to support the growth of the aerobic commensal Streptococcus gordonii and the anaerobic pathogens Fusobacterium nucleatum and Porphyromonas gingivalis in the biofilm environment. RNA-Sequencing with the Illumina platform was then utilized to identify C. albicans gene expression and functional pathways involved during such interactions in dual-species and a 4-species biofilm model. Results indicated that C. albicans was capable of supporting growth of all three bacteria, with a significant increase in colony counts of each bacteria in the dual-species biofilm (p < 0.05). We identified specific functional enrichment of pathways in our 4-species community as well as transcriptional profiles unique to the F. nucleatum and S. gordonii dual-species biofilms, indicating a species-specific effect on C. albicans. Candida-related hemin acquisition and heat shock protein mediated processes were unique to the organism following co-culture with anaerobic and aerobic bacteria, respectively, suggestive that such pathways may be feasible options for therapeutic targeting to interfere with these fungal-bacterial interactions. Targeted antifungal therapy may be considered as an option for biofilm destabilization and treatment of complex communities. Moving forward, we propose that further studies must continue to investigate the role of this fungal organism in the context of the interkingdom nature of oral diseases.

Green synthesis of multi-functional carbon dots from medicinal plant leaves for antimicrobial, antioxidant, and bioimaging applications.

In this research work, carbon dots (CDs) were synthesized from the renewable leaves of an indigenous medicinal plant by the one-pot sand bath method, Azadirachta indica. The synthesized CDs were characterized for its optical properties using UV-Vis, Fluorescence and Fourier transform infrared (FT-IR) spectrophotometry and for structural properties using dynamic light scattering (DLS), X-ray Diffraction (XRD) and high resolution Transmission electron microscopy (HR-TEM). The synthesized CDs exhibited concentration dependent biocompatibility when tested in mouse fibroblast L929 cell line. The EC50 values of biomedical studies, free radical scavenging activity (13.87 µgmL-1), and total antioxidant capacity (38 µgmL-1) proved CDs were exceptionally good. These CDs showed an appreciable zone of inhibition when examined on four bacterial (two gram-positive and gram-negative) and two fungal strains at minimum concentrations. Cellular internalisation studies performed on human breast cancer cells (MCF 7- bioimaging) revealed the applicability of CDs in bioimaging, wherein the inherent fluorescence of CDs were utilised. Thus, the CDs developed are potential as bioimaging, antioxidants and antimicrobial agents.

Limitations of using 16S rRNA microbiome sequencing to predict oral squamous cell carcinoma.

A new era of next-generation sequencing has changed our perception of the oral microbiome in health and disease, and with this there is a growing understanding that the oral microbiome is a contributing factor to oral squamous cell carcinoma (OSCC), a malignancy of the oral cavity. This study aimed to analyse the trends and relevant literature based on the 16S rRNA oral microbiome in head and neck cancer using next-generation sequencing technologies, and to conduct a meta-analysis of the studies with OSCC cases and healthy controls. A literature search using the databases Web of Science and PubMed was conducted in a scoping-like review to collect information based on the study design, and plots were generated using RStudio. We selected case-control studies using 16S rRNA oral microbiome sequencing analysis in OSCC cases versus healthy controls for re-analysis. Statistical analyses were conducted using R. Out of 916 original articles, we filtered and selected 58 studies for review, and 11 studies for meta-analysis. Differences between sampling type, DNA extraction methods, next-generation sequencing technology and region of the 16S rRNA were identified. No significant differences in the α- and ß-diversity between health and oral squamous cell carcinoma were observed (p < 0.05). Random Forest classification marginally improved predictability of four studies (training set) when split 80/20. We found an increase in Selenomonas, Leptotrichia and Prevotella species to be indicative of disease. A number of technological advances have been accomplished to study oral microbial dysbiosis in oral squamous cell carcinoma. There is a clear need for standardization of study design and methodology to ensure 16S rRNA outputs are comparable across the discipline in the hope of identifying 'biomarker' organisms for designing screening or diagnostic tools.

Immunomodulatory nanosystems: An emerging strategy to combat viral infections.

The viral infection spreads with the assistance of a host. Traditional antiviral therapies cannot provide long-term immunity against emerging and drug-resistant viral infections. Immunotherapy has evolved as an efficient approach for disease prevention and treatment, which include cancer, infections, inflammatory, and immune disorders. Immunomodulatory nanosystems can dramatically enhance therapeutic outcomes by combating many therapeutic challenges, such as poor immune stimulation and off-target adverse effects. Recently, immunomodulatory nanosystems have emerged as a potent antiviral strategy to intercept viral infections effectively. This review introduces major viral infections with their primary symptoms, route of transmission & targeted organ, and different stages of the viral life cycle with respective traditional blockers. The IMNs have an exceptional capacity for precisely modulating the immune system for therapeutic applications. The nano sized immunomodulatory systems permit the immune cells to interact with infectious agents enhancing lymphatic drainage and endocytosis by the over-reactive immune cells in the infected areas. Immune cells that can be modulated upon viral infection via various immunomodulatory nanosystems have been discussed. Advancement in theranostics can yield an accurate diagnosis, adequate treatment, and real-time screening of viral infections. Nanosystem-based drug delivery can continue to thrive in diagnosing, treating, and preventing viral infections. The curative medicine for remerging and drug-resistant viruses remains challenging, though certain systems have expanded our perception and initiated a new research domain in antiviral treatments.

Camptothecin loaded casein nanosystem for tuning the therapeutic efficacy against highly metastatic triple-negative breast cancer cells.

The heterogenic of TNBC and the side effects of chemo drugs lead to the failure of therapy. Protein-based nanoplatforms have emerged as an important domain in protein-engineered biomedicine for delivering anticancer therapeutics. Protein-based nanosystems are biocompatible and biodegradable, with a long half-life and high purity. TNBC is sensitive to DNA-damaging chemo drugs. In this study, we used 10-hydroxy camptothecin, which causes DNA damage in cancer cells. However, the inappropriate solubility and toxic side effects limit its application in cancer therapy. We encapsulated 10-Hydroxycamptothecin in biocompatible casein by synthesizing nanoparticles from it. The synthesized CS and CCS NPs showed excellent biocompatibility in fibroblast cell lines L929, NIH-3T3, and zebrafish embryos. Enhanced uptake of CCS NPs in zebrafish embryos and 4T1 cells, cancer cell toxicity of nearly 80-85%, sub-cellular mitochondrial localization, alterations of mitochondrial membrane potential, lysosomal localization, and reactive oxygen species generation that causes cancer cell apoptosis have been observed. Growth inhibition of 4T1 cell colonies and antimetastatic activity were also noted. Further upregulation of γ-H2AX which causes DNA damage, downregulation of the PARP protein related to DNA repair, and increased level of the CHOP protein marker for endoplasmic reticulum stress-mediated cell death were observed. The 3-D model of 4T1 cells exhibited deep tumor penetration with significant therapeutic efficacy for CCS NPs. These results imply that casein-based nanoformulation could open a new scope for safe and affordable cancer therapy in TNBC.

Generation of Multispecies Oral Bacteria Biofilm Models.

It is well-recognized that oral biofilms that occur in health and disease have a polymicrobial composition, though these are poorly reflected in the literature, with many studies focussing on simple mono-species biofilm model systems. The utility of polymicrobial biofilm model systems is that they more accurately reflect the oral cavity and allow researchers to ask relevant questions in basic science studies, pharmaceutical screening, and investigating inflammatory interactions. Here we describe the detailed methodology of how to sequentially construct and maintain polymicrobial biofilm models pertinent to caries, periodontal disease, and denture stomatitis.

Meta-analysis of caries microbiome studies can improve upon disease prediction outcomes.

As one of the most prevalent infective diseases worldwide, it is crucial that we not only know the constituents of the oral microbiome in dental caries but also understand its functionality. Herein, we present a reproducible meta-analysis to effectively report the key components and the associated functional signature of the oral microbiome in dental caries. Publicly available sequencing data were downloaded from online repositories and subjected to a standardized analysis pipeline before analysis. Meta-analyses identified significant differences in alpha and beta diversities of carious microbiomes when compared to healthy ones. Additionally, machine learning and receiver operator characteristic analysis showed an ability to discriminate between healthy and disease microbiomes. We identified from importance values, as derived from random forest analyses, a group of genera, notably containing Selenomonas, Aggregatibacter, Actinomyces and Treponema, which can be predictive of dental caries. Finally, we propose the most appropriate study design for investigating the microbiome of dental caries by synthesizing the studies, which had the most accurate differentiation based on random forest modelling. In conclusion, we have developed a non-biased, reproducible pipeline, which can be applied to microbiome meta-analyses of multiple diseases, but importantly we have derived from our meta-analysis a key group of organisms that can be used to identify individuals at risk of developing dental caries based on oral microbiome inhabitants.

In vitro anti-cancer activity of doxorubicin against human RNA helicase, DDX3.

RNA helicase, DDX3 is a multifunctional enzyme and is known to be associated with several diseases like HIV progression, brain and breast cancer. Some of the ring expanded nucleoside compounds such as REN: NZ51, fused di imidazodiazepine ring (RK33), (Z)-3-(5- (3-bromo benzylidene)-4-oxo-2-thioxothiazolidin-3-yl)-N-(2- hydroxy phenyl) propanamide compound (FE15) have been documented to inhibit DDX3 helicase activity. However, synthesis of these drugs is limited to few research groups. Prevalence of literature study, we found that doxorubicin form strong hydrogen bond interactions with crystallized form of DDX3 using in-silico molecular docking approach. To evaluate the biological inhibitory action of doxorubicin, we performed the ATPase activity assay and anti-cancer activity using H357 cancer cell lines. Results showed that doxorubicin continually declined the inorganic phosphate (Pi) release and inhibited the ATP hydrolysis by directly interacting with DDX3. Anticancer activity was detected by MTT assay. The half maximal inhibitory concentrations of doxorubicin (IC50) for H357 cancer cell line is 50 µM and also doxorubicin significantly down regulated the expression of DDX3. Taken together, our results demonstrate, that inhibition of DDX3 expression by using doxorubicin can be used as an ideal drug candidate to treat DDX3 associated cancer disorder by interacting with unique amino acid residues (Thr 198) and common amino acid residues (Tyr 200 and Thr 201).

A Randomized Controlled Study to Compare the Total and Hidden Blood Loss in Computer-Assisted Surgery and Conventional Surgical Technique of Total Knee Replacement

BACKGROUND: Total knee arthroplasty (TKA) is associated with considerable blood loss. Computer-assisted surgery (CAS) is different from conventional TKA as it avoids opening the intramedullary canal. Hence, CAS should be associated with less blood loss. METHODS: Fifty-seven patients were randomized into two groups of CAS and conventional TKA. In conventional group intramedullary femoral and extramedullary tibial jigs were used whereas in CAS group imageless navigation system was used. All surgeries were done under tourniquet. Total and hidden blood loss was calculated in both groups and compared. RESULTS: The mean total blood loss was 980 mL in conventional group and 970 mL in CAS group with median of 1,067 mL (range, 59 to 1,791 mL) in conventional group and 863 mL (range, 111 to 2,032 mL) in CAS group. There was no significant difference in total blood loss between the two groups (p = 0.811). We have found significant hidden blood loss in both techniques, which is 54.8% of the total loss in the conventional technique and 59.5% in the computer-assisted navigation technique. CONCLUSIONS: There is no significant difference in total and hidden blood loss in the TKA in CAS and conventional TKA. However, there is significant hidden blood loss in both techniques. There was no relation of tourniquet time with blood loss.