Jain, Neha

Curcumin exhibits a broad spectrum of beneficial health properties that include anti-tumor and anti-cancer activities. The down-regulation of c-myc transcription via stabilizing the G-quadruplex structure formed at the promoter region of the human c-myc gene allows the repression in cancer growth. Small molecules can bind and stabilize this structure to provide an exciting and promising strategy for anti-cancer therapeutics. Herein, we investigated the interaction of Curcumin and its synthetic analogs with G-quadruplex DNA formed at the c-myc promoter by using various biophysical and biochemical assays. Further, its cytotoxic effect and mechanistic insights were explored in various cancer cell lines as well as in multicellular tumor spheroid (MCTS) model. The MCTS possesses almost similar microenvironment as avascular tumors, and micro-metastases can be used as a suitable model for the small molecule-based therapeutics development. Our study provides an expanded overview of the anti-cancer effect of a new Curcumin analog via targeting G-quadruplex structures formed at the promoter region of the human c-myc gene.

Bacteria are known to produce amyloids, proteins characterized by a conserved cross-beta sheet structure, which exhibit structural and functional similarities to human amyloids. The deposition of human amyloids into fibrillar plaques within organs is closely linked to several debilitating human diseases, including Alzheimer's and Parkinson's disease. Recently, bacterial amyloids have garnered significant attention as potential initiators of human amyloid-associated diseases as well as autoimmune diseases. This review aims to explore how bacterial amyloid, particularly curli found in gut biofilms, can act as a trigger for neurodegenerative and autoimmune diseases. We will elucidate three primary mechanisms through which bacterial amyloids exert their influence: 1. Direct interaction with human amyloids: Bacterial amyloids can directly interact with human amyloids, potentially accelerating the aggregation and deposition of amyloid fibrils associated with diseases such as Alzheimer's and Parkinson's disease. This direct interaction may contribute to the pathological progression of these conditions. 2. Induction of inflammation: Bacterial amyloids have the capacity to induce inflammatory responses within the host organism. Chronic inflammation is increasingly recognized as a contributor to neurodegenerative and autoimmune diseases. We will explore how the activation of inflammatory pathways and neuroinflammation by bacterial amyloids can exacerbate disease pathogenesis. 3. Acting as a DNA carrier: Bacterial amyloids may also serve as carriers of DNA, facilitating the activation of host DNA sensors. This mechanism can potentially lead to alterations in the host's immune response and also contribute to the development of autoantibodies. By delving into these three distinct modes of action, this review will provide valuable insights into the intricate relationship between bacterial amyloids and the onset or progression of neurodegenerative and autoimmune diseases. A comprehensive understanding of these mechanisms may open new avenues for therapeutic interventions and preventive strategies targeting amyloid-associated diseases.

Biofilms are consortia of microorganisms encased in extracellular matrix that protect cells from adverse conditions. A biofilm matrix is typically composed of extracellular DNA, cellulose and proteinaceous amyloid fibers. The matrix aids in adhesion to abiotic and biotic surface including medical devices and host tissues. The presence of biofilm makes bacteria more resilient and non-responsive to most current treatment regimes at disposal. Therefore, biofilm-associated infections are serious threat in hospital set-tings and pose a huge burden on economy. Inhibition of matrix components (cellulose and/or amyloid formation) has emerged as a lucrative alternative strategy to cure biofilm-related infections and combat antibiotic resistance. Here we review the current and emerging therapeutic interventions to mitigate persistent infections due to biofilms. The successful implementation of these interventions will have a huge impact on alleviating the current financial burden on healthcare services.

Deposition of human amyloids is associated with complex human diseases such as Alzheimer’s and Parkinson’s. Amyloid proteins are also produced by bacteria. The bacterial amyloid curli, found in the extracellular matrix of both commensal and pathogenic enteric bacterial biofilms, forms complexes with extracellular DNA, and recognition of these complexes by the host immune system may initiate an autoimmune response. Here, we isolated early intermediate, intermediate, and mature curli fibrils that form throughout the biofilm development and investigated the structural and pathogenic properties of each. Early intermediate aggregates were smaller than intermediate and mature curli fibrils, and circular dichroism, tryptophan, and thioflavin T analyses confirmed the establishment of a beta-sheet secondary structure as the curli conformations matured. Intermediate and mature curli fibrils were more immune stimulatory than early intermediate fibrils in vitro. The intermediate curli was cytotoxic to macrophages independent of Toll-like receptor 2. Mature curli fibrils had the highest DNA content and induced the highest levels of Isg15 expression and TNFα production in macrophages. In mice, mature curli fibrils induced the highest levels of anti-double-stranded DNA autoantibodies. The levels of autoantibodies were higher in autoimmune-prone NZBWxF/1 mice than wild-type C57BL/6 mice. Chronic exposure to all curli forms led to significant histopathological changes and synovial proliferation in the joints of autoimmune-prone mice; mature curli was the most detrimental. In conclusion, curli fibrils, generated during biofilm formation, cause pathogenic autoimmune responses that are stronger when curli complexes contain higher levels of DNA and in mice predisposed to autoimmunity.

Neurodegenerative disorders such as Parkinson's (PD) and Alzheimer's diseases (AD) are linked with the assembly and accumulation of proteins into structured scaffold called amyloids. These diseases pose significant challenges due to their complex and multifaceted nature. While the primary focus has been on endogenous amyloids, recent evidence suggests that bacterial amyloids may contribute to the development and exacerbation of such disorders. The gut-brain axis is emerging as a communication pathway between bacterial and human amyloids. This review delves into the novel role and potential mechanism of bacterial amyloids in modulating human amyloid formation and the progression of AD and PD.

Water and food contamination has become the major contributor to infections and deaths. However, rapid and sensitive bacterial detection still remains an unmet demand that has attracted widespread attention. Often water and food samples are sent out for laboratory testing to detect the presence of contamination, which is time-consuming and laborious. Herein, we have developed a highly sensitive, tenable, affordable, and robust (STAR) paper-based colorimetric dipstick sensor based on the principle of Prussian blue (PB) synthesis as an indicator of bacterial contamination. In the presence of bacteria, it leads to the formation of PB, a dye that acts as a colorimetric indicator. The intensity of the PB is the direct measure of the degree of contamination. The fabrication of the STAR dipstick sensor involves a simple and cost-effective process. The STAR dipstick sensor is ultrasensitive and can detect up to 101 CFU/mL of bacteria within minutes of contact with the test sample. The STAR dipstick sensor is fabricated using biodegradable components, which is speculated to facilitate quick and environmentally friendly degradation after each use. The sensor has been validated for its properties and capabilities at different pH to detect both Gram-positive and Gram-negative bacterial strains in real-time samples. The stability and degradation were also monitored. Comprehensively, the proposed STAR dipstick sensor can serve as a point-of-care device to detect bacterial contamination in a swift and sensitive manner.

Amyloids are a class of protein with unique self-aggregation properties, and their aberrant accumulation can lead to cellular dysfunctions associated with neurodegenerative diseases. While genetic and environmental factors can influence amyloid formation, molecular triggers and/or facilitators are not well defined. Growing evidence suggests that non-identical amyloid proteins may accelerate reciprocal amyloid aggregation in a prion-like fashion. While humans encode ~30 amyloidogenic proteins, the gut microbiome also produces functional amyloids. For example, curli are cell surface amyloid proteins abundantly expressed by certain gut bacteria. In mice overexpressing the human amyloid α-synuclein (α Syn), we reveal that colonization with curli-producing Escherichia coli promotes α Syn pathology in the gut and the brain. Curli expression is required for E. coli to exacerbate α Syn-induced behavioral deficits, including intestinal and motor impairments. Purified curli subunits accelerate α Syn aggregation in biochemical assays, while oral treatment of mice with a gut-restricted amyloid inhibitor prevents curli-mediated acceleration of pathology and behavioral abnormalities. We propose that exposure to microbial amyloids in the gastrointestinal tract can accelerate aSyn aggregation and disease in the gut and the brain.

Far UV-C light at wavelength 222 nm is gaining popularity nowadays due to its properties that it cannot penetrate even the outer dead skin of humans and the tear layer of the eyes. This wavelength has been proven to be much safer for human health. In this paper, a dielectric barrier discharge (DBD) based Far UV-C excimer lamp with a very narrow and intense spectrum peaking at a wavelength of 222 nm has been reported. Optimization of high voltage electrodes has been carried out to minimize the lamp heating without using any external cooling. The discharge produced in this configuration is diffused discharge at a low pressure of 140 mbar. Generally, at low pressure, a very wide band of spectra having full-width half maxima (FWHM) of 8-15 nm is obtained. In this case, due to the confined gas gap and bi-polar pulse power arrangements, the spectra obtained are very narrow, having an FWHM of 1.7 nm. Applied voltage, frequency and gas pressure are optimized to get high electrical-to-optical conversion efficiency of the lamp. The measured radiated intensity at the applied input electrical power of 31 W from the optimized lamp is ∼2.5 mW cm−2, which results in the electrical to optical conversion efficiency as high as 12.5%. The bacterial efficiency of the developed lamp is also examined on pathogenic gram-positive (S. aureus) and gram-negative (E. coli) bacteria. Complete inactivation of S. aureus and E. coli has been achieved at a UV dose of 3 mJ/cm2 and 12 mJ cm-2, respectively. Morphological studies of treated bacteria have also been performed to correlate the results.

Altered protein folding leading to the formation of structured aggregates such as amyloid fibrils has gained significant attention due to its association with neurodegenerative diseases. α-Synuclein, a small intrinsically disordered protein, gets transformed into amyloid fibrils under unfavorable conditions and contributes to the progression and pathology of Parkinson’s disease (PD). Under normal physiological conditions, amyloid formation is controlled by many chaperones and chaperone-like proteins. However, with aging, the protein homeostasis machinery becomes less efficient, causing the loss of proper functioning of chaperones and leading to aberrant protein folding and amyloid formation. Here, we provide in-depth information on the modulation of α-synuclein amyloid assembly by a heterogeneous complex of bovine eye lens protein, α-crystallin, which is known to possess chaperone-like activity. We have used a multiparametric approach to discern the critical events through which α-crystallin abolishes α-synuclein amyloid formation. Our biochemical and biophysical data analysis revealed that α-crystallin, at substoichiometric ratios, alleviates α-synuclein amyloid assembly and drives it into soluble dead-end intermediates. We also demonstrated that α-crystallin was equally efficient in arresting amyloid assembly by some of the PD-related mutants suggesting the significance of chaperone-like activity of α-crystallin under pathological conditions. Finally, we validated our results using human crystallin derived from cataract patients. Based on our findings, we propose that the interaction of α-crystallin directs α-synuclein into a soluble amyloid-incompetent form. Our results suggest that the generic antiamyloid property of chaperone-like proteins, such as α-crystallin, can be harnessed to design protein and peptide-based novel therapeutics for prevention and treatment of deadly neurodegenerative diseases.

In this paper, we present a surface decontamination system that substitutes traditional chemicals and scrubbing agents, which will be useful for the general public during a pandemic. The technique is based on a hybrid process in which UV-C light and its photons interact with metal oxide nano-catalysts to generate hydroxyl radicals, which can enhance the deactivation process, and the system can work even in the shadow regions via a dry process. The optimum number of UV light sources in combination with TiO2 nanoparticles catalysts on aluminum plates have been used synergistically in the system. The UV dose in the disinfection chamber has been optimized, which is between 60 and 500 mJ/cm2 throughout the disinfection chamber. The concentration of hydroxyl radicals is reported more than 25 000 ions/cm3 within the disinfection chamber. These ions are circulated throughout the disinfection volume. The disinfection efficiency has been tested on bacteria and spores, and the obtained results are correlated. Around 8 log reductions in the counts of the test bacteria of Escherichia coli and Klebsiella pneumoniae have been achieved in just 2 min of exposure in the continuous operation of the system. Tests have also been performed on Geobacillus stearothermophilus spores, and the method described here is the result of multiple tests, a review of the scientific literature, and the incorporation of current laboratory practice. The deactivation tested in the system is larger than that of known bacteria and viruses in terms of UV-doses, signifying its utility during the pandemic.