Functional ß-mannooligosaccharides: Sources, enzymatic production and application as prebiotics.

One of the emerging non-digestible oligosaccharide prebiotics is ß-mannooligosaccharides (ß-MOS). ß-MOS are ß-mannan derived oligosaccharides, they are selectively fermented by gut microbiota, promoting the growth of beneficial microorganisms (probiotics), whereas the growth of enteric pathogens remains unaffected or gets inhibited in their presence, along with production of metabolites such as short-chain fatty acids. ß-MOS also exhibit several other bioactive properties and health-promoting effects. Production of ß-MOS using the enzymes such as ß-mannanases is the most effective and eco-friendly approach. For the application of ß-MOS on a large scale, their production needs to be standardized using low-cost substrates, efficient enzymes and optimization of the production conditions. Moreover, for their application, detailed in-vivo and clinical studies are required. For this, a thorough information of various studies in this regard is needed. The current review provides a comprehensive account of the enzymatic production of ß-MOS along with an evaluation of their prebiotic and other bioactive properties. Their characterization, structural-functional relationship and in-vivo studies have also been summarized. Research gaps and future prospects have also been discussed, which will help in conducting further research for the commercialization of ß-MOS as prebiotics, functional food ingredients and therapeutic agents.

Azo-Stilbene and Pyridine-Amine Hybrid Multifunctional Molecules to Target Metal-Mediated Neurotoxicity and Amyloid-ß Aggregation in Alzheimer's Disease.

Neurodegenerative diseases such as Alzheimer's disease (AD) are associated with progressive neuronal cell death, and they are commonly correlated with aberrant protein misfolding and aggregation of Aß peptides. Transition metal ions (Cu, Fe, and Zn) have been shown to promote aggregation and oxidative stress through formation of Aß-metal complexes. In this context, integrating molecular scaffolds rationally is used here to generate multifunctional molecules as modulators for metal-induced abnormalities. This work encompasses two azo-stilbene (AS)-derived compounds (AS-HL1 and AS-HL2), the rationale behind the design, their synthesis, characterization, and metal chelation ability [Cu(II) and Zn(II)]. The molecular frameworks of the designed compounds consist of stilbene as an Aß-interacting moiety, whereas N,N,O and N,N,N,O donor atoms are linked to generate the metal chelation moiety. Furthermore, we went on exploring their multifunctionality with respect to (w.r.t.) (i) their metal chelating capacities and (ii) their utility to modulate the aggregation pathways of both metal-free and metal-bound amyloid-ß, (iii) scavenge free radicals, and (iv) inhibit the activity of acetylcholinesterase and (v) cytotoxicity. Moreover, the compounds were able to sequester Cu2+ from the Aß-Cu complex as studied by the UV-visible spectroscopic assay. Molecular docking studies were also performed with Aß and acetylcholinesterase enzyme. Overall, the studies presented here qualify these molecules as promising candidates for further investigation in the quest for finding a treatment for Alzheimer's disease.

Combinatorial Biobleaching of Mixedwood Pulp with Lignolytic and Hemicellulolytic Enzymes for Paper Making.

Microbial enzymes are the safe alternatives to chemical based bleaching of pulp in paper mills. For effective biobleaching, both hemicellulolytic and lignolytic enzymes are required. This study reports laccase (L) + xylanase (X) and laccase (L) + mannanase (M) enzyme concoctions for pulp biobleaching derived from Bacillus sp. LX and Bacillus sp. LM isolated from the decaying organic matter. All enzymes were thermo-alkali-stable, hence were suitable for their application in pulp biobleaching. When a mixture of L + X/L + M was used for mixedwood pulp biobleaching, 46.32/40.25% reduction in kappa number; 13.21/10.01% and 3.36/2.76% improvement in brightness and whiteness was achieved respectively. Moreover, no laccase mediator system was required in the current process. Significant changes in the structure of enzymatically treated pulp were also observed. All these properties make these concoctions of enzymes suitable for their application in pulp and paper mill.

Pheromone peptide cOB1 from native Enterococcus faecalis forms amyloid-like structures: A new paradigm for peptide pheromones.

Pheromone peptides are an important component of bacterial quorum-sensing system. The pheromone peptide cOB1 (VAVLVLGA) of native commensal Enterococcus faecalis has also been identified as an antimicrobial peptide (AMP) and reported to kill the prototype clinical isolate strain of E. faecalis V583. In this study, the pheromone peptide cOB1 has shown to form amyloid-like structures, a characteristic which is never reported for a pheromone peptide so far. With in silico analysis, the peptide was predicted to be highly amyloidogenic. Further, under experimental conditions, cOB1 formed aggregates displaying characteristics of amyloid structures such as bathochromic shift in Congo red absorbance, enhancement in thioflavin T fluorescence, and fibrillar morphology under transmission electron microscopy. This novel property of pheromone peptide cOB1 may have some direct effects on the binding of the pheromone to the receptor cells and subsequent conjugative transfer, making this observation more important for the therapeutics, dealing with the generation of virulent and multidrug-resistant pathogenic strains.

Azo-dyes based small bifunctional molecules for metal chelation and controlling amyloid formation.

Chemical tools are needed to discover new effective drugs for tackling multifaceted complex neurodegenerative diseases like Alzheimer's disease (AD). Multifunctional nature of two compounds, 5-((4-nitro-phenyl)diazenyl)quinolin-8-ol (HL1) and 4-((4-nitrophenyl)diazenyl)benzene-1,3-diol (HL2) is reported w.r.t. their ability to bind Cu2+ ions and amyloid aggregates related to AD. HL1 and HL2 have half congo-red type azo-stilbene structural framework incorporated with metal chelating groups, designed to chelate metal ions from metal-amyloid species. Metal binding studies of HL1 and HL2 are established by the methods of Job's Plot, UV-vis spectra with metal ions and stability constant determination. In addition, their metal complexes are isolated, purity checked by elemental analysis, spectroscopically characterized and their structural analyses were obtained from DFT based calculations including binding energy determination. Chicken egg white Lysozyme (CEWL) was used as a model peptide for fibrillation studies. HL1 is found as an excellent colorimetric sensor for amyloid fibrils. Inhibitory effect of HL1 and HL2 and their isolated metal complexes L1-Cu and L2-Cu on CEWL fibrillation was studied using ThT and ANS fluorescence assay along with TEM imaging. In addition, the cell toxicity studies on these compounds suggest that although azo dyes may be non-toxic but having a nitro-substitution lead to significant cell toxicity. Overall, these results suggest that this new class of multifunctional small molecules can interact with amyloids as well as metal ions and could be potential anti-aggregation metal chelating agents.

Economic Burden of Otitis Media Globally and an Overview of the Current Scenario to Alleviate the Disease Burden: A Systematic Review.

Introduction The prevalence of otitis media (OM) is substantial all over the world. Epidemiological data related to the economic burden of OM globally is minimal. The present systematic review was undertaken to estimate the economic burden of this disease in various parts of the world. Objectives An extensive literature search was done using PRISMA guidelines to identify relevant studies that estimated the economic burden of OM in monetary terms. The databases searched were PubMed Central, Ovid, and Embase. The cost estimation was done for one specific year and then compared considering the inflation rate. Data Synthesis The literature search led to the inclusion of 10 studies. The studies evaluated direct and indirect costs in monetary terms. Direct costs (health system and patient perspective) ranged from USD (United States Dollar) 122.64 (Netherlands) to USD 633.6 (USA) per episode of OM. Looking at only the patient perspective, the costs ranged from USD 19.32 (Oman) to USD 80.5 (Saudi Arabia). The total costs (direct and indirect) ranged from USD 232.7 to USD 977 (UK) per episode of OM. The economic burden per year was highest in the USA (USD 5 billion). The incidence of OM episodes was found more in children < 5 years old. Introduction of pneumococcal conjugate vaccines decreased the incidence in children and now the prevalence in adults is of concern. Conclusion The economic burden of OM is relatively high globally and addressing this public health burden is important. Approaches for the prevention, diagnosis, and treatment should be undertaken by the health system to alleviate this disease burden.

An integrated approach for pulp biobleaching: application of cocktail of enzymes.

One of the paper industry's major focuses is shifting toward eco-friendly paper production. Chemical-based bleaching of pulp, which is widely used in the paper industry, is a highly polluting step. Replacing it with enzymatic biobleaching is the most viable alternative to make the process of papermaking greener. Enzymes such as xylanase, mannanase, and laccase are suitable for the biobleaching of pulp, which involves the removal of hemicelluloses, lignins, and other undesirable components. However, as no single enzyme can achieve this, their application in industry is limited. To overcome these limitations, a cocktail of enzymes is required. A number of strategies have been explored for the production and application of a cocktail of enzymes for pulp biobleaching, but no comprehensive information is available in the literature. The present short communication has summarized, compared, and discussed the various studies in this regard, which will be highly useful to pursue further research in this regard and make the process of papermaking greener.

Cost-Effectiveness of Currently Available Diagnostic Tools for Diagnosis of Pediatric Tuberculosis Under National Tuberculosis Elimination Program.

In India, children do not get diagnosed with tuberculosis (TB) for reasons such as lack of screening modality at the health-care settings, inadequate sputum sample, and low detection rate. This study aims to assess various modalities for diagnosis of pediatric TB and their cost-effectiveness. Cost-effectiveness was found for various diagnostic modalities for TB diagnosis in children of India below 15 years of age. TrueNat MTB was the intervention being compared to GeneXpert MTB and sputum microscopy. Evidence pertinent to effectiveness and cost per test, and health benefits in terms of disability adjusted life years were researched and documented. Modeling a cohort of children through a decision tree and assimilating costs and disability-adjusted life years (DALYs) at each step gave results in the form of cost-effectiveness. Interventions were compared by calculating the cost-effectiveness ratio. The results revealed that TrueNat is more cost effective (Rs. 9450/DALY averted) compared to GeneXpert MTB/RIF (Rs. 9750/DALY averted). The incremental cost effectiveness ratio of TrueNat with respect to GeneXpert was found to be Rs. 5925 per DALY averted. Diagnosis through TrueNat point of care (POC) will avert 962 more DALYs compared to GeneXpert. As is evident from the results, TrueNat does alleviate disability caused by TB in children as more DALYs are averted. At an additional cost of Rs. 5925 to avert one DALY, which is below the gross domestic product (GDP) per capita for India (for 2021, it was $2277), TrueNat can have significant health benefits.

Prediction of Placenta Accreta Spectrum by Prenatal Ultrasound Staging System in Women with Placenta Previa with Scarred Uterus.

Background: Placenta accreta spectrum (PAS) disorders are defined as range of pathological adherence/invasion of placenta. Prenatal diagnosis of PAS disorders using ultrasound doppler can optimize fetomaternal outcome and reduce complications. Objectives: To study the predictive value of prenatal ultrasound staging system for the presence and severity of placenta accreta spectrum and its correlation with fetomaternal outcomes. Method: This was a prospective cohort study conducted in Obstetrics and Gynecology department at VMMC and Safdarjung Hospital, New Delhi, over a period of 18 months. It included 50 women with singleton pregnancy > 28 weeks with placenta previa with scarred uterus after taking informed consent and ethics committee approval. All the women underwent ultrasound and PAS score was assigned, which was correlated with intraoperative FIGO grade, histopathology and fetomaternal outcomes. Results: In 50 women enrolled, prenatal ultrasound staging was performed and PAS score 0, 1, 2 and 3 was assigned. Cesarean hysterectomy was required in all 21(42%) women with PAS score > 0 (PAS 1, 2, 3). Intraoperative, focal and complete invasion was seen in 4% and 38%, respectively, and FIGO grade 1, 2, 3, 4, 5 and 6 was observed in 46%, 16%, 30%, 0%, 6% and 2%, respectively. On histopathology, 14.28% (3/21) with PAS > 0 did not have any invasion, while 85.71% (18/21) had invasion, i.e., accreta, increta and percreta in 57.14%, 19.05% and 9.52%, respectively. Considering histopathology as gold standard, the overall sensitivity, specificity, PPV, NPV and diagnostic accuracy of PAS score were 100%, 90.62%, 85.71%, 100% and 94%, respectively. Conclusion: Prenatal ultrasound staging system is a simple and feasible screening modality. Hence, it should be used in all high-risk women with placenta previa and scarred uterus for definitive prenatal diagnosis of PAS.

Otitis Media Prevalence in Children Below 18 Years of Age of India and the Associated Risk Factors: A Systematic Review and Meta-Analysis.

Ear ailments in children are a major public health problem in India. This systematic review and meta-analysis aim to quantitatively pool the epidemiologic evidence on the prevalence of all forms of otitis media in children of India. In this review PRISMA guidelines (preferred reporting items for systematic reviews and meta-analysis) were followed. We did extensive literature search in PubMed, Embase, Cinahl and Web of Science to identify relevant community based cross sectional studies that investigated the prevalence of otitis media in children of India. We used STATA version 16.0 software to perform meta-analysis. Six studies reporting the prevalence of otitis media in children were included in the final analysis. Based on the results of the random-effects sub-group meta-analysis model, the pooled estimated prevalence of Chronic suppurative otitis media in children of India was 3.78% (95% CI 2.72-4.84), Otitis media with effusion was found to be 2.68% (95% CI 1.80, 3.55) and Acute suppurative otitis media to be 0.55 (95% CI 0.32, 0.78). This review suggests substantial otitis media related disease burden in children of India. But due to lack of epidemiological studies, the actual disease burden remains concealed. It is imperative to promote more epidemiological studies that will aid policy makers in recommendation of preventive, diagnostic and treatment strategies for this disease.

Multisystem Inflammatory Syndrome Associated With COVID-19 in Children (MIS-C): A Systematic Review of Studies From India.

BACKGROUND: With wide clinical spectrum, multisystem inflammatory syndrome associated with coronavirus disease 2019 (COVID-19) in children (MIS-C) is a relatively novel condition occurring weeks to months' post SARS-CoV-2 infection. The aim was to systematically review data on clinical features, laboratory parameters and therapeutics of MIS-C from India. Methods: This systematic review was done as per the PRISMA guidelines, and quality assessment was done using NIH tool for case-series. A systematic search through databases yielded studies whose data was pooled to calculate the mean frequencies with standard deviation using GraphPad software. RESULTS: Screening of 2548 articles published till December, 2021, yielded 11 case-series. World Health Organization case definition was used widely. There was a slight preponderance of males (57%), median (IQR) age was 7 (6,7) years, 63% (n=305) required intensive care unit admissions, and mortality rate was 10% (n=261). Clinical features included fever, mucocutaneous features (72%), and gastrointestinal problems (62%) in majority. Widely used treatment was corticosteroids (76%) and intravenous immunoglobulin (62%) with other options depending on patient's state. An increased level of inflammatory markers and derangement in other parameters corroborated with disease status. Kawasaki disease like features, not reported in many studies, ranged from 4-76% of patients. CONCLUSION: MIS-C presents with a wide spectrum clinical features, increased inflammatory markers and managed as per the disease course and presentation. Future studies monitoring the long-term effects of MIS-C are recommended.

Aryldiazoquinoline based multifunctional small molecules for modulating Aß42 aggregation and cholinesterase activity related to Alzheimer's disease.

Research continues to find a breakthrough for the treatment of Alzheimer's Disease (AD) due to its complicated pathology. Presented herein is a novel series of arydiazoquinoline molecules investigated for their multifunctional properties against the factors contributing to Alzheimer's disease (AD). The inhibitory properties of fourteen closely related aryldiazoquinoline derivatives have been evaluated for their inhibitory effect on Aß42 peptide aggregation. Most of these molecules inhibited Aß42 fibrillation by 50-80%. Selected molecules were also investigated for their binding behaviour to preformed Aß40 aggregates indicating a nanomolar affinity. In addition, these compounds were further investigated as cholinesterase inhibitors. Interestingly, some of the compounds turned out to be moderate in vitro inhibitors for AChE activity with IC50 values in low micro molar range. The highest anti-AChE activity was shown by compound labelled as 2a with an IC50 value of 6.2 µM followed by 2b with IC50 value of 7.0 µM. In order to understand the inhibitory effect, binding of selected molecules to AChE enzyme was studied using molecular docking. In addition, cell toxicity studies using Neuro2a cells were performed to assess their effect on neuronal cell viability which suggests that these molecules possess a non-toxic molecular framework. Overall, the study identifies a family of molecules that show good in vitro anti-Aß-aggregation properties and moderately inhibit cholinesterase activity.

Cu and Zn interactions with Aß peptides: consequence of coordination on aggregation and formation of neurotoxic soluble Aß oligomers.

The coordination chemistry of transition metal ions (Fe, Cu, Zn) with the amyloid-ß (Aß) peptides has attracted a lot of attention in recent years due to its repercussions in Alzheimer's disease (AD). Aß peptide undergoes self-aggregation to form amyloid plaques and soluble oligomers, which are believed to play a central role in AD pathology. Metal ions and Aß-metal adducts can generate toxic radical species capable of modifying biomolecules, ultimately causing death of the neuronal cells. The impact of these metal ions on Aß aggregation and neurotoxic species formation is still not well understood. A large number of reports indicate that transition metal ions such as Cu and Zn have significant effects on Aß peptide aggregation and stabilization of neurotoxic soluble Aß aggregates; some of these reports are contradictory too. A review on the effects of Cu and Zn metal ions on Aß peptide aggregation due to their coordination with these peptides is presented herein. The review includes brief discussions with regards to the levels of Cu and Zn in an AD affected brain, structures of Aß peptides, and the coordination of Aß peptides with Cu and Zn. In the current scenario, a consensus appears to be emerging regarding the coordination mode and the effect of metal ions (especially Cu and Zn) on the aggregation of Aß peptides. Towards the end, a short discussion on current research trends in the field of bifunctional metal chelators for tackling the metal effect on Aß aggregation and toxicity has also been presented. It is expected that this review would aid in gaining a better understanding of the current status of various aspects of AD from an inorganic chemistry perspective.

Purification and characterization of lectin from fruiting body of Ganoderma lucidum: lectin from Ganoderma lucidum.

A novel 114 kDa hexameric lectin was purified from the fruiting bodies of the mushroom Ganoderma lucidum. Biochemical characterization revealed it to be a glycoprotein having 9.3% neutral sugar and it showed hemagglutinating activity on pronase treated human erythrocytes. The lectin was stable in the pH range of 5-9 and temperature up to 50 degrees C. The hemagglutinating activity was inhibited by glycoproteins that possessed N-as well as O-linked glycans. Chemical modification of the G. lucidum lectin revealed contribution of tryptophan and lysine to binding activity. The thermodynamics of binding of bi- and triantennary N-glycans to G. lucidum lectin was studied by spectrofluorimetry. The lectin showed very high affinity for asialo N-linked triantennary glycan and a preference for asialo glycans over sialylated glycans. The binding was accompanied with a large negative change in enthalpy as well as entropy, indicating primarily involvement of polar hydrogen, van der Waals and hydrophobic interactions in the binding.

MCM-41 Nanoparticles for Brain Delivery: Better Choline-Esterase and Amyloid Formation Inhibition with Improved Kinetics.

The present study was aimed at delivering a low bioavailability drug, rivastigmine hydrogen tartrate (RTG), to the brain through its encapsulation in mesoporous silica nanoparticles (MSNs) and targeted to amyloid inhibition in the brain. MSNs were characterized for size, zeta potential, and drug entrapment using SEM, TEM, HR-TEM, FT-IR, and PXRD. Drug-loaded MSNs were assessed for in vitro release kinetics and ex vivo followed by animal studies. The average size of the prepared blank (MCM-41B) and drug-loaded MSNs (MCM-41L) was 114 ± 2.0 and 145 ± 0.4 nm with the zeta potential of approximately -43.5 ± 1.1 and -37.6 ± 1.4 mV, respectively. MCM-41L exhibited an average entrapment efficiency of 88%. In vitro release studies exhibited early surge followed by a sluggish persistent or constant release (biphasic pattern). Hemolytic studies proved that the developed MCM-41L NPs are less hemolytic compared to RTG. A reduced ThT fluorescence was observed with MCM-41L compared to MCM-41B and RTG in the amyloid inhibition studies. A significant (p < 0.05) inhibition of AChE (acetycholinesterase) was observed for MCM-41L (80 ± 4.98%), RTG (62 ± 3.25%), and MCM-41B (54 ± 4.25%). In vivo pharmacokinetics in Wistar rats revealed that the AUC and mean residence time (MRT) for MCM-41L was sustained and significantly higher (p < 0.05) (780 ± 3.30 ng/L; 5.49 ± 0.25 h) compared to RTG solution (430 ± 3.50 ng/L; 0.768 ± 0.17 h). Similarly, the half-life was found to be significantly higher in case of MCM-41L. The promising result was brain delivery of RTG in Wistar rats which was enhanced almost 127 folds in vivo, using MCM-41L nanoparticles. MCM-41L nanoparticles effectively enhanced the bioavailability of RTG. Conclusively, these can be used for the administration of RTG and other related low bioavailability drugs for improved brain delivery.