Search

COVID-19 related morbidities and mortalities are still continued due to the emergence of new variants of SARS-CoV-2. In the last few years, viral miRNAs have been the centre of study to understand the disease pathophysiology. In this work, we aimed to predict the change in coding potential of the viral miRNAs in SARS-CoV-2's VOCs, Delta and Omicron compared to the Reference (Wuhan origin) strain using bioinformatics tools. After ab-intio based screening by the Vmir tool and validation, we retrieved 22, 6, and 6 pre-miRNAs for Reference, Delta, and Omicron. Most of the predicted unique pre-miRNAs of Delta and Omicron were found to be encoded from the terminal and origin of the genomic sequence, respectively. Mature miRNAs identified by MatureBayes from the unique pre-miRNAs were used for target identification using miRDB. A total of 1786, 216, and 143 high-confidence target genes were captured for GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis. The GO and KEGG pathways terms analysis revealed the involvement of Delta miRNAs targeted genes in the pathways such as Human cytomegalovirus infection, Breast cancer, Apoptosis, Neurotrophin signaling, and Axon guidance whereas the Sphingolipid signaling pathway was found for the Omicron. Furthermore, we focussed our analysis on target genes that were validated through GEO's (Gene Expression Omnibus) DEGs (Differentially Expressed Genes) dataset, in which FGL2, TNSF12, OGN, GDF11, and BMP11 target genes were found to be down-regulated by Reference miRNAs and YAE1 and RSU1 by Delta. Few genes were also observed to be validated among in up-regulated gene set of the GEO dataset, in which MMP14, TNFRSF21, SGMS1, and TMEM192 were related to Reference whereas ZEB2 was detected in all three strains. This study thus provides an in-silico based analysis that deciphered the unique pre-miRNAs in Delta and Omicron compared to Reference. However, the findings need future wet lab studies for validation.

The aggregation of Aβ plays a major role in the progression of Alzheimer’s disease (AD) and induces neuroinflammation, neurodegeneration and cognitive decline. Recent studies have shown that the soluble aggregates of Aβ are the major culprits in the development of these aberrations inside the brain. In this study, we investigated the neuroprotective potential of carbenoxolone (Cbx), which has been found to possess anti-inflammatory and nootropic properties. Male SD rats (250−300 g) were divided into the four groups (n = 8 per group): (1) sham control rats injected with vehicles, (2) Aβ 1–42 group rats injected i.c.v. with Aβ 42 oligomers (10 μl/rat), (3) Aβ 1–42+Cbx group rats injected i.c.v. with Aβ 42 oligomers (10 μl/rat) and i.p. with carbenoxolone disodium (20 mg/kg body weight) for six-weeks and (4) Cbx group rats injected i.p. with carbenoxolone disodium (20 mg/kg body weight) for six-weeks. Progressive learning and memory deficits were seen through a battery of behavioral tests and a significant increase in the expressions of GFAP and Iba-1 was observed which resulted in the release of pro-inflammatory cytokines post Aβ oligomer injection. The levels of BDNF, Bcl-2 and pCREB were decreased while Bax, caspase-3, caspase-9 and cytochrome c levels were induced. Also, neurotransmitter levels were altered and neuronal damage was observed through histopathological studies. After Cbx supplementation, the expressions of GFAP, IBA-1, pro-inflammatory cytokines, iNOS, nNOS and nitric oxide levels were normalized. The expression levels of pro-apoptotic markers were decreased and neurotrophin levels were restored. Also, neurotransmitter levels and neuronal profile were improved and progressive improvements in behavioural performance were observed. Our results demonstrated that Cbx might have prevented the Aβ induced neurodegeneration and cognitive decline by inhibiting the neuroinflammation and inducing BDNF/CREB signalling. These findings suggest that Cbx can be explored as a potential therapeutic agent against the progression of AD.

Membranes with selective filtering capabilities are being designed globally, to tackle freshwater scarcity. In this study, we report the formulation of a bovine serum albumin (BSA) fabricated graphene oxide (GO) membrane for adsorptive removal of cobalt(II) from water. Large surface area along with abundant oxygen moieties upon interaction with biomolecules such as proteins, enable enhanced water purification. Free standing GO-BSA membrane was formulated by using covalent conjugating approach using cross—linkers, followed by vacuum-assisted filtration process. The chemical composition and structural morphology of the membrane was analyzed by different spectroscopic techniques. Water contact angle (WCA) studies exhibited hydrophilic behavior (58°) of GO which enabled efficacious conjugation of the protein to the graphitic derivative. Brunauer-Emmert–Teller (BET) surface area analysis showed an increase in surface area from 3.60 to 10.2 m2 g−1 in GO and GO-BSA conjugate, respectively. Further, the adsorption efficiency of cobalt by the prepared membranes was studied at different physical parameters such as concentration, pH, temperature and contact time of the adsorbent with the membrane. The GO-BSA membrane exhibited maximum adsorptive capacity of 184 mg/g at pH 6 which further amplified with rise in temperature from 25 to 35 °C. The reported work demonstrates formulation of a facile, low cost approach to efficiently remove cobalt ions from simulated wastewaters. The composed GO-BSA membrane will open new avenues for construction of portable water purification systems in future. Schematic depicting adsorptive removal of Cobalt from water by using covalently conjugated GO-BSA membrane by application of vacuum filtration

Excessive activation of α-amino-3-hydroxy-5-methyl-4-isoxazole propoinic acid (AMPA) receptors instigates excitotoxicity via enhanced calcium influx in the neurons thus inciting deleterious consequences. Additionally, Endoplasmic Reticulum (ER) is pivotal in maintaining the intracellular calcium balance. Considering this, studying the aftermath of enhanced calcium uptake by neurons and its effect on ER environment can assist in delineating the pathophysiological events incurred by excitotoxicty. The current study was premeditated to decipher the role of ER pertaining to calcium homeostasis in AMPA-induced excitotoxicity. The findings showed, increased intracellular calcium levels (measured by flowcytometry and spectroflourimeter using Fura 2AM) in AMPA excitotoxic animals (male Sprague dawely rats) (intra-hippocampal injection of 10 mM AMPA). Further, ER resident proteins like calnexin, PDI and ERp72 were found to be upregulated, which further modulated the functioning of ER membrane calcium channels viz. IP3R, RyR, and SERCA pump. Altered calcium homeostasis further led to ER stress and deranged the protein folding capacity of ER post AMPA toxicity, which was ascertained by unfolded protein response (UPR) pathway markers such as IRE1α, eIF2α, and ATF6α. Chemical chaperone, 4-phenybutric acid (4-PBA), ameliorated the protein folding capacity and subsequent UPR markers. In addition, modulation of calcium channels and calcium regulating machinery of ER post 4-PBA administration restored the calcium homeostasis. Therefore the study reinforces the significance of ER stress, a debilitating outcome of impaired calcium homeostasis, under AMPA-induced excitotoxicity. Also, employing chaperone-based therapeutic approach to curb ER stress can restore the calcium imbalance in the neuropathological diseases.

Sepsis is a severe infectious disease with high mortality, and it occurs when chemicals released in the bloodstream to fight an infection trigger inflammation throughout the body and it can cause a cascade of changes that damage multiple organ systems, leading them to fail, even resulting in death. In order to reduce the possibility of sepsis or infection antiseptics are used and process is known as antisepsis. Antiseptic peptides (ASPs) show properties similar to antigram-negative peptides, antigram-positive peptides and many more. Machine learning algorithms are useful in screening and identification of therapeutic peptides and thus provide initial filters or built confidence before using time consuming and laborious experimental approaches. In this study, various machine learning algorithms like Support Vector Machine (SVM), Random Forest (RF), K-Nearest Neighbour (KNN) and Logistic Regression (LR) were evaluated for prediction of ASPs. Moreover, the characteristics physicochemical features of ASPs were also explored to use them in machine learning. Both manual and automatic feature selection methodology was employed to achieve best performance of machine learning algorithms. A 5-fold cross validation and independent data set validation proved RF as the best model for prediction of ASPs. Our RF model showed an accuracy of 97%, Matthew’s Correlation Coefficient (MCC) of 0.93, which are indication of a robust and good model. To our knowledge this is the first attempt to build a machine learning classifier for prediction of ASPs.

The biogenic synthesis of carbon micro composites (CMCs) using a simple chemical method was accomplished by assorting mushroom (Asparagus Disporus) as the organic precursor. Synthesized CMCs ensued the good yield of 0.425 g. The resulted product was characterized using CHN (O) elemental analysis displaying the carbon, nitrogen and hydrogen content as 63.57%, 0.861%, and 0.304%, respectively. FT-IR spectrum clearly displayed C=O, C-N, O-H and C≡N stretch. FE-SEM depicted straight rod-shaped materials having an average diameter of 22.0 μm, with individual rods of 5.0 μm diameter

The decreasing effectiveness of conventional drugs due to multidrug-resistance is a major challenge for the scientific community, necessitating development of novel antimicrobial agents. In the present era of coronavirus 2 (COVID-19) pandemic, patients are being widely exposed to antimicrobial drugs and hence the problem of multidrug-resistance shall be aggravated in the days to come. Consequently, revisiting the phenomena of multidrug resistance leading to formulation of effective antimicrobial agents is the need of the hour. As a result, this review sheds light on the looming crisis of multidrug resistance in wake of the COVID-19 pandemic. It highlights the problem, significance and approaches for tackling microbial resistance with special emphasis on anti-microbial peptides as next-generation therapeutics against multidrug resistance associated diseases. Antimicrobial peptides exhibit exceptional mechanism of action enabling rapid killing of microbes at low concentration, antibiofilm activity, immunomodulatory properties along with a low tendency for resistance development providing them an edge over conventional antibiotics. The review is unique as it discusses the mode of action, pharmacodynamic properties and application of antimicrobial peptides in areas ranging from therapeutics to agriculture., Graphical Abstract ga1

Biosensors are devices that capture the biological signal and convert it into a detectable electrical signal through transduction. Biological entities like DNA, RNA, and proteins/enzymes can be conjugated onto the biosensor surface to detect and observe certain biological analytes in environment, biomedical, and food industries. Peptides have been efficiently used in the fabrication of peptide-based biosensors due to their attractive properties like established synthesis protocols, diverse structures, and as highly enzyme-selective substrates. However, owing to their labile nature, peptidomimetics are the best alternatives at the bioreceptor interface due to their specificity and stability, relatively low cost and easy modifications, and capability to form supramolecular assemblies like nanosheets. Such bioconjugation strategies efficiently convert interaction information into a measurable signal, thus highlighting the importance in the fabrication of next-generation novel robust biosensors desirable for detection and dissemination of pathogens causing infections in the living and non-living worlds.

Despite recent advances in the treatment of colorectal cancer (CRC), low patient survival rate due to emergence of drug resistant cancer cells, metastasis and multiple deleterious side effects of chemotherapy, is a cause of public concern globally. To negate these clinical conundrums, search for effective and harmless novel molecular entities for the treatment of CRC is an urgent necessity. Since antimicrobial peptides (AMPs) are part of innate immunity of living beings, it is quite imperative to look for essential attributes of these peptides which may contribute to their effectiveness against carcinogenesis. Once identified, those characteristics can be suitably modified using several synthetic and computational techniques to further enhance their selectivity and pharmacokinetic profiles. Hence, this review analyses scientific reports describing the antiproliferative action of AMPs derived from several sources, particularly focusing on various colon cancer in vitro/in vivo investigations. On perusal of the literature, it appears that AMPs based therapeutics would definitely find special place in CRC therapy in future either alone or as an adjunct to chemotherapy provided some necessary alterations are made in their natural structures to make them more compatible with modern clinical practice. In this context, further in-depth research is warranted in adequate in vivo models.

Bioengineered nanoconjugates have enormous potential as a multifunctional platform for biomedical applications. Conjugation between biotic and abiotic materials enables formulation of nanoconjugates with enhanced physico-chemical properties, increased stability and ability to overcome the inherent shortcomings of individual materials. In this study, we report the preparation and biophysical characterization of an antibacterial system formulated by functionalizing reduced graphene oxide (rGO) with an antimicrobial peptide via covalent as well as non-covalent interaction mechanisms. Environmentally benign synthesis approach was adopted for the formation of rGO, using L-ascorbic acid as a reducing agent. Covalently conjugated peptide-graphitic conjugate displayed improved antibacterial efficacy against Escherichia coli with considerably low cytotoxic activity towards erythrocytes in comparison to self-assembled conjugate and rGO alone. The studies described herein are highly significant in the field of biomaterials and aims to open new avenues of research focusing on a plethora of applications as a prospective non-toxic substitute to conventional antibacterial approaches.

The characteristic feature of Alzheimer's disease (AD) is the deposition of amyloid beta inside the brain mainly consisting of Aβ 40 and 42 aggregates. Soluble aggregates of Aβ 42 are reported to be more toxic and exert their neurotoxicity by the induction of oxidative damage and cognitive deficits such as anxiety-like behavior. These alterations emerge due to the induction of gap junction communication through increased activity and expression of connexins such as connexin43 (Cx43) leading to the release of small neurotoxic molecules. In the present study, single intracerebroventricular (icv) injection of Aβ 42 oligomers (10 μl/rat) was used to induce oxidative damage and anxiety-related behavior in rats. Carbenoxolone (Cbx), a gap junction blocker, was tested (20 mg/kg body weight, i.p., for 6 weeks) against these alterations. Cbx supplementation reversed the Aβ 42 oligomer-induced alterations in the antioxidant defense system. The levels ROS, lipid peroxidation, and protein carbonyls were normalized with Cbx co-treatment leading to the decreased DNA fragmentation and pyknosis in different regions of the rat brain. Cbx induced the anxiolytic behavior and ameliorated the cognitive decline in rats post Aβ 42 oligomer injection. The increased expression of Cx43 post Aβ 42 oligomer injection was also reduced with Cbx supplementation, which might have inhibited the release of small neurotoxic molecules. Our results showed that Cbx prevents the Aβ 42 oligomer-induced oxidative damage and anxiety-like behavior partly by blocking the gap junction communication, which suggests that the therapeutic potential of Cbx may be explored in the progression of AD.

Peptides exhibit unique binding behavior with graphene and its derivatives by forming bonds on its edges and planes. This makes them useful for sensing and imaging applications. This review with (155 refs.) summarizes the advances made in the last decade in the field of peptide-GO bioconjugation, and the use of these conjugates in analytical sciences and imaging. The introduction emphasizes the need for understanding the biotic-abiotic interactions in order to construct controllable peptide-functionalized graphitic material-based nanotools. The next section covers covalent and non-covalent interactions between peptide and oxidized graphene derivatives along with a discussion of the adsorption events during interfacing. We then describe applications of peptide-graphene conjugates in bioassays, with subsections on (a) detection of cancer cells, (b) monitoring protease activity, (c) determination of environmental pollutants and (d) determination of pathogenic microorganisms. The concluding section describes the current status of peptide functionalized graphitic bioconjugates and addresses future perspectives. Graphical abstractSchematic representation depicting biosensing applications of peptide functionalized graphene oxide.

The equilibrium between cerebral production and clearance of Aβ is maintained either by the active removal through blood–brain barrier or by the uptake and degradation through ubiquitin–proteasome system (UPS) and autophagy. The dysfunction of UPS and dysregulation of molecular chaperones such as heat shock proteins (HSPs) is well correlated with the progression of Alzheimer’s disease (AD). Therefore, the restoration of heat shock system and UPS appears to be an effective approach to maintain the Aβ homeostasis. The alteration in the Aβ homeostasis was induced by a single bilateral intrahippocampal injection of Aβ 42 oligomers (10 μl/rat) into the dorsal hippocampus of the rat brain. Cbx (carbenoxolone), a HSP inducer and Aβ 42 aggregation inhibitor, was tested (20 mg/kg body weight, i.p. for six-weeks) against the altered Aβ homeostasis in the rat brain. Aβ 42 oligomers downregulated the expression of HSPs and co-treatment with Cbx prevented this decline. Cbx was able to restore the UPS function post Aβ 42 oligomer injection. Aβ 42 oligomers induced upregulation of the expression levels of APP, BACE-1 and Tau was also normalized after the co-treatment with Cbx. A significant decrease in the thioflavin-T and Aβ positive deposits in different regions of the rat brain was observed after Cbx co-treatment. Thus, the present study projects Cbx as a potential candidate for the maintenance of Aβ homeostasis through inhibition of amyloid aggregation and restoration of the functioning of molecular chaperones and UPS system in the progression of AD.

Conformations of achiral and chiral aromatic homopolypeptoids of Nphe, Nspe and Nrpe were studied by quantum mechanics and molecular dynamics approaches. The amide bond geometry in model peptoids Ac-X-NMe2 could be both cis and trans and the Nphe peptoids adopted degenerate conformations of opposite handedness with Φ, Ψ values of ~ ± 120o, ± 150o with trans amide bond geometry. This degeneracy was lifted with increase in chain length; in favor of the structure with Φ = -120o, Ψ = -150o. Polypeptoids of Nspe and Nrpe with and without protecting groups populated states with Φ, Ψ values of ~ 110o, 155o & -110o, -165o respectively with trans amide bond geometry. Simulation studies in water revealed that with protecting groups peptoid Ac-(Nspe/Nrpe)5-NMe2 populated with cis amide bond geometry in PP type I and inverse PP type I helices respectively due to interactions between the solvent molecules and carbonyl oxygens of the backbone. Without protecting groups these polypeptoids populated poly-Lproline type II conformations. In DMSO these peptoids were shown to populate in PP type-I and inverse PP type-I helices and without protecting groups they could be realized in PP type-I as well as inverse PP type-I conformation whereas the peptoid -Nrpe6-NH2 could be realized in inverse PP type-I conformation. Analysis of simulation results as a function of time ruled out amide bond inter-conversions between cis and trans geometry. Hence, like polyproline peptoids can also be exploited as molecular spacers.

Background: To date, the use of sialic acid that are reported to be elevated during malignancy has been largely unexplored for tumor imaging. The purpose of the present study was to study the modeled stable conformers of n-acetyl neuraminic acid (Neu5Ac) and its radiolabeled conjugate (Tc-99m-Neu5Ac) through computational chemistry approach and its in-vitro bioevaluation in rat C6 cell lines. Materials and Methods: The Neu5Ac was radiolabeled with Tc-99m using stannous reduction method and the radiochemical purity of Tc-99m-Neu5Ac was determined by instant thin layer chromatography. A Cheminformatic study of Tc-99m-Neu5Ac was performed by using Marvin application of ChemAxon. Glioma cancer cells were taken to evaluate the cytotoxicity and binding efficacy of Tc-99m-Neu5Ac. Results: Cheminformatic studies exhibited that the most stable conformer of Tc-99m-Neu5Ac is 15 kcal/mol more stable energetically over least stable conformer. The radiochemical yield of Tc-99m labeled Neu5Ac was observed to be greater than 90%. Further, the radiolabeled complex (Tc-99m-Neu5Ac)exhibited specificity for C6 glioma with time and concentration dependent cytotoxicity. Conclusion: In conclusion, Tc-99m-Neu5Ac has the potential to be exploited as an in-vivo radionuclide probe for tumor imaging.

Tubulin binding compounds are key players in orchestrating anticancer effects by modulating microtubule dynamics that in turn disrupts cell motility and promotes apoptosis. However, their clinical application is limited by high toxicity resulting from their lack of specificity for cancer cells. Consequently, identifying microtubule interacting agents that demonstrate higher specificity for tumor cells continues to be a key objective in the search for more effective cancer treatments. In this context, small tubulin binding peptides (22–35 amino acids) from some intermediate filaments (IFs) were reported to bind unassembled tubulin and disrupt microtubules. To date there are no structural studies on these peptides as it is difficult to crystallize IF proteins. To narrow this wide gap in knowledge, two such peptides corresponding to the tubulin binding sites of the IF protein Desmin were studied using molecular mechanics and molecular dynamics based techniques. This is the first report on the structural plasticity of these peptides and sheds light on the imperative role of non-covalent interactions in directing the secondary structures. These findings shall be significant in guiding and facilitating the future efforts of designing peptide based anti-mitotic drugs.

Effective anticancer therapies are required to overcome limitations of conventional chemotherapy. Current study demonstrated successful preparation of stable gold nanoparticles (GNPs) and other conjugates viz. nisin-GNPs, doxorubicin-GNPs and nisin-doxorubicin-GNPs followed by their physico-chemical characterizations. The resulting uniformly dispersed water soluble spherical GNPs had an average diameter of 8–12 nm and ζ-potential of −30.9 mV. These parameters of GNP-conjugates showed slight alterations after conjugation. Further, in vivo therapeutic effects of GNPs/GNP-conjugates were evaluated in DMBA (7,12-Dimethylbenz(a)anthracene) induced skin carcinogenesis. Substantial reduction in mean tumor volume(s) (26.3%–52.6%), at the end of therapy period (~7 weeks) were observed in various treatment groups when compared to untreated control group as confirmed by histopathological and scanning electron microscopic studies. Furthermore, there was significant decline in serum levels of all tested cytokines (TNF-α {17.39–47.89%}; TNF-β {24.52–69.88%}; NF-κβ {19.74–27.33%}; {IL-1 25.37–52.59%} and IL-10 {31.91–62.76%}), significant increase in tissue reactive oxygen species (ROS) levels [nitrite {42.54–65.87%} and lipid peroxides{10–42.78%}] and superoxide dismutase activities (34.42–57.65%) in various treatment groups when compared to untreated tumor group. Hence, present study revealed therapeutic efficacy of GNPs assisted co-delivery of nisin, doxorubicin and nisin-doxorubicin combination against DMBA induced murine skin cancer probably through ROS mediated apoptotic effects and immunomodulation either alone or synergistically.

Identification of bioinspired yet nonnatural low cost and stable chemical scaffolds has been a long term goal for a plethora of applications, ranging from medicinal chemistry to material science. To meet the goal of biomimicry the use of peptoids has been one of the most symbolic approaches of the last two decades, due to their ability to adopt folded nanostructures, and thus be designed to adopt specific conformations. They have attracted significant attention as peptide and protein mimics due to their ability to circumvent complications associated with peptide therapeutics. Peptoids are oligomers based on a polyglycine backbone in which the side chains are appended to the amide nitrogen (poly- N -substituted glycines). This modification bestows protease resistance, while allowing suitable mimicry of the spacing between the critical chemical functionalities of bioactive peptides. Consequently, peptoids have found numerous applications in therapeutics, diagnostics, and biomedical applications. They are attractive targets for the drug discovery process because they can be amicably designed and developed as peptide mimics. Methods to direct the peptoid backbone toward formation of specific secondary structures, such as helices and also nanoparticles, have also been explored for the discovery of potent bioactive peptoid modules. So far, peptoids have established bioactivity as lung surfactants, small molecule drugs, drug delivery vehicles, cancer therapy and antimicrobial agents. In this chapter, we discuss the potential of peptoids in future therapeutics.

Self-healing materials have been inspired by the ability of human/animal skins and plant tissues to self-repair their minor damages. Self-healing polymers and fibre-reinforced polymer composites acquire the ability to heal small ruptures and cracks during their service life. Presence of microscopic cracks and other types of damage depletes thermal, electrical, mechanical and acoustical properties, and seriously impairs performance of the material. This can ultimately lead to complete failure. Self-healing materials are imbibed with huge quantities of inorganic conducting fillers to trigger self-healing behaviours which are influenced by external forces, such as temperature, change in light intensity and spectrum, pH, or ambient chemistry. Three conceptual approaches of healing system exists which are based upon encapsulation, arterial network and intrinsic capabilities. Self-healing can be generated intrinsically by auto-response mode without manual intervention or requiring external stimulus. Primarily self-healing mechanisms entail resuming mechanical integration lost during cracking and crazing. As polymers are critical products used in coatings, electronics, transportation and energy industries, it is important to induce them with self-repairing mechanisms. Self-healing materials possess remarkable potential in enhancing the longevity of load bearing and tribological materials. Consequently, a large number of academic and industrial research organizations have come forward to explore new concepts in design and synthesis of such materials like thermosets, thermoplastic, elastomers, polymer composites, supramolecular gels, nanostructure conductive hydrogels. These materials can be easily processed, re-used and recycled. Their unique self-repairing properties, the simplicity of their synthesis, their availability from renewable resources and the low cost of raw ingredients augur well for futuristic applications.

Amyloid-beta (Aβ) peptide deposition into insoluble plaques is a pathological hallmark of Alzheimer's disease (AD), but soluble oligomeric Aβ is considered to be more potent and has been hypothesized to directly impair learning and memory. Also, evidences from some clinical studies indicated that Aβ oligomer formation is the major cause for early AD onset. However, the biochemical mechanism involved in the oligomer-induced toxicity is not very well addressed. So, thise present study was undertaken to study the effects of single intracerebroventricular (icv) injection of protofibrillar Aβ 1-42 on the behavioral and biochemical profile in rats.Rats were divided into two groups (n = 8 per group): (1) sham control group and (2) Aβ 1-42 injected group. A single dose of protofibrillar Aβ 1-42 (5 ul) through icv injection was bilaterally administered into the dorsal hippocampus, while sham control animals were administered with 5 µl of vehicle.The results demonstrated that the protofibrillar Aβ significantly inhibited long-term memory retention and increased anxiety levels as shown by the behavioral studies. The amyloid deposits were present inside the brain even six weeks after injection as confirmed by thioflavin-T staining and the neurodegeneration induced by these deposits was confirmed by Nissl's staining in hippocampal and cortical regions. The amyloid aggregates induced reactive oxygen species (ROS) production, acetylcholinesterase activity, nitrite levels, lipid peroxidation, and inhibited antioxidant enzyme activity in hippocampus, cortex, and striatum regions of rat brain after six weeks.The present study indicated that protofibrillar Aβ 1-42 injection altered long term memory, induced anxiety-like behavior and also developed Alzheimer's disease like pathology in rats.

New Delhi metallo-β-lactamase (NDM-1) has created a medical storm ever since it was first reported; as it is active on virtually all clinically used β-lactam antibiotics. NDM-1 rampancy worldwide is now considered a nightmare scenario, particularly due to its rapid dissemination. An underlying theme in the majority of recent studies is structural characterization as knowledge of the three-dimensional structure of NDM-1 shall help find connections between its structure and function. Moreover, structural details are even critical in order to reveal the resistance mechanism to β-lactam antibiotics. In this perspective, we review structural characteristics of NDM-1 that have been delineated since its first report. We anticipate that these structure-function connections made by its characterization shall further serve as future guidelines for elucidating pathways towards de novo design of functional inhibitors.

Aliphatic homo-polypeptoids of NAla, NVal, NIle and NLeu both in the presence and absence of protecting groups adopt helical structures without hydrogen bonds with Φ, Ψ values of ~ 0, ± 90° with trans amide bonds. These structures are stabilized by carbonyl-carbonyl interactions and characterized by ~ 3.16 residues per turn with a pitch of ~ 6.13 A. It has been shown that like polyvaline and polyleucine peptides, poly-peptoids can also be exploited for the construction of potential surfactant like molecules by incorporating charged amino acid residues at the N terminal. A single-handed template with Φ, Ψ values of ~ 0, 90° can be attained by incorporating L-leu or L-val at the C-terminal of poly-NIle. Analysis of the simulation results in water as a function of time reveals that the opening of helical structures without hydrogen bonds takes place at sub-picosecond time scale starting from the N-terminal. This leads to the formation of collagen or inverse-collagen type structures (Φ, Ψ ~ -60, 145° and 60, -145° respectively) stabilized by interactions of water molecules with the backbone carbonyl groups.

Development of peptides as clinically useful drugs is limited by their poor metabolic stability and low bioavailability. Recent progresses in chemical synthesis and design have led to several strategies for producing potent mimetics. This study aims to analyze sequence/structure requirements and composition for antimicrobial peptoid designs, as use of peptoids is one of the most representative approaches to meet the goal of biomimicry. Analysis of the designs showed that for maximum activity and minimum hemolysis, the plane of the aromatic residues should be at an angle between 0 and 90° with respect to membranes, cationic residues need not be at the terminal position, and central positions should be uniform in NIle, NLys, and NPhe residues.

In peptoids due to the absence of amide protons, the backbone is devoid of hydrogen bond donor, linked by tertiary amide, which can be iso-energetic between cis and trans-amide bond geometry. The peptoids can be realized with cis amide bond if the side chain of ith residue can engage the carbonyl group of ith-1 residue in CH--O interactions. Simulations studies both in water and DMSO have been carried out. The peptoid Ac-(N(tle))(7) -NMe(2) can adopt degenerate conformations with alternate φ, ψ values of inverse PP-I and PP-I type structure's, or vice versa in water. In DMSO, Ac-(N(tle))(7)-NMe(2) also adopts inverse PP-I type structure. Like polyproline, molecule adopting a rigid structure can be used as molecular markers or spacers in biological studies.The peptoid Ac-(N(ala)-N(tle))(3)-NMe(2) with alternate trans and cis amide bond geometry for N(ala) and N(tle) residue corresponding to inverse PP-II/PP-II type and for N(tle) residue of PP-I type.

The plasma membrane presents a remarkable barrier for the delivery of peptide and nucleic acid based drugs to the inside of cells. This restraint in the path of their development as therapeutic agents can be offset by their conjugation to cell penetrating peptides (CPPs) that can lead to an improved pharmacological profile. In this context, conformational behavior of Vimentin Tubulin Binding Site (TBS) peptide, Vim-TBS (58-81), was investigated for its acknowledged cell penetrating properties along with Trans-activating Tat (48-60) peptide and a pro-apoptogenic peptide of p21/WAFI protein (p10). Also, the fusion peptides Vim- TBS (58-81)-p10 & Tat (48-60)-p10 were studied using molecular mechanics (MM) and molecular dynamics (MD) based strategies. MM results revealed formation of stable α-helix like secondary structures in Vim-TBS (58-81), Tat (48-60) and p10 peptides. In water, three peptides adopted either a helical structure or a random conformation; the stability of either of the two states being governed by the formation of polar contacts with the solvent. The fusion peptides formed helical structures after MD simulations but the structure obtained for the fusion peptide, Vim-TBS-p10 is relatively better characterized in terms of its amphipathic nature with a hydrophilic face formed by the positively charged residues facilitating a better interaction of this fusion peptide with the membrane as compared to that of Tat-p10 peptide. This is the first report on the conformational characteristics of the Vim-TBS (58-81) peptide and the fusion peptide, Vim-TBS (58-81)-p10. The results presented here are significant for their potential role in guiding and facilitating the future efforts of designing peptide based cell penetrating drugs.

Polytheonamide B, a 48 residue long highly cytotoxic polypeptide extracted from marine sponges contains amino acids of alternate chirality and the N-terminal region is rich in t-Leu residues. The aim of this study is to analyze the effect of these alternate chiralities and conformational behavior of various model peptides containing t-Leu, in order to explore their role in designing bioactive peptides that shall offer advantages comparable to polytheonamide B, while circumventing its limitations. The conformational behavior of various peptides constructed from t-Leu of the form Ac-(L/D-X-L/D-Y)n-NHMe, where X = Gly/Ala/Leu and Y = t-Leu has been studied and compared with the corresponding peptides containing Leu residue. The results show that the helix driving capacity of L and D forms of t-Leu is less than that of Leu residue. In poly t-Leu peptides, the population of collagen/inverse collagen-type structures or right/left handed-helical structures for L and D forms respectively is found to be chain length-dependent. The stability of the helical structures is increased by -2 kcal per residue over the collagen-type structure in poly t-Leu peptides with chain length greater than five residues. Molecular view of peptides in collagen-type structure shows that the bulky side chains of t-Leu residues mask the NH moieties of the peptide bond, while the carbonyl groups lying along the helical groove are accessible to the small solvent molecules. Molecular model building suggests that one ethylene glycol molecule interacts by forming hydrogen bonds with carbonyl groups of two adjacent t-Leu residues. To the best of our knowledge, this is the first study of its own kind on the construction of a single-strand collagen/inverse collagen-type structure using unusual amino acid residues. Such synthetic collagen mimetic peptides shall exhibit specific affinity to natural collagen under controlled thermal conditions (heat or laser treatment) and hence can be explored as a new targeting method to attach therapeutic drugs to collagens in the living tissues and to biomaterials that incorporate natural collagens.

1. Sixty marasmic children and fifteen normal age-matched controls were investigated for the absorption of fats and proteins. Their duodenal juice samples were also analysed for bile salts and microflora.2. A significant amount of malabsorption, with respect to both the dietary ingredients, was observed in the majority of the marasmic children.3. The levels of conjugated bile acids in the duodenal juice samples of marasmic children were significantly lower as compared with those of normal controls, while the reverse was true for free bile acids and bacterial counts.4. Significant correlations were observed between bile acid levels and fat absorption and also between microflora and free bile acids.5. The pathophysiology of malabsorption in marasmus is discussed in the light of these findings.

1. Plasma tyrosine and urinary p-hydroxyphenyl lactic acid (PHPLA) and p-hydroxyphenyl acetic acid (PHPAA) were studied in thirty patients with marasmus and twenty normal controls in the same age group.2. In the control group conventional tyrosyluria was not observed but 30% of the group excreted high levels of PHPAA. In the group with marasmus, plasma tyrosine and urinary PHPLA and PHPAA values were significantly higher than the control values. However only 13.3% of the patients were considered to have conventional tyrosyluria and 52.3% were found to excrete high levels of PHPAA.3. Administration of ascorbic acid resulted in a reduction of PHPLA excretion while it had no effect on PHPAA excretion.4. It was inferred that (a) tyrosyluria in marasmus is due to the reduced activity of the hepatic enzyme 4-hydroxyphenyl pyruvate: oxygen oxidoreductase (hydroxylating, decarboxylating) (PHPPA-oxidase; EC 1. 13. 11. 27) due to the deficiency of ascorbic acid and (b) high excretion of PHPAA is related to age and nutrition of the child and is unaffected by the administration of ascorbic acid.5. It was further inferred that urinary excretion of PHPLA is a reliable index of tyrosyluria.

Red blood cells (RBC) from iron-deficient chidren were found to have decreased levels of reduced glutathione and reduced content of glucose-6-phosphate dehydrogenase, glutathione peroxidase and glutathione reductase than RBC from normal control children. These findings suggest an increased oxidant stress on iron-deficient red cells which may be one of the mechanisms responsible for membrane alterations leading to shortened life span of erythrocytes in iron-deficiency anaemia.

Glucose utilization coefficient was determined in 50 marasmic patients and 25 age matched healthy controls after administering glucose intravenously in three dosage schedules. The coefficient was directly related to the amount of glucose administered and the values were comparable in the marasmic and control subjects in their respectve schedules indicating normal glucose utilization in marasmus. Fasting blood glucose levels were significantly low in the patients compared to the controls. However, in only two patients fasting blood glucose value fell in the hypoglycemic range (less than 50 mg/dl).

1. Sixty marasmic children were investigated for the absorption of xylose, proteins and fats. Their duodenal juice samples were also analysed for bile salts and microflora.2. The marasmic children were then studied in three groups of twenty by allocating them to three different dietary schedules: a high-protein diet (30% of the total energy from protein), a high-fat diet (40% of the total energy from fat) and a high-carbohydrate diet (70% of the total energy from carbohydrate) for 2 weeks and the previous measurements repeated.3. Whereas the high-fat diet resulted in improved fat absorption, along with an increase in total and conjugated bile acids, and the high-carbohydrate diet led to improved xylose absorption, the diet rich in protein resulted in an improvement in the absorption of all three dietary ingredients. It appears that a high-protein diet improves the overall absorption process by improving the intestinal environment as a whole, while high-carbohydrate and high-fat diets bring about adaptive changes related to the respective absorptive processes.