The synthesis of a tropoelastin-based polypeptide (PP), poly(AAGVP) (where A denotes Alanine, G for Glycine, V for Valine, and P for Proline), is performed using a solution-phase approach. The miscibility of PP and polyvinyl alcohol (PVA) is examined in various ratios to develop membranes for suitable biomedical applications. Miscibility in the solution phase was evaluated using viscometric parameters (KH, ∆[η]m, ∆B, μ, α, β, ΔK as proposed by Huggins, Garcia, Chee, Sun, Jiang, and Han, individually), indicating that PVA is miscible with PP up to 60

The elastin-like polypentapeptide, poly(GVGVP), composed of valine (V), glycine (G), and proline (P), has been synthesized and investigated for its physicochemical characteristics in polymeric blends with chitosan. The structural, morphological, and intermolecular interactions between poly(GVGVP) and chitosan in both aqueous and solid phases at room temperature were investigated using viscometry, scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD). The thermal characteristics of the blends, including thermal stability and glass transition temperature (Tg), were assessed using thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), individually. The blend combinations exhibited improved thermal stability compared to the distinct polymers. The results indicate strong intermolecular interactions between chitosan and the polypentapeptide in both aqueous and solid phases. Further, in vitro studies of various polypentapeptide-chitosan proportions demonstrated alpha-amylase inhibition, with IC50 values ranging from 9.1 and 5.8 mu g, comparable to that of acarbose. Furthermore, this was verified by kinetic parameters (Km and Vmax) obtained from Michaelis-Menten and Lineweaver-Burk plots. These novel blends demonstrate the potential for expanding biomaterials with promising biomedical applications.

In this study, the synthesis of poly(AVGVP) [where A-Alanine, V-Valine, G-Glycine, and P-Proline] is executed by the stepwise solution phase method. The interaction between Chitosan and synthetic polypentapeptide in blends was examined in the liquid and solid phases. Viscosity criteria that establish the total miscibility with Chitosan are the Δ[η]m, the intrinsic viscosity [η], Huggins coefficient [KH], by Garcia ΔB, α by Sun, and μ suggested by Chee, ΔK, and β buttressed by Jiang and Han. Besides, the results are corroborated in the solid phase by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and X-ray diffraction (XRD). Miscibility in the blends led to higher thermal stability than that of pure polymers, according to thermogravimetric analysis (TGA). In vitro, studies offered the absence of cytotoxicity, and in vivo histopathological results advocated that the blend shows less inflammation and is more compact as against cotton gauge, evincing an enhanced healing environment and promising the possibility of use in wound therapeutic applications.

Malaria infection causes multiple organ-specific lethal pathologies, including cerebral malaria, and severe liver and lung pathologies by inducing strong inflammatory responses. Gene polymorphism studies suggest that TLR4 and TLR2 contribute to severe malaria, but the roles of these signaling molecules in malaria pathogenesis remain incompletely understood. We hypothesize that danger-associated molecular patterns produced in response to malaria activate TLR2 and TLR4 signaling and contribute to liver and lung pathologies. By using a mouse model of Plasmodium berghei NK65 infection, we show that the combined TLR2 and TLR4 signaling contributes to malaria liver and lung pathologies and mortality. Macrophages, neutrophils, natural killer cells, and T cells infiltrate to the livers and lungs of infected wild-type mice more than TLR2,4-/- mice. Additionally, endothelial barrier disruption, tissue necrosis, and hemorrhage were higher in the livers and lungs of infected wild-type mice than in those of TLR2,4-/- mice. Consistent with these results, the levels of chemokine production, chemokine receptor expression, and liver and lung pathologic markers were higher in infected wild-type mice than in TLR2,4-/- mice. In addition, the levels of HMGB1, a potent TLR2- and TLR4-activating danger-associated molecular pattern, were higher in livers and lungs of wild-type mice than TLR2,4-/- mice. Treatment with glycyrrhizin, an immunomodulatory agent known to inhibit HMGB1 activity, markedly reduced mortality in wild-type mice. These results suggest that TLR2 and TLR4 activation by HMGB1 and possibly other endogenously produced danger-associated molecular patterns contribute to malaria liver and lung injury via signaling mechanisms distinct from those involved in cerebral malaria pathogenesis.

A suitable condition is needed to foster a rapid recovery of wounds, which is a dynamic and intricate process. The development and characterization of mats of plastic-like peptide polymer (PLP) with collagen for wound healing applications are reported in this work. Viscosity parameters such as the Huggins coefficient [KH], the intrinsic viscosity [η], α by Sun, ∆[η]m by Garcia ∆B and μ suggested by Chee, ∆K, and β advocated by Jiang and Han, recommend the miscibility of the polypeptide in solution phase. Fourier transform infrared spectroscopy (FTIR), Scanning Electron Microscopy (SEM), and X-ray diffraction (XRD) methods in a solid phase. Thermal characteristics using a differential scanning calorimeter (DSC) and thermogravimetric analysis (TGA) showed higher stability for the blends than the pure polymers. The collagen and PLP blends showed exceptional in vitro cytocompatibility, and the in vivo wound-healing studies on the Sprague-Dawley rats demonstrated faster wound healing within two weeks compared to the cotton gauze-treated injuries. Therefore, these membranes can be a possible alternative for treating skin injuries.

Peptide-based drugs are gaining significant momentum in the modern drug discovery, which is witnessed by the approval of new drugs by the FDA in recent years. On the other hand, small molecules-based drugs are an integral part of drug development since the past several decades. Peptide-containing drugs are placed between small molecules and the biologics. Both the peptides as well as the small molecules (mainly heterocycles) pose several drawbacks as therapeutics despite their success in curing many diseases. This gap may be bridged by utilising the so called ‘conjugation chemistry’, in which both the partners are linked to one another through a stable chemical bond, and the resulting conjugates are found to possess attracting benefits, thus eliminating the stigma associated with the individual partners. Over the past decades, the field of molecular hybridisation has emerged to afford us new and efficient molecular architectures that have shown high promise in medicinal chemistry. Taking advantage of this and also considering our experience in this field, we present herein a review concerning the molecules obtained by the conjugation of peptides (amino acids) to small molecules (heterocycles as well as bioactive compounds). More than 125 examples of the conjugates citing nearly 100 references published during the period 2000 to 2022 having therapeutic applications in curing infectious diseases have been covered.

Poly(GVGVP), where G-Glycine, V-Valine, and P-Proline, is a synthetic elastin-like polypentapeptide that has been studied for its interaction with collagen in blends using viscometry, Fourier transform infrared spectroscopy (FTIR), Scanning electron microscopy (SEM), and X-ray diffractogram (XRD) techniques. Additionally, the thermal characteristics such as glass transition temperature (Tg) and thermal stability of the blends were studied respectively by Differential Scanning Calorimetry (DSC) and Thermogravimetric analysis (TGA). The results showed that amide A and B band's positions in FTIR spectra of collagen were shifted correspondingly to higher and lower wavenumbers after blending with polypentapeptide. DSC study unveiled characteristic glass transition temperatures (Tg) for the blends and the particular components. All the blends show thermal stability in between the pure polymers. Viscosity evaluations also showed a strong association between collagen and poly(GVGVP). Collagen and poly(GVGVP) together may provide the opportunity to assemble novel, promising materials for biomedical purposes.

VAR2CSA, a multidomain Plasmodium falciparum protein, mediates the adherence of parasite-infected red blood cells to chondroitin 4-sulfate (C4S) in the placenta, contributing to placental malaria. Therefore, detailed understanding of VAR2CSA structure likely help developing strategies to treat placental malaria. The VAR2CSA ectodomain consists of an N-terminal segment (NTS), six Duffy binding-like (DBL) domains, and three interdomains (IDs) present in sequence NTS-DBL1x-ID1-DBL2x-ID2-DBL3x-DBL4ε-ID3-DBL5ε-DBL6ε. Recent electron microscopy studies showed that VAR2CSA is compactly organized into a globular structure containing C4S-binding channel, and that DBL5ε-DBL6ε arm is attached to the NTS-ID3 core structure. However, the structural elements involved in inter-domain interactions that stabilize the VAR2CSA structure remain largely not understood. Here, limited proteolysis and peptide mapping by mass spectrometry showed that VAR2CSA contains several inter-domain disulfide bonds that stabilize its compact structure. Chemical crosslinking-mass spectrometry showed that all IDs interact with DBL4ε; additionally, IDs interact with other DBL domains, demonstrating that IDs are the key structural scaffolds that shape the functional NTS-ID3 core. Ligand binding analysis suggested that NTS considerably restricts the C4S binding. Overall, our study revealed that inter-domain disulfide bonds and interactions between IDs and DBL domains contribute to the stability of VAR2CSA structural architecture and formation of C4S-binding channel.

This work portrays the synthesis of Elastin-based polymer poly(GVGIP) (where; G-Glycine, V-Valine, I-Isoleucine, P-Proline) through the solution-phase strategy by stepwise approach followed by characterization with modern analytical tools. The miscibility attributes of the polypeptide were explored with hydroxypropylmethylcellulose (HPMC) using dilute solution viscometry method, spectroscopic, thermal, SEM, and XRD analysis. Explicitly the Huggins coefficient [KH], the intrinsic viscosity [η], parameters such as α by Sun, ∆[η]m by Garcia ∆B, and µ suggested by Chee, ∆K, and β advocated by Jiang and Han, recommend the miscibility up to 50% of the polypeptide. In the solid phase, DSC and TGA analysis showed that miscible blends possessed a higher glass transition temperature (Tg) and thermal stability, respectively. The Scanning Electron Microscopy (SEM) evinced the smooth morphology for miscible blends. Besides, XRD showed broadening of the diffraction pattern ratified the miscibility. The change in frequency and intensity of FTIR peaks demonstrated the existence of intermolecular interchanges between two polymers. Overall, the approach successfully synthesized poly(GVGIP)/HPMC miscible blends up to 50%, make it an excellent choice for biomedical and pharmaceutical purposes.

The sequestration of Plasmodium falciparum in the placenta contributes to multiple placental malaria pathologies. VAR2CSA, a member of P. falciparum erythrocyte membrane protein 1 family of variant proteins, mediates the sequestration via the binding of parasite‐infected red blood cells to chondroitin 4‐sulfate in the placenta. This selective binding makes VAR2CSA a specific target for developing placental malaria treatment strategies. VAR2CSA contains ~310‐kDa C4S‐binding ectodomain, which thought to consist of an N‐terminal segment (NTS), six canonical Duffy‐binding‐like domains (DBL1‐DBL6), and interdomain (ID1 and ID2) segments. The ectodomain contains 116 cysteine residues. Up to eight intradomain disulfide bonds may be observed in canonical DBL domains; however, not all cysteine residues in a DBL domain conform to this pattern and additional ones are located outside the DBL domains. Recent cryo‐electron microscopy reconstructions revealed the functional core structure containing a third interdomain component (ID3) and substantiated the carbohydrate‐binding channel identified earlier. However, up to 46 % of the core, including the paths of ID1, regions of ID2 remain untraced in these structures. Here, by chemical cross‐linking/mass spectrometry of VAR2CSA, we identify additional interdomain interactions in the unmodeled regions of VAR2CSA. Disulfide bond mapping identifies roles for non‐canonical disulfide bonds and reveals previously un‐modelled interdomain disulfide bonds that link ID2 to DBL4ε. In addition, we resolve a disagreement in the interpretation of ID3 by unambiguously identifying the cysteine residues involved in the disulfide bond between DBL4ε and ID3.

In this work, the novel glutamic acid-containing polypentapeptide, poly[0.8(AVGVP),0.2(AEGVP)] (where A-Alanine, V-Valine, G-Glycine, E-Glutamic acid, and P-Proline), was synthesized and generated the thin membranes with polyvinyl alcohol (PVA). The viscometric parameters registered that two polymers were miscible up to 30% of the polypentapeptide in the blend. DSC analysis showed a single Tg (glass transition temperature), distinctive of a miscible mixture. The depth of inter associative interplays depends reasonably on the formation of hydrogen bonds, as demonstrated in FTIR (Fourier transform infrared) spectroscopy. TGA (Thermogravimetric analysis) attested to the uppermost thermal stability of miscible combinations against immiscible blends. Besides, the SEM and X-Ray Diffraction study validated the outcomes. Furthermore, electrospinning of the miscible blends produced the membranes. Also, the consequent non-woven mats may aid in the advancement of alternative biomaterials with novel peculiarities.

A novel series of amino acids conjugated quinazolinone-Schiff's bases were synthesized and characterized by analytical and spectroscopic methods. All the synthesized analogues (8–43) and the intermediates (1–7) were screened for their in vitro antioxidant and anti-inflammatory activities. Antioxidant activities were determined by three different in vitro assays such as DPPH, ABTS and DMPD cation radical activity methods. Compounds 15, 16, 23–25, 30–34 and 39–43 shows potent antioxidants compared to standards gallic acid and ascorbic acid in all the three antioxidants methods. Compounds 9–11, 18–20, 27–29 and 36–38 showed potent anti-inflammatory activity compared to standards indomethacin and ibuprofen. Preliminary structure-activity relationship revealed that the tryptophan and phenylalanine derived compounds with electron donating groups (OH and OCH3) were found to be excellent antioxidant activity compared to glycine and alanine derivatives. Tryptophan and phenylalanine containing compounds with electron withdrawing groups (Cl, NO2 and F) were found to be excellent anti-inflammatory agents.

Background and Objectives: Pregnancy malaria is a major underestimated global public health problem. To understand the involvement of oxidative stress (OS) in the pathophysiology of placental malaria, OS biomarkers, malondialdehyde (MDA), uric acid (UA), and superoxide dismutase (SOD) levels were analyzed and correlated to placental histopathological changes and pregnancy outcomes. Methods: A hospital-based study was conducted in Mangaluru, Karnataka, India, to analyze the changes in hematological parameters and the serum OS biomarker levels. Histological analysis of placenta, associated complications, and pregnancy outcomes were compared using Kruskal–Wallis test, and pairwise comparison between two groups was made by Mann–Whitney U-test. Correlations were calculated by Pearson's and Spearman's rank correlations. Results: Among 105 pregnant women, 34 were healthy controls and the infected group comprised of Plasmodium Vivax (Pv) (n = 48), Plasmodium falciparum (Pf) (n = 13), and mixed (n = 10) malaria infections. Of 71 infected cases, 67.6% had mild malaria, whereas 32.4% had severe malaria. The white blood cell and C-reactive protein levels were found to increase, whereas hemoglobin, red blood cell, and platelet levels decreased during both types of malarial infections. The MDA and UA values increased and SOD levels decreased particularly during severe Pf infections. Histological changes such as syncytial knots, syncytial ruptures, and fibrinoid necrosis were observed particularly during Pf infections and leukocyte infiltration was observed in Pv malaria Conclusion: Evaluation of MDA, UA, and SOD levels can serve as an indicator of OS during pregnancy malaria. The OS during pregnancy may lead to complications such as severe anemia, pulmonary edema, intra uterine growth retardation, premature delivery, and low birth weight, not only during Pf but also in Pv malaria. It is important to create awareness among rural and immigrant population residing in Mangaluru and its surroundings about required preventive measures and free government-supported antenatal care services.

ABSTRACT The polypeptide, poly(AVGVP), a prominent member of the synthetic polypeptides (PLP), exhibiting plastic properties for biomedical applications. Their miscibility characteristics with polyacrylamide (PAM) were scrutinized in different weight proportions manipulating viscometry in the aqueous phase. The interaction parameters confirmed that the two polymers are miscible up to 20/80 weight portion of PLP/PAM. Further, the outcomes were supported by Fourier transform infrared (FTIR) spectroscopy, and differential scanning calorimetry (DSC), XRD, and SEM individually. Moreover, blends resulted in nanofibers (75 ± 25 nm) at 26 kV by the electrospinning method, and they may be the potential alternatives for prospective biomedical applications. GRAPHICAL ABSTRACT

Dakshina Kannada district in the Southwestern region of Karnataka State in India is endemic to malaria for the last three decades. About 80% of malaria infections in Mangaluru and its surrounding areas are caused by Plasmodium vivax (Pv) and the remainder are due to Plasmodium falciparum (Pf). Malarial infections during pregnancy led to pregnancy-associated malaria (PAM), which are also being reported commonly in this region. The PAM could lead to serious clinical complications to both the mother and fetus resulting in morbidity and mortality. Despite high endemicity, to-date, very little has been reported on the epidemiology and burden of PAM in this area. Keeping in view of this, we conducted a systematic longitudinal study during 2015 across four malaria active hotspot areas in Mangalore city and recruited both long-time residents and immigrant laborers (temporary residents) to find out the actual burden of PAM. Data on socio-demographic, literacy, knowledge of malaria and treatment-seeking behavior were collected to understand the various contributing factors to PAM in this region.Analyses of the results show that the majority of PAM malaria illnesses were seen in local individuals associated with mild clinical complications. Of the 6 detected PAM cases, 4 were due to P. vivax and one each due to P.falciparum and mixed (P. vivax and P.falciparum) infections as diagnosed by microscopic examinations.These cases were referred to local government hospitals for further monitoring and treatment. These data suggest that P. vivax causes a significant number of PAM infections in this region. Introducing stringent preventive public measures by governments and creating awareness of using preventive protective and environmental hygienic measures through educational programs may substantially reduce the risk of contracting malaria infection.

Persistent high levels of proinflammatory and Th1 responses contribute to cerebral malaria (CM). Suppression of inflammatory responses and promotion of Th2 responses prevent pathogenesis. IL-4 commonly promotes Th2 responses and inhibits inflammatory and Th1 responses. Therefore, IL-4 is widely considered as a beneficial cytokine via its Th2-promoting role that is predicted to provide protection against severe malaria by inhibiting inflammatory responses. However, IL-4 may also induce inflammatory responses, as the result of IL-4 action depends on the timing and levels of its production and the tissue environment in which it is produced. Recently, we showed that dendritic cells (DCs) produce IL-4 early during malaria infection in response to a parasite protein and that this IL-4 response may contribute to severe malaria. However, the mechanism by which IL-4 produced by DCs contributing to lethal malaria is unknown. Using Plasmodium berghei ANKA-infected C57BL/6 mice, a CM model, we show here that mice lacking IL-4R alpha only in CD8 alpha(+) DCs are protected against CM pathogenesis and survive, whereas WT mice develop CM and die. Compared with WT mice, mice lacking IL-4R alpha in CD11c(+) or CD8 alpha(+) DCs showed reduced inflammatory responses leading to decreased Th1 and cytotoxic CD8(+) T cell responses, lower infiltration of CD8(+) T cells to the brain, and negligible brain pathology. The novel results presented here reveal a paradoxical role of IL-4R alpha signaling in CM pathogenesis that promotes CD8 alpha(+) DC-mediated inflammatory responses that generate damaging Th1 and cytotoxic CD8(+) T cell responses.

Cytokine responses to malaria play important roles in both protective immunity development and pathogenesis. Although the roles of cytokines such as TNF-α, IL-12, IFN-γ, and IL-10 in immunity and pathogenesis to the blood stage malaria are largely known, the role of IL-4 remains less understood. IL-4 targets many cell types and induces multiple effects, including cell proliferation, gene expression, protection from apoptosis, and immune regulation. Accordingly, IL-4 has been exploited as a therapeutic for several inflammatory diseases. Malaria caused by Plasmodium falciparum manifests in many organ-specific fatal pathologies, including cerebral malaria (CM), driven by a high parasite load, leading to parasite sequestration in organs and consequent excessive inflammatory responses and endothelial damage. We investigated the therapeutic potential of IL-4 against fatal malaria in Plasmodium berghei ANKA-infected C57BL/6J mice, an experimental CM model. IL-4 treatment significantly reduced parasitemia, CM pathology, and mortality. The therapeutic effect of IL-4 is mediated through multiple mechanisms, including enhanced parasite clearance mediated by upregulation of phagocytic receptors and increased IgM production, and decreased brain inflammatory responses, including reduced chemokine (CXCL10) production, reduced chemokine receptor (CXCR3) and adhesion molecule (LFA-1) expression by T cells, and downregulation of cytotoxic T cell lytic potential. IL-4 treatment markedly reduced the infiltration of CD8+ T cells and brain pathology. STAT6, PI3K-Akt-NF-κB, and Src signaling mediated the cellular and molecular events that contributed to the IL-4-dependent decrease in parasitemia. Overall, our results provide mechanistic insights into how IL-4 treatment mitigates experimental CM and have implications in developing treatment strategies for organ-specific fatal malaria.