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Heme is involved in many critical processes in pathogenic bacteria as iron acquisition by these microorganisms is achieved by either direct uptake of heme or use of heme-binding proteins called hemophores. Exploring the underlying mechanisms on a molecular level can open new avenues in understanding the host-pathogen interactions. Any imbalance of the heme concentration has a direct impact on the bacterial growth and survival. Thus, heme-regulated proteins that are involved in heme homeostasis poise to be promising targets for research. Similarly, naturally occurring compounds, including cysteine-rich peptides from either plant secondary metabolites or venom toxins from vertebrates and invertebrates, have been studied for their therapeutic potential. NCR247 is such a cysteine-rich peptide, known to be crucial for nitrogenase activity in M. truncatula and its symbiotic relation with S. meliloti. NCR247-derived peptides were suggested to serve as high-affinity heme-binding molecules with remarkable heme-capturing properties. A comprehensive biochemical and computational analysis of NCR247-derived peptides, however, redefines their heme-binding capacity and consequently their potential therapeutic role., (© 2024 The Author(s). ChemBioChem published by Wiley-VCH GmbH.)

Background Diabetes mellitus (DM), especially type 2 diabetes mellitus (T2DM), is a serious worldwide health concern that is becoming more common and often develops at a young age, particularly in developing countries. Given the increasing incidence of diabetes in India, efficient management techniques are advantageous. The aim of this study is to evaluate the impact of physical activity on body measurements, biochemical markers, and clinical outcomes in Indian individuals with T2DM. Methodology Utilizing a universal sampling approach, a longitudinal interventional study was performed with T2DM patients at a metropolitan health and training facility over an eight-month duration. Over the course of six months, they were told to walk briskly for 2.5 hours each week. Initial and follow-up evaluations included monitoring arterial pressure, body mass, abdominal circumference, and glucose concentrations. During monthly follow-ups, participants self-reported their compliance. Results The study of 210 participants shows a diverse age distribution with the majority in the 35-54 years range and a higher number of females (56.19%) compared to males (43.81%). Most were Hindu (77.6%), with varying education levels and a predominance of unemployment (69.5%) and marital status (91.0% married). Post-exercise, significant improvements were observed in fasting blood glucose (160.45 to 140.20 mg/dL; p = 0.004), postprandial blood glucose (270.35 to 240.55 mg/dL; p = 0.002), body weight (70.00 to 66.50 kg; p = 0.03), and waist circumference (95.00 to 90.50 cm; p = 0.01). Conclusion The outcomes of this prolonged study reveal that along with promoting weight reduction in T2DM patients, regular engagement in moderate exercise can substantially improve both fasting and post-meal blood glucose levels., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Ethics Committee of Mahatma Gandhi Institute of Medical Sciences, Wardha issued approval MGIMS/IEC/PHY/08/2019. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Kothari et al.)

Haemolytic disorders, such as sickle cell disease, are accompanied by the release of high amounts of labile heme into the intravascular compartment resulting in the induction of proinflammatory and prothrombotic complications in affected patients. In addition to the relevance of heme-regulated proteins from the complement and blood coagulation systems, activation of the TLR4 signalling pathway by heme was ascribed a crucial role in the progression of these pathological processes. Heme binding to the TLR4-MD2 complex has been proposed recently, however, essential mechanistic information of the processes at the molecular level, such as heme-binding kinetics, the heme-binding capacity and the respective heme-binding sites (HBMs) is still missing. We report the interaction of TLR4, MD2 and the TLR4-MD2 complex with heme and the consequences thereof by employing biochemical, spectroscopic, bioinformatic and physiologically relevant approaches. Heme binding occurs transiently through interaction with up to four HBMs in TLR4, two HBMs in MD2 and at least four HBMs in their complex. Functional studies highlight that mutations of individual HBMs in TLR4 preserve full receptor activation by heme, suggesting that heme interacts with TLR4 through different binding sites independently of MD2. Furthermore, we confirm and extend the major role of TLR4 for heme-mediated cytokine responses in human immune cells., (© 2023 The Authors. Immunology published by John Wiley & Sons Ltd.)

With technology advancing, many prediction algorithms have been developed to facilitate the modeling of inherently dynamic and flexible macromolecules such as proteins. Improvements in the prediction of protein structures have attracted a great deal of attention due to the advantages they offer, e.g., in drug design. While trusted experimental methods, such as X-ray crystallography, NMR spectroscopy, and electron microscopy, are preferred structure analysis techniques, in silico approaches are also being widely used. Two computational methods, which are on opposite ends of the spectrum with respect to their modus operandi, i.e., homology modeling and AlphaFold, have been established to provide high-quality structures. Here, a comparative study of the quality of structures either predicted by homology modeling or by AlphaFold is presented based on the characteristics determined by experimental studies using structure validation servers to fulfill the purpose. Although AlphaFold is able to predict high-quality structures, high-confidence parts are sometimes observed to be in disagreement with experimental data. On the other hand, while the structures obtained from homology modeling are successful in incorporating all aspects of the experimental structure used as a template, this method may struggle to accurately model a structure in the absence of a suitable template. In general, although both methods produce high-quality models, the criteria by which they are superior to each other are different and thus discussed in detail.

Amyotrophic lateral sclerosis (ALS) is a fatal and incurable disease requiring a multidisciplinary treatment approach and a collaborative therapeutic effort. A combination of both upper and lower motor neuron degeneration ultimately leads to respiratory failure, similar to other dementia-type neurodegenerative diseases. The aim of this paper is to pioneer current ALS research by carrying out a narrative literature review of the current treatment modalities of the disease. Through these efforts, we hope to condense the most pertinent information regarding current treatments and enhance the management of ALS patients as a whole, giving these patients a better quality of life as the search for a cure continues. We used a Pubmed search strategy and specific MeSH terms for the selection of the literature articles using the keywords "ALS," "new treatment," "treatment," and "symptomatic treatment." A combination of pharmaceutical interventions, psychological support, and physical rehabilitation has been most effective in enhancing the quality of life of patients with ALS (PALS). Among potential pharmacological therapies, only a few have been approved by the US Food and Drug Administration(FDA) to be used to treat ALS and its symptoms. Other treatment modalities being considered include gene therapy, cellular therapy, psychological therapy, physical therapy, and speech therapy, alongside robotics, alternative feeding methods, and communication devices., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Hoxhaj et al.)

Heme is a double-edged sword. On the one hand, it has a pivotal role as a prosthetic group of hemoproteins in many biological processes ranging from oxygen transport and storage to miRNA processing. On the other hand, heme can transiently associate with proteins, thereby regulating biochemical pathways. During hemolysis, excess heme, which is released into the plasma, can bind to proteins and regulate their activity and function. The role of heme in these processes is under-investigated, with one problem being the lack of knowledge concerning recognition mechanisms for the initial association of heme with the target protein and the formation of the resulting complex. A specific heme-binding sequence motif is a prerequisite for such complex formation. Although numerous short signature sequences indicating a particular protein function are known, a comprehensive analysis of the heme-binding motifs (HBMs) which have been identified in proteins, concerning specific patterns and structural peculiarities, is missing. In this report, we focus on the evaluation of known mammalian heme-regulated proteins concerning specific recognition and structural patterns in their HBMs. The Cys-Pro dipeptide motifs are particularly emphasized because of their more frequent occurrence. This analysis presents a comparative insight into the sequence and structural anomalies observed during transient heme binding, and consequently, in the regulation of the relevant protein.

In most severe cases, SARS-CoV-2-induced autoimmune reactions have been associated with hemolytic complications. Hemolysis-derived heme from ruptured red blood cells has been shown to trigger a variety of fatal proinflammatory and procoagulant effects, which might deteriorate the progression of COVID-19. In addition, the virus itself can induce proinflammatory signals via the accessory protein 7a. Direct heme binding to the SARS-CoV-2 protein 7a ectodomain and other COVID-19-related proteins has been suggested earlier. Here, we report the experimental analysis of heme binding to the viral proteins spike glycoprotein, protein 7a as well as the host protein ACE2. Thus, protein 7a chemical synthesis was established, including an in-depth analysis of the three different disulfide-bonded isomers. Surface plasmon resonance spectroscopy and in silico studies confirm a transient, biphasic binding behavior, and heme-binding affinities in the nano- to low micromolar range. These results confirm the presence of the earlier identified heme-binding motifs and emphasize the relevance for consideration of labile heme in preexisting or SARS-CoV-2-induced hemolytic conditions in COVID-19 patients., (© 2022 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)

Under hemolytic conditions, hemoglobin and subsequently heme are rapidly released, leading to the toxic effects characterizing diseases such as β -thalassemia and sickle cell disease. Herein, we provide evidence that human hemoglobin can bind heme in a transient fashion via surface-exposed sequence motifs. Following the synthesis of potential heme-binding motifs (HBMs) as peptides, their heme-binding capacity was investigated by UV-vis spectroscopy and ranked according to their binding affinity. Heme binding to human hemoglobin was subsequently studied by UV-vis and surface plasmon resonance (SPR) spectroscopy, revealing a heme-binding affinity in the sub- to micromolar range and a stoichiometry that clearly exceeds a 1:1 ratio. In silico molecular docking and simulation studies confirmed heme binding to the respective motifs in the β -chain of hemoglobin. Finally, the peroxidase-like activity of hemoglobin and the hemoglobin-heme complex was monitored, which indicated a much higher activity (>1800%) than other heme-peptide/protein complexes reported so far. The present study provides novel insights into the nature of intact hemoglobin concerning its transient interaction with heme, which suggests for the first time potential heme-scavenging properties of the protein at concomitant disassembly and, consequently, a potentiation of hemolysis and related processes., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)