Monocytes in Neonatal Bacterial Sepsis: Think Tank or Workhorse?

Infection and sepsis remain among the leading causes of neonatal mortality. The susceptibility of newborns to infection can be attributed to their immature immune system. Regarding immune response, monocytes represent a numerically minor population of leukocytes. However, they contribute to a variety of immunological demands, such as continuous replenishment of resident macrophages under non-infectious conditions and migration to inflamed sites where they neutralize pathogens and secrete cytokines. Further functions include the presentation of antigens and T-cell activation. Cytokines coordinate host responses to bacterial and viral infections and orchestrate ongoing physiological signaling between cells of non-immune tissues. A critical event is the skewing of the cytokine repertoire to achieve a resolution of infection. In this regard, monocytes may hold a key position as deciders in addition to their phagocytic activity, securing the extinction of pathogens to prevent broader organ damage by toxins and pro-inflammatory reactions. Neonatal monocytes undergo various regulatory and metabolic changes. Thus, they are thought to be vulnerable in anticipating pro-inflammatory conditions and cause severe progressions which increase the risk of developing sepsis. Furthermore, clinical studies have shown that exposure to inflammation puts neonates at a high risk for adverse pulmonary, immunological and other organ developments, which may result in multiorgan disease. This review discusses significant functions and impairments of neonatal monocytes that are decisive for the outcome of bacterial infections.

The Future Is Bright for Polyoxometalates

Polyoxometalates (POMs) are clusters of units of oxoanions of transition metals, such as Mo, W, V and Nb, that can be formed upon acidification of neutral solutions. Once formed, some POMs have shown to persist in solution, even in the neutral and basic pH range. These inorganic clusters, amenable of a variety of structures, have been studied in environmental, chemical, and industrial fields, having applications in catalysis and macromolecular crystallography, as well as applications in biomedicine, such as cancer, bacterial and viral infections, among others. Herein, we connect recent POMs environmental applications in the decomposition of emergent pollutants with POMs’ biomedical activities and effects against cancer, bacteria, and viruses. With recent insights in POMs being pure, organic/inorganic hybrid materials, POM-based ionic liquid crystals and POM-ILs, and their applications in emergent pollutants degradation, including microplastics, are referred. It is perceived that the majority of the POMs studies against cancer, bacteria, and viruses were performed in the last ten years. POMs’ biological effects include apoptosis, cell cycle arrest, interference with the ions transport system, inhibition of mRNA synthesis, cell morphology changes, formation of reaction oxygen species, inhibition of virus binding to the host cell, and interaction with virus protein cages, among others. We additionally refer to POMs’ interactions with various proteins, including P-type ATPases, aquoporins, cinases, phosphatases, among others. Finally, POMs’ stability and speciation at physiological conditions are addressed.

Drug Repositioning Ketamine as a New Treatment for Bipolar Disorder Using Text Mining

Bipolar Disorder (BD), a chronic mental illness, does not have an ideal treatment, and patients with BD have a higher chance of being diagnosed with alcohol abuse, liver disease, and diabetes. The goal of treatment is to prevent a relapse in BD episodes and find a new treatment. The research here looks at the genetics of BD and ignores environmental factors, as they are subjective. Therapy treats known environmental triggers and stressors and explores methods to reduce them. However, therapy alone cannot fully alleviate the symptoms of BD. My research employs text-mining as a primary strategy to obtain relevant genes and drugs pertaining to BD. The main gene involved is the Brain-Derived Neurotrophic Factor (BDNF). Popular drugs currently used for treatment of BD are Lithium and Carbamazepine. Using CMapPy to look at gene expression data, one sees a relationship between the two drug therapies and BDNF. Lithium fails to treat mania and Carbamazepine fails to treat depression, relatively speaking. When comparing gene expression data of Lithium and Carbamazepine with Ketamine, a newer therapy for BD, Ketamine, raises the BDNF level, keeps it elevated, and effectively controls BD episodes. Ketamine does not have the shortcomings that Lithium and Carbamazepine have. Next steps would include conducting a clinical trial with the hopeful application of Ketamine as a new treatment for BD.

MALDI MS-Based Investigations for SARS-CoV-2 Detection

The urgent need to fight the COVID-19 pandemic has impressively stimulated the efforts of the international scientific community, providing an extraordinary wealth of studies. After the sequence of the virus became available in early January 2020, safe and effective vaccines were developed in a time frame much shorter than everybody expected. However, additional studies are required since viral mutations have the potential of facilitating viral transmission, thus reducing the efficacy of developed vaccines. Therefore, improving the current laboratory testing methods and developing new rapid and reliable diagnostic approaches might be useful in managing contact tracing in the fight against both the original SARS-CoV-2 strain and the new, potentially fast-spreading CoV-2 variants. Mass Spectrometry (MS)-based testing methods are being explored, with the challenging promise to overcome the many limitations arising from currently used laboratory testing assays. More specifically, MALDI-MS, since its advent in the mid 1980s, has demonstrated without any doubt the great potential to overcome many unresolved analytical challenges, becoming an effective proteomic tool in several applications, including pathogen identification. With the aim of highlighting the challenges and opportunities that derive from MALDI-based approaches for the detection of SARS-CoV-2 and its variants, we extensively examined the most promising proofs of concept for MALDI studies related to the COVID-19 outbreak.

Antidiabetic and Antioxidant Activities of the Twigs of Andrograhis paniculata on Streptozotocin-Induced Diabetic Male Rats

Background: Diabetes is associated with chronic hyperglycaemia, long-term damage, dysfunction, and organ failure. This study aims to evaluate the antidiabetic activity of the twigs of Andrographis paniculata and its toxicological markers on Streptozotocin (STZ)-induced diabetic Albino rats. Methods: A total of thirty rats were randomly divided into five groups of six animals each. Non-diabetic animals were treated with distilled water as non-diabetic sham control group 1, while diabetic animals (group 2, 3, 4 and 5) were treated with 60 mg/kg bw STZ intravenous (iv) and 100 mg/kg body weight (bwt) of metformin orally for group 2, distilled water for group 3, and 250 and 500 mg/kg bwt of Andrograhis paniculata (A. paniculata) for groups 4 and 5, respectively. The animals were dosed for 28 days, after which they were sacrificed. Liver and kidney function tests as well as livid profile tests were used as the biomarkers of toxicological assessment. Fasting blood glucose was carried out weekly. Oral Glucose Tolerance Test (OGTT) was conducted on the 28th day of the antidiabetic assessment. Results: A. paniculata groups 4 and 5 were significant at different doses (p < 0.05) in reducing the blood glucose level in comparison with metformin. There were significant changes in total and direct bilirubin, total protein, potassium, triglyceride and inorganic phosphorus in 500 mg/kg bwt of the treated group in comparison with the metformin and diabetic group groups. A. paniculata at 500 mg/kg bwt is most effective for its antidiabetic and organ protecting effects.

“Multiomics” Approaches to Understand and Treat COVID-19: Mass Spectrometry and Next-Generation Sequencing

In the race against COVID-19 for timely therapeutic developments, mass spectrometry-based high-throughput methods have been valuable. COVID-19 manifests an extremely diverse spectrum of phenotypes from asymptomatic to life-threatening, drastic elevations in immune response or cytokine storm, multiple organ failure and death. These observations warrant a detailed understanding of associated molecular mechanisms to develop therapies. In this direction, high-throughput methods that generate large datasets focusing on changes in protein interactions, lipid metabolism, transcription, and epigenetic regulation of gene expression are extremely beneficial sources of information. Hence, mass spectrometry-based methods have been employed in several studies to detect changes in interactions among host proteins, and between host and viral proteins in COVID-19 patients. The methods have also been used to characterize host and viral proteins, and analyze lipid metabolism in COVID-19 patients. Information obtained using the above methods are complemented by high-throughput analysis of transcriptomic and epigenomic changes associated with COVID-19, coupled with next-generation sequencing. Hence, this review discusses the most recent studies focusing on the methods described above. The results establish the importance of mass spectrometry-based studies towards understanding the infection process, immune imbalance, disease mechanism, and indicate the potential of the methods’ therapeutic developments and biomarker screening against COVID-19 and future outbreaks.

HIV-1 Gag Non-Cleavage Site PI Resistance Mutations Stabilize Protease/Gag Substrate Complexes in Silico via a Substrate-Clamp

HIV-1 protease active site inhibitors are a key part of antiretroviral therapy, though resistance can evolve rendering therapy ineffective. Protease inhibitor resistance typically starts with primary mutations around the active site, which reduces inhibitor binding, protease affinity for substrate cleavage site residues P4-P4′, and viral replication. This is often followed by secondary mutations in the protease substrate-grooves which restore viral replication by increasing protease affinity for cleavage site residues P12-P5/P5′-P12′, while maintaining resistance. However, mutations in Gag alone can also result in resistance. The Gag resistance mutations can occur in cleavage sites (P12-P12′) to increase PR binding, as well as at non-cleavage sites. Here we show in silico that Gag non-cleavage site protease inhibitor resistance mutations can stabilize protease binding to Gag cleavage sites which contain structured subdomains on both sides: SP1/NC, SP2/p6, and MA/CA. The Gag non-cleavage site resistance mutations coordinated a network of H-bond interactions between the adjacent structured subdomains of the Gag substrates to form a substrate-clamp around the protease bound to cleavage site residues P12-P12′. The substrate-clamp likely slows protease disassociation from the substrate, restoring the cleavage rate in the presence of the inhibitor. Native Gag substrates can also form somewhat weaker substrate-clamps. This explains the 350-fold slower cleavage rate for the Gag CA/SP1 cleavage site in that the CA-SP1 substrate lacks structured subdomains on both sides of the cleavage site, and so cannot form a substrate-clamp around the PR.

Isopanduratin A Inhibits Tumor Necrosis Factor (TNF)-α-Induced Nuclear Factor κB Signaling Pathway by Promoting Extracellular Signal-Regulated Kinase-Dependent Ectodomain Shedding of TNF Receptor 1 in Human Lung Adenocarcinoma A549 Cells

Tumor necrosis factor α (TNF-α) induces the nuclear factor κB (NF-κB) signaling pathway via TNF receptor 1 (TNF-R1). We recently reported that isopanduratin A inhibited the TNF-α-induced NF-κB signaling pathway in human lung adenocarcinoma A549 cells. In the present study, we found that isopanduratin A did not inhibit the interleukin-1α-induced NF-κB signaling pathway in A549 cells. Isopanduratin A down-regulated the expression of TNF-R1 in these cells. We also revealed that isopanduratin A down-regulated the cell surface expression of TNF-R1 by promoting the cleavage of TNF-R1 into its soluble forms. TAPI-2, an inhibitor of TNF-α-converting enzyme, suppressed the inhibitory activity of isopanduratin A against the TNF-α-induced activation of NF-κB. The mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) kinase inhibitor U0126, but not the p38 MAP kinase inhibitor SB203580, blocked the ectodomain shedding of TNF-R1 induced by isopanduratin A. Consistent with this result, isopanduratin A induced the rapid phosphorylation of ERK, but not p38 MAP kinase. Isopanduratin A also promoted the phosphorylation of eukaryotic initiation factor 2α (eIF2α). The present results indicate that isopanduratin A inhibits TNF-α-induced NF-κB signaling pathway by promoting ERK-dependent ectodomain shedding of cell surface TNF-R1, and also decreases cellular TNF-R1 levels through the phosphorylation of eIF2α in A549 cells.

Revisit of the Photoirradiation of α-Lipoic Acid—Role of Hydrogen Sulfide Produced in the Reaction

α-Lipoic acid (LA) has the specific absorption band at 330 nm and is quite vulnerable to UV irradiation, affording a variety of compounds including polymeric materials and hydrogen sulfide. A better understanding of the photochemical reaction of LA has already been carried out focusing mainly on the reaction product analysis derived from LA. We re-investigated the photochemical reaction of LA focusing our attention on the fate of hydrogen sulfide (H2S) produced in the photochemical reaction procedure. The photoirradiation of LA in the presence of oxidized glutathione (GSSG) formed glutathione trisulfide (GSSSG) and a reduced form of glutathione (GSH). Similar results were obtained in the co-presence of cystine and dimethyl disulfide. The concentration of H2S was reaching the maximum concentration, which was gradually decreasing within 10 min after photoirradiation, while the concentration of GSSSG was increasing with the decrease of H2S concentration. The structural confirmation of GSSSG and the plausible mechanism for the formation of GSSSG are proposed based on the time-dependent and pH-dependent profile of the photoirradiation.

Natural Products as Protective Agents for Male Fertility

The male reproductive system is highly susceptible to noxious influences, such as oxidative stress, inflammation, drugs, and even diseases that can induce germ cell damage and alterations in spermatogenesis. All of these factors, which are caused by actions at the testicular level and/or at the excurrent ducts and accessory glands, significantly affect sperm parameters and male fertility. For this reason, it is of major importance to investigate possible ways to protect the male reproductive system since males are exposed to these toxic factors constantly. For centuries, natural products have been used by humans in folk medicine as therapeutic agents, and because of their beneficial properties for human health, plenty of them have been introduced to the pharmaceutical market as supplementary therapies. The present review aims to compile available information regarding different natural exogenous factors that demonstrate potential useful activity in the male reproductive system. The studies presented here reopen the perspective of using natural products as protective agents and eventually as new supplementary therapeutic options for the recovery of hampered spermatogenesis and/or male infertility.