Analyzing VEGFA/VEGFR1 Interaction: Application of the Resonant Recognition Model-Stockwell Transform Method to Explore Potential Therapeutics for Angiogenesis-Related Diseases.

The interaction between vascular endothelial growth factor A (VEGFA) and VEGF receptor 1(VEGFR1) is a central focus for drug development in pathological angiogenesis, where aberrant angiogenesis underlies various anomalies necessitating therapeutic intervention. Identifying hotspots of these proteins is crucial for developing new therapeutics. Although machine learning techniques have succeeded significantly in prediction tasks, they struggle to pinpoint hotspots linked to angiogenic activity accurately. This study involves the collection of diverse VEGFA and VEGFR1 protein sequences from various species via the UniProt database. Electron-ion interaction Potential (EIIP) values were assigned to individual amino acids and transformed into frequency-domain representations using discrete Fast Fourier Transform (FFT). A consensus spectrum emerged by consolidating FFT data from multiple sequences, unveiling specific characteristic frequencies. Subsequently, the Stockwell Transform (ST) was employed to yield the hotspots. The Resonant Recognition Model (RRM) identified a characteristic frequency of 0.128007 with an associated wavelength of 1570 nm and RRM-ST identified hotspots for VEGFA (Human 36, 46, 48, 67, 71, 74, 82, 86, 89, 93) and VEGFR1 (Human 224, 259, 263, 290, 807, 841, 877, 881, 885, 892, 894, 909, 913, 1018, 1022, 1026, 1043). These findings were cross-validated by Hotspots Wizard 3.0 webserver and Protein Data Bank (PDB). The study proposes using a 1570 nm wavelength for photo bio modulation to boost VEGFA/VEGFR1 interaction in the condition that is needed. It also aims to reduce VEGFA/VEGFR2 interaction, limiting harmful angiogenesis in conditions like diabetic retinopathy. Also, the identified hotspots assist in designing agonistic or antagonistic peptides tailored to specific medical requirements with abnormal angiogenesis.

Sirtuin 3 in renal diseases and aging: From mechanisms to potential therapies.

The longevity protein sirtuins (SIRTs) belong to a family of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases. In mammals, SIRTs comprise seven members (SIRT1-7) which are localized to different subcellular compartments. As the most prominent mitochondrial deacetylases, SIRT3 is known to be regulated by various mechanisms and participate in virtually all aspects of mitochondrial homeostasis and metabolism, exerting significant impact on multiple organs. Notably, the kidneys possess an abundance of mitochondria that provide substantial energy for filtration and reabsorption. A growing body of evidence now supports the involvement of SIRT3 in several renal diseases, including acute kidney injury, chronic kidney disease, and diabetic nephropathy; notably, these diseases are all associated with aging. In this review, we summarize the emerging role of SIRT3 in renal diseases and aging, and highlights the intricate mechanisms by which SIRT3 exerts its effects. In addition, we highlight the potential therapeutic significance of modulating SIRT3 and provide valuable insights into the therapeutic role of SIRT3 in renal diseases to facilitate clinical application.

The role of novel programmed cell death in head and neck squamous cell carcinoma: from mechanisms to potential therapies.

Head and neck squamous cell carcinoma (HNSCC) is a common oral cancer with poor prognosis and for which no targeted therapeutic strategies are currently available. Accumulating evidence has demonstrated that programmed cell death (PCD) is essential in the development of HNSCC as a second messenger. PCD can be categorized into numerous different subroutines: in addition to the two well-known types of apoptosis and autophagy, novel forms of programmed cell death (e.g., necroptosis, pyroptosis, ferroptosis, and NETosis) also serve as key alternatives in tumorigenesis. Cancer cells are not able to avoid all types of cell death simultaneously, since different cell death subroutines follow different regulatory pathways. Herein, we summarize the roles of novel programmed cell death in tumorigenesis and present our interpretations of the molecular mechanisms with a view to the development of further potential therapies.

Secreted Protein Acidic and Rich in Cysteine (SPARC) to Manage Coronavirus Disease-2019 (COVID-19) Pandemic and the Post-COVID-19 Health Crisis.

Coronavirus disease-2019 (COVID-19) has had and will have impacts on public health and health system expenses. Indeed, not only it has led to high numbers of confirmed COVID-19 cases and hospitalizations, but its consequences will remain even after the end of the COVID-19 crisis. Therefore, therapeutic options are required to both tackle the COVID-19 crisis and manage its consequences during the post COVID-19 era. Secreted protein acidic and rich in cysteine (SPARC) is a biomolecule that is associated with various properties and functions that situate it as a candidate which may be used to prevent, treat and manage COVID-19 as well as the post-COVID-19-era health problems. This paper highlights how SPARC could be of such therapeutic use.

The NO-cGMP-PKG Axis in HFpEF: From Pathological Mechanisms to Potential Therapies.

Heart failure with preserved ejection fraction (HFpEF) accounts for almost half of all heart failure (HF) cases worldwide. Unfortunately, its incidence is expected to continue to rise, and effective therapy to improve clinical outcomes is lacking. Numerous efforts currently directed towards the pathophysiology of human HFpEF are uncovering signal transduction pathways and novel therapeutic targets. The nitric oxide-cyclic guanosine phosphate-protein kinase G (NO-cGMP-PKG) axis has been described as an important regulator of cardiac function. Suppression of the NO-cGMP-PKG signalling pathway is involved in the progression of HFpEF. Therefore, the NO-cGMP-PKG signalling pathway is a potential therapeutic target for HFpEF. In this review, we aim to explore the mechanism of NO-cGMP-PKG in the progression of HFpEF and to summarize potential therapeutic drugs that target this signalling pathway.

Polypeptide N-acetylgalactosamine transferase 3: a post-translational writer on human health.

Polypeptide N-acetylgalactosamine transferase 3 (ppGalNAc-T3) is an enzyme involved in the initiation of O-GalNAc glycan biosynthesis. Acting as a writer of frequent post-translational modification (PTM) on human proteins, ppGalNAc-T3 has key functions in the homeostasis of human cells and tissues. We review the relevant roles of this molecule in the biosynthesis of O-GalNAc glycans, as well as in biological functions related to human physiological and pathological conditions. With main emphasis in ppGalNAc-T3, we draw attention to the different ways involved in the modulation of ppGalNAc-Ts enzymatic activity. In addition, we take notice on recent reports of ppGalNAc-T3 having different subcellular localizations, highlight critical intrinsic and extrinsic functions in cellular physiology that are exerted by ppGalNAc-T3-synthesized PTMs, and provide an update on several human pathologies associated with dysfunctional ppGalNAc-T3. Finally, we propose biotechnological tools as new therapeutic options for the treatment of pathologies related to altered ppGalNAc-T3. KEY MESSAGES: ppGalNAc-T3 is a key enzyme in the human O-GalNAc glycans biosynthesis. enzyme activity is regulated by PTMs, lectin domain and protein-protein interactions. ppGalNAc-T3 is located in human Golgi apparatus and cell nucleus. ppGalNAc-T3 has a central role in cell physiology as well as in several pathologies. Biotechnological tools for pathological management are proposed.

Placental Ischemia Says "NO" to Proper NOS-Mediated Control of Vascular Tone and Blood Pressure in Preeclampsia.

In this review, we first provide a brief overview of the nitric oxide synthase (NOS) isoforms and biochemistry. This is followed by describing what is known about NOS-mediated blood pressure control during normal pregnancy. Circulating nitric oxide (NO) bioavailability has been assessed by measuring its metabolites, nitrite (NO2) and/or nitrate (NO3), and shown to rise throughout normal pregnancy in humans and rats and decline postpartum. In contrast, placental malperfusion/ischemia leads to systemic reductions in NO bioavailability leading to maternal endothelial and vascular dysfunction with subsequent development of hypertension in PE. We end this article by describing emergent risk factors for placental malperfusion and ischemic disease and discussing strategies to target the NOS system therapeutically to increase NO bioavailability in preeclamptic patients. Throughout this discussion, we highlight the critical importance that experimental animal studies have played in our current understanding of NOS biology in normal pregnancy and their use in finding novel ways to preserve this signaling pathway to prevent the development, treat symptoms, or reduce the severity of PE.

How glycobiology can help us treat and beat the COVID-19 pandemic.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged during the last months of 2019, spreading throughout the world as a highly transmissible infectious illness designated as COVID-19. Vaccines have now appeared, but the challenges in producing sufficient material and distributing them around the world means that effective treatments to limit infection and improve recovery are still urgently needed. This review focuses on the relevance of different glycobiological molecules that could potentially serve as or inspire therapeutic tools during SARS-CoV-2 infection. As such, we highlight the glycobiology of the SARS-CoV-2 infection process, where glycans on viral proteins and on host glycosaminoglycans have critical roles in efficient infection. We also take notice of the glycan-binding proteins involved in the infective capacity of virus and in human defense. In addition, we critically evaluate the glycobiological contribution of candidate drugs for COVID-19 therapy such as glycans for vaccines, anti-glycan antibodies, recombinant lectins, lectin inhibitors, glycosidase inhibitors, polysaccharides, and numerous glycosides, emphasizing some opportunities to repurpose FDA-approved drugs. For the next-generation drugs suggested here, biotechnological engineering of new probes to block the SARS-CoV-2 infection might be based on the essential glycobiological insight on glycosyltransferases, glycans, glycan-binding proteins, and glycosidases related to this pathology.

The application of direct viral cytopathic hypothesis to design drug trials in the battle against COVID-19.

COVID-19 has caused many deaths worldwide. Systemic complications alongside coagulopathy, and ARDS account for the majority of COVID-19 mortalities. The pathogenesis of the disease can be explained by two theories of direct viral cytopathy and systemic inflammatory cascade of events. ACE-2 is shown to be the cellular host receptor for SARS-CoV-2. It might be the key to explain the pathogenesis of systemic complications with a focus on the direct viral cytopathic hypothesis. Different medications tend to show up in many in vitro drug screens. However, more trials are needed to translate their application into in vivo efficacy.

Review of various treatment options and potential therapies for osteonecrosis of the femoral head.

Size and location of the lesion, subchondral collapse occurrence, and articular cartilage involvement are general disease progression criteria for direct osteonecrosis of the femoral head (ONFH) classifications. Treatment options for ONFH are usually based on individual factors and lesion characteristics. Although spontaneous repair of ONFH occurs in some cases, untreated ONFH is unlikely to escape the fate of subchondral collapse and usually ends up with total hip arthroplasty. Operations to preserve the femoral head, e.g., core decompression and bone grafting, are usually recommended in younger patients. They are helpful to relieve pain and improve function in the affected femoral head without subchondral collapse, however, poor prognosis after surgical procedures remains the major problem for ONFH. Pharmacological and physical therapies only work in the early stage of ONFH and have also been recommended as a supplement or prevention treatment for osteonecrosis. Following advances in basic science, many new insights focus on bone tissue engineering to optimize therapies and facilitate prognosis of ONFH. In this review, disease classifications, current treatment options, potential therapies, and the relevant translational barriers are reviewed in the context of clinical application and preclinical exploration, which would provide guidance for preferable treatment options and translation into novel therapies.