Mutual Inhibition of Antithrombin III and SARS-CoV-2 Cellular Attachment to Syndecans: Implications for COVID-19 Treatment and Vaccination.

Antithrombin III (ATIII) is a potent endogenous anticoagulant that binds to heparan sulfate proteoglycans (HSPGs) on endothelial cells' surfaces. Among these HSPGs, syndecans (SDCs) are crucial as transmembrane receptors bridging extracellular ligands with intracellular signaling pathways. Specifically, syndecan-4 (SDC4) has been identified as a key receptor on endothelial cells for transmitting the signaling effects of ATIII.

The solute carrier SLC7A1 may act as a protein transporter at the blood-brain barrier.

Despite extensive research, targeted delivery of substances to the brain still poses a great challenge due to the selectivity of the blood-brain barrier (BBB). Most molecules require either carrier- or receptor-mediated transport systems to reach the central nervous system (CNS). These transport systems form attractive routes for the delivery of therapeutics into the CNS, yet the number of known brain endothelium-enriched receptors allowing the transport of large molecules into the brain is scarce.

Exploring the Syndecan-Mediated Cellular Internalization of the SARS-CoV-2 Omicron Variant.

SARS-CoV-2 variants evolve to rely more on heparan sulfate (HS) for viral attachment and subsequent infection. In our earlier work, we demonstrated that the Delta variant's spike protein binds more strongly to HS compared to WT SARS-CoV-2, leading to enhanced cell internalization via syndecans (SDCs), a family of transmembrane HS proteoglycans (HSPGs) facilitating the cellular entry of the original strain. Using our previously established ACE2- or SDC-overexpressing cellular models, we now compare the ACE2- and SDC-dependent cellular uptake of heat-inactivated WT SARS-CoV-2 with the Delta and Omicron variants.

Reconsidering Dogmas about the Growth of Bacterial Populations.

The growth of bacterial populations has been described as a dynamic process of continuous reproduction and cell death. However, this is far from the reality. In a well fed, growing bacterial population, the stationary phase inevitably occurs, and it is not due to accumulated toxins or cell death.

Syndecan-4 Mediates the Cellular Entry of Adeno-Associated Virus 9.

Due to their low pathogenicity, immunogenicity, and long-term gene expression, adeno-associated virus (AAV) vectors emerged as safe and efficient gene delivery tools, over-coming setbacks experienced with other viral gene delivery systems in early gene therapy trials. Among AAVs, AAV9 can translocate through the blood-brain barrier (BBB), making it a promising gene delivery tool for transducing the central nervous system (CNS) via systemic administration. Recent reports on the shortcomings of AAV9-mediated gene delivery into the CNS require reviewing the molecular base of AAV9 cellular biology.

Biodistribution and Cellular Internalization of Inactivated SARS-CoV-2 in Wild-Type Mice.

Despite the growing list of identified SARS-CoV-2 receptors, the human angiotensin-converting enzyme 2 (ACE2) is still viewed as the main cell entry receptor mediating SARS-CoV-2 internalization. It has been reported that wild-type mice, like other rodent species of the Muridae family, cannot be infected with SARS-CoV-2 due to differences in their ACE2 receptors. On the other hand, the consensus heparin-binding motif of SARS-CoV-2's spike protein, PRRAR, enables the attachment to rodent heparan sulfate proteoglycans (HSPGs), including syndecans, a transmembrane HSPG family with a well-established role in clathrin- and caveolin-independent endocytosis.

Syndecan-3 as a Novel Biomarker in Alzheimer's Disease.

Early diagnosis of Alzheimer's disease (AD) is of paramount importance in preserving the patient's mental and physical health in a fairly manageable condition for a longer period. Reliable AD detection requires novel biomarkers indicating central nervous system (CNS) degeneration in the periphery. Members of the syndecan family of transmembrane proteoglycans are emerging new targets in inflammatory and neurodegenerative disorders.

Syndecan-4 Is a Key Facilitator of the SARS-CoV-2 Delta Variant's Superior Transmission.

Emerging SARS-CoV-2 variants pose threats to vaccination campaigns against COVID-19. Being more transmissible than the original virus, the SARS-CoV-2 B.1.

The Interplay of Apoes with Syndecans in Influencing Key Cellular Events of Amyloid Pathology.

Apolipoprotein E (ApoE) isoforms exert intricate effects on cellular physiology beyond lipid transport and metabolism. ApoEs influence the onset of Alzheimer's disease (AD) in an isoform-dependent manner: ApoE4 increases AD risk, while ApoE2 decreases it. Previously we demonstrated that syndecans, a transmembrane proteoglycan family with increased expression in AD, trigger the aggregation and modulate the cellular uptake of amyloid beta (Aβ).

Contribution of Syndecans to the Cellular Entry of SARS-CoV-2.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel emerging pathogen causing an unprecedented pandemic in 21st century medicine. Due to the significant health and economic burden of the current SARS-CoV-2 outbreak, there is a huge unmet medical need for novel interventions effectively blocking SARS-CoV-2 infection. Unknown details of SARS-CoV-2 cellular biology hamper the development of potent and highly specific SARS-CoV-2 therapeutics.

Contribution of syndecans to cellular uptake and fibrillation of α-synuclein and tau.

Scientific evidence suggests that α-synuclein and tau have prion-like properties and that prion-like spreading and seeding of misfolded protein aggregates constitutes a central mechanism for neurodegeneration. Heparan sulfate proteoglycans (HSPGs) in the plasma membrane support this process by attaching misfolded protein fibrils. Despite of intense studies, contribution of specific HSPGs to seeding and spreading of α-synuclein and tau has not been explored yet.

Contribution of syndecans to cellular internalization and fibrillation of amyloid-β(1-42).

Intraneuronal accumulation of amyloid-β(1-42) (Aβ1-42) is one of the earliest signs of Alzheimer's disease (AD). Cell surface heparan sulfate proteoglycans (HSPGs) have profound influence on the cellular uptake of Aβ1-42 by mediating its attachment and subsequent internalization into the cells. Colocalization of amyloid plaques with members of the syndecan family of HSPGs, along with the increased expression of syndecan-3 and -4 have already been reported in postmortem AD brains.

The phosphomimetic mutation of syndecan-4 binds and inhibits Tiam1 modulating Rac1 activity in PDZ interaction-dependent manner.

The small GTPases of the Rho family comprising RhoA, Rac1 and Cdc42 function as molecular switches controlling several essential biochemical pathways in eukaryotic cells. Their activity is cycling between an active GTP-bound and an inactive GDP-bound conformation. The exchange of GDP to GTP is catalyzed by guanine nucleotide exchange factors (GEFs).

Propylene-glycol aggravates LPS-induced sepsis through production of TNF-α and IL-6.

Background: Propylene glycol (1,2-propanediol, PG) is a commonly used solvent for oral, intravenous, as well as topical pharmaceutical preparations. While PG is generally considered to be safe, it has been known that large intravenous doses given over a short period of time can be toxic.

Objective: To evaluate the effect of PG in sepsis induced by the bacterial endotoxin lipopolysaccharide (LPS).

Contribution of syndecans to lipoplex-mediated gene delivery.

The long awaited breakthrough of gene therapy significantly depends on the in vivo efficiency of targeted intracellular delivery. Hidden details of cellular uptake present a great hurdle for non-viral gene delivery with liposomes. Growing scientific evidence supports the involvement of polyanionic cell surface carbohydrates in cellular internalization of cationic liposomes.

Divalent heavy metal cations block the TRPV1 Ca(2+) channel.

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel involved in pain sensation and in a wide range of non-pain-related physiological and pathological conditions. The aim of the present study was to explore the effects of selected heavy metal cations on the function of TRPV1. The cations ranked in the following sequence of pore-blocking activity: Co(2+) [half-maximal inhibitory concentration (IC(50)) = 13 μM] > Cd(2+) (I (50) = 38 μM) > Ni(2+) (IC(50) = 62 μM) > Cu(2+) (IC(50) = 200 μM).

Cell-penetrating peptide exploited syndecans.

Cell-penetrating peptides (CPPs) are short peptides capable of translocating across the plasma membrane of live cells and transporting conjugated compounds intracellularly. Fifteen years after discovering the first model cationic CPPs, penetratin and TAT, CPP internalization is still challenging many questions. Particularly it has been unknown whether CPPs enter the cells with or without mediation of a specific surface receptor.

Resiniferatoxin mediated ablation of TRPV1+ neurons removes TRPA1 as well.

Objectives: Resiniferatoxin, the most potent agonist of inflammatory pain/vanilloid receptor/cation channel (TRPV1) can be used for neuron subtype specific ablation of pain generating cells at the level of the peripheral nervous system by Ca(2+)-excytotoxicity. Molecular neurosurgery is an emerging technology either to alleviate severe pain in cancer or treat/prevent different local neuropathies. Our aim was determining sensory modalities that may be lost after resiniferatoxin treatment.

Human keratinocytes are vanilloid resistant.

Background: Use of capsaicin or resiniferatoxin (RTX) as analgesics is an attractive therapeutic option. RTX opens the cation channel inflammatory pain/vanilloid receptor type 1 (TRPV1) permanently and selectively removes nociceptive neurons by Ca(2+)-cytotoxicity. Paradoxically, not only nociceptors, but non-neuronal cells, including keratinocytes express full length TRPV1 mRNA, while patient dogs and experimental animals that underwent topical treatment or anatomically targeted molecular surgery have shown neither obvious behavioral, nor pathological side effects.

Therapeutic proteasome inhibition in experimental acute pancreatitis.

Aim: To establish the therapeutic potential of proteasome inhibition, we examined the therapeutic effects of MG132 (Z-Leu-Leu-Leu-aldehyde) in an experimental model of acute pancreatitis.

Methods: Pancreatitis was induced in rats by two hourly intraperitoneal (ip) injections of cholecystokinin octapeptide (CCK; 2 x 100 microg/kg) and the proteasome inhibitor MG132 (10 mg/kg ip) was administered 30 min after the second CCK injection. Animals were sacrificed 4 h after the first injection of CCK.

Anti-calmodulins and tricyclic adjuvants in pain therapy block the TRPV1 channel.

Ca(2+)-loaded calmodulin normally inhibits multiple Ca(2+)-channels upon dangerous elevation of intracellular Ca(2+) and protects cells from Ca(2+)-cytotoxicity, so blocking of calmodulin should theoretically lead to uncontrolled elevation of intracellular Ca(2+). Paradoxically, classical anti-psychotic, anti-calmodulin drugs were noted here to inhibit Ca(2+)-uptake via the vanilloid inducible Ca(2+)-channel/inflamatory pain receptor 1 (TRPV1), which suggests that calmodulin inhibitors may block pore formation and Ca(2+) entry. Functional assays on TRPV1 expressing cells support direct, dose-dependent inhibition of vanilloid-induced (45)Ca(2+)-uptake at microM concentrations: calmidazolium (broad range) > or = trifluoperazine (narrow range) chlorpromazine/amitriptyline>fluphenazine>>W-7 and W-13 (only partially).

In vitro and in vivo nuclear factor-kappaB inhibitory effects of the cell-penetrating penetratin peptide.

Penetratin is a cationic cell-penetrating peptide that has been frequently used for the intracellular delivery of polar bioactive compounds. Recent studies have just revealed the major role of polyanionic membrane proteoglycans and cholesterol-enriched lipid rafts in the uptake of the peptide. Both proteoglycans and lipid-rafts influence inflammatory processes by binding a wide array of proinflammatory mediators; thus, we decided to analyze the effect of penetratin on in vitro and in vivo inflammatory responses.

Beneficial effect of resveratrol on cholecystokinin-induced experimental pancreatitis.

Resveratrol is a phytoalexin with strong antioxidant and anti-inflammatory effects reaching high concentrations in red wine. The aim of our study was to test the effects of resveratrol pretreatment on cholecystokinin-octapeptide (CCK-8)-induced acute pancreatitis in rats. Animals were divided into a control group, a group treated with CCK-8 and a group receiving 10 mg/kg resveratrol prior to CCK-8 administration.

Effect of melatonin on the severity of L-arginine-induced experimental acute pancreatitis in rats.

Aim: To determine the effect of melatonin pre- and post-treatment on the severity of L-arginine (L-Arg) -induced experimental pancreatitis in rats.

Methods: Male Wistar rats (25) were divided into five groups. Those in group A received two injections of 3.