Since its discovery at the beginning of the 20th century, histamine has been established to play a pathophysiological regulatory role in cellular events through binding to four types of G-protein-coupled histamine receptors that are differentially expressed in various cell types. The discovery, at the turn of the millennium, that the histamine H4 receptor is largely expressed in haemopoietic cells as well as its chemotactic properties designate its regulatory role in the immune system. H4 receptors modulate eosinophil migration and selective recruitment of mast cells leading to amplification of histamine-mediated immune responses and eventually to chronic inflammation. H4 receptor involvement in dendritic cell activation and T cell differentiation documents its immunomodulatory function. The characterization of the H4 as the immune system histamine receptor directed growing attention towards its therapeutic exploitation in inflammatory disorders, such as allergy, asthma, chronic pruritus and autoimmune diseases. The efficacy of a number of H4 receptor ligands has been evaluated in in vivo and in vitro animal models of disease and in human biological samples. However, before reaching decisive conclusions on H4 receptor pathophysiological functions and therapeutic exploitation, identification of genetic polymorphisms and interspecies differences in its relative actions and pharmacological profile need to be addressed and taken into consideration. Despite certain variations in the reported findings, the available data strongly point to the H4 receptor as a novel target for the pharmacological modulation of histamine-transferred immune signals and offer an optimistic perspective for the therapeutic exploitation of this promising new drug target in inflammatory disorders.

/pdf/the-role-of-histamine-h4-receptor-in-immune-and-inflammatory-14ps2p1xia.pdf

The role of histamine H4 receptor in immune and inflammatory disorders

Neuronal histamine and cognitive symptoms in Alzheimer's disease

The aim of this study is to compare the expression level of histamine H4 receptor (H4R) mRNA in synovial tissues of rheumatoid arthritis (RA) and osteoarthritis (OA) patients, and to study correlation of results with clinical characteristics of patients with RA. Synovial tissues were obtained from 7 RA and 7 OA patients undergoing artificial arthroplasty. Serum levels of erythrocyte sedimentation rate, C-reactive protein, matrix metalloproteinase-3 (MMP-3), rheumatoid factors, and cyclic citrullinated peptide antibodies were determined. The expression of H4R mRNA in synovial tissues was determined by real-time polymerase chain reaction. Expression of H1R and H4R mRNA were significantly lower in RA compared with OA patients (P < 0.005), while expression of H2R mRNA was comparable in both. While a significant negative correlation was found between H4R expression and serum MMP-3 concentration (r = −0.70, P < 0.05), no correlation was found between MMP-3 and H1R (r = −0.52) or H2R (r = 0.23). This study supports the supposition that H4R in synovial tissue may play a role in cartilage and bone destruction by influencing the secretion of MMP-3 in patients with RA.

Lower expression of histamine H4 receptor in synovial tissues from patients with rheumatoid arthritis compared to those with osteoarthritis

There is a need to develop bifunctional scaffolds that provide antibacterial protection while encouraging host cell attachment/proliferation. This study evaluates HyStem®-C, and photo-cross-linked GelMA hydrogels for encapsulation and stabilisation of silver nanoparticles (AgNPs). We studied the behaviour of AgNPs and matrix interactions within both hydrogel systems. The cell viability of encapsulated human gingival fibroblasts (HGFs) was determined by Prestoblue® assay and live/dead staining. The release of AgNPs was monitored by inductively coupled plasma-mass spectroscopy. The antibacterial properties of the GelMA-AgNP constructs were determined using disc diffusion. Even distribution of AgNPs in GelMA induced a significant decrease in cell viability (p < 0.0001), whereas AgNP aggregates did not induce cytotoxicity in HyStem®-C. AgNPs doses ≥ 0.5 µg/mL in GelMA were significantly toxic to the HGFs (p < 0.0001). The release of AgNPs from GelMA after 48 h was 20% w/w for 0.1 µg/mL and 51% for 100 µg/mL of AgNPs. At ≥5 µg/mL, a significant intra-construct bactericidal effect was observed. The disc diffusion assay shows that GelMA-incorporated AgNPs were found to be effective against both Escherichia coli and Staphylococcus aureus at 50 and 100 µg/mL, respectively. Visible photo-cross-linked GelMA stably incorporated AgNPs to provide an antimicrobial regenerative construct for oral applications. 

/pdf/three-dimensional-evaluation-of-the-cytotoxicity-and-2cuzaw40.pdf

Three-Dimensional Evaluation of the Cytotoxicity and Antibacterial Properties of Alpha Lipoic Acid-Capped Silver Nanoparticle Constructs for Oral Applications

Co-crystallization of kojic acid (HKA) with silver(I), copper(II), zinc(II), or gallium(III) salts yielded three 1D coordination polymers and one 0D complex in which kojic acid was present as a neutral or anionic terminal or bridging ligand. All reactions were conducted mechanochemically via ball milling and manual grinding, or via slurry. All solids were fully characterized via single-crystal and/or powder X-ray diffraction. As kojic acid is a mild antimicrobial compound that is widely used in cosmetics, and the metal cations possess antibacterial properties, their combinations were tested for potential antibacterial applications. The minimal inhibition concentrations (MICs) and minimal biocidal concentrations (MBCs) for all compounds were measured against standard strains of the bacteria P. aeruginosa, S. aureus, and E. coli. All compounds exerted appreciable antimicrobial activity in the order of silver, zinc, copper, and gallium complexes.

/pdf/exploring-the-co-crystallization-of-kojic-acid-with-silver-i-2601mknz.pdf

Exploring the Co-Crystallization of Kojic Acid with Silver(I), Copper(II), Zinc(II), and Gallium(III) for Potential Antibacterial Applications

Background: The increase of multi-drug-resistant organisms has revived the use of silver as an alternative antibiotic-independent antimicrobial. Although silver's multimodal mechanism of action provides low risk for bacterial resistance, high local and uncontrolled concentrations have shown toxicity. This has resulted in efforts to develop novel silver formulations that are safer and more predictable in their application. Optimization of silver as an antimicrobial is crucial given the growing resistance profile against antibiotics. This article reviews formulations of silver used as antimicrobials, focusing on the mechanisms of action, potential for toxicity, and clinical applications. Methods: A search of four electronic databases (PubMed, Embase, MEDLINE, and Cochrane Library) was conducted for relevant studies up to January 2022. Searches were conducted for the following types of silver: ionic, nanoparticles, colloidal, silver nitrate, silver sulfadiazine, silver oxide, silver carboxylate, and AQUACEL® (ConvaTec, Berkshire, UK). Sources were compiled based on title and abstract and screened for inclusion based on relevance and study design. Results: A review of the antimicrobial activity and uses of ionic silver, silver nanoparticles, colloidal silver, silver nitrate, silver sulfadiazine, silver oxide, Aquacel, and silver carboxylate was conducted. The mechanisms of action, clinical uses, and potential for toxicity were studied, and general trends between earlier and more advanced formulations noted. Conclusions: Early forms of silver have more limited utility because of their uncontrolled release of silver ions and potential for systemic toxicity. Multiple new formulations show promise; however, there is a need for more prospective in vivo studies to validate the clinical potential of these formulations.

Silver as an Antibiotic-Independent Antimicrobial: Review of Current Formulations and Clinical Relevance.

The increasing prevalence of multi-drug resistant pathogens has led to a renewed focus on the use of silver as an antibiotic-independent antimicrobial. Unfortunately, the use of many silver formulations may be limited by an uncontrolled release of silver with the potential for significant cytotoxic effects. Silver carboxylate (AgCar) has emerged as an alternative formulation of silver with the potential to mitigate these concerns while still displaying significant bactericidal activity. This article reviews the efficacy of silver carboxylate formulations as a promising novel antibiotic-independent antimicrobial. This study was conducted through a search of five electronic databases (PubMed, Embase, MEDLINE, Cochrane Library, and Web of Science) for relevant studies up to September 2022. Searches were conducted for types of “silver carboxylate” formulations. Sources were compiled based on title and abstract and screened for inclusion based on relevance and study design. A review of the antimicrobial activity and cytotoxicity of silver carboxylate was compiled based on this search. Current body of data suggests that silver carboxylate shows promise as an emerging antibiotic-independent antimicrobial, with significant bactericidal effects while minimizing cytotoxicity. Silver carboxylate addresses several of the limitations of more primitive formulations, including controlled dosing and fewer negative effects on eukaryotic cell lines. These factors are concentration-dependent and largely rely on the vehicle system used to deliver it. Although several silver carboxylate-based formulations like titanium dioxide/polydimethylsiloxane (TiO2/PDMS) matrix-eluting AgCar have shown promising results in vitro, and could potentially be utilized independently or in conjunction with current and future antimicrobial therapies, there is a need for further in vivo studies to validate their overall safety and efficacy profile.

/pdf/silver-carboxylate-as-an-antibiotic-independent-2hagov4z.pdf

Silver Carboxylate as an Antibiotic-Independent Antimicrobial: A Review of Current Formulations, in vitro Efficacy, and Clinical Relevance

The H-4 histamine receptor is functionally expressed on neurons in the mammalian CNS

Background: Vancomycin-resistant Enterococcus faecalis and multi-drug-resistant (MDR) Acinetobacter baumannii are rising contributors to spinal fusion and fracture-associated infections (FAI), respectively. These MDR bacteria can form protective biofilms, complicating traditional antibiotic treatment. This study explores the effects of the antibiotic-independent antimicrobial silver carboxylate (AgCar)-doped coating on the adherence sand proliferation of these pathogens on orthopedic implant materials utilized in spinal fusion and orthopedic trauma fixation. Methods: Multi-drug-resistant Acinetobacter baumannii and vancomycin-resistant Enterococcus faecalis were inoculated on five common implant materials: cobalt chromium, titanium, titanium alloy, polyether ether ketone, and stainless steel. Dose response curves were generated to assess antimicrobial potency. Scanning electron microscopy and confocal laser scanning microscopy were utilized to characterize and quantify growth and adherence on each material. Results: The optimal AgCar concentration was a 95% titanium dioxide (TiO2)-5% polydimethylsiloxane (PDMS) matrix combined with 10 × silver carboxylate, which inhibited bacterial proliferation by 89.40% (p = 0.001) for MDR Acinetobacter baumannii and 84.02% (p = 0.001) for vancomycin-resistant Enterococcus faecalis compared with uncoated implants. A 95% TiO2-5% PDMS matrix combined with 10 × AgCar was equally effective at inhibiting bacterial proliferation across all implant materials for MDR Acinetobacter baumannii (p = 0.19) and vancomycin-resistant Enterococcus faecalis (p = 0.07). A 95% TiO2-5% PDMS matrix with 10 × AgCar is effective at decreasing bacterial adherence of both MDR Acinetobacter baumannii and vancomycin-resistant Enterococcus faecalis on implant materials. Conclusions: Application of this antibiotic-independent coating for surgery in which these implant materials might be used may prevent adherence, biofilm formation, spinal infections, and FAI by MDR Acinetobacter baumannii and vancomycin-resistant Enterococcus faecalis.

Silver Carboxylate-Eluting Titanium-Dioxide Polydimethylsiloxane Coating Inhibits Multi-Drug-Resistant Acinetobacterium baumannii and Vancomycin-Resistant Enterococcus faecalis Adherence and Proliferation on Orthopedic Trauma Fixation and Spinal Fusion Materials.

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Silver as an Antibiotic-Independent Antimicrobial: Review of Current Formulations and Clinical Relevance.

Silver Carboxylate as an Antibiotic-Independent Antimicrobial: A Review of Current Formulations, in vitro Efficacy, and Clinical Relevance

The H-4 histamine receptor is functionally expressed on neurons in the mammalian CNS

Silver Carboxylate-Eluting Titanium-Dioxide Polydimethylsiloxane Coating Inhibits Multi-Drug-Resistant Acinetobacterium baumannii and Vancomycin-Resistant Enterococcus faecalis Adherence and Proliferation on Orthopedic Trauma Fixation and Spinal Fusion Materials.