Phytocannabinoids: Chromatographic Screening of Cannabinoids and Loading into Lipid Nanoparticles.

Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC) are receiving increasing interest as an approach to encapsulate natural extracts to increase the physicochemical stability of bioactives. Cannabis extract-derived cannabidiol (CBD) has potent therapeutic properties, including anti-inflammatory, antioxidant, and neuroprotective properties. In this work, physicochemical characterization was carried out after producing Compritol-based nanoparticles (cSLN or cNLC) loaded with CBD. Then, the determination of the encapsulation efficiency (EE), loading capacity (LC), particle size (Z-Ave), polydispersity index (PDI), and zeta potential were performed. Additionally, the viscoelastic profiles and differential scanning calorimetry (DSC) patterns were recorded. As a result, CBD-loaded SLN showed a mean particle size of 217.2 ± 6.5 nm, PDI of 0.273 ± 0.023, and EE of about 74%, while CBD-loaded NLC showed Z-Ave of 158.3 ± 6.6 nm, PDI of 0.325 ± 0.016, and EE of about 70%. The rheological analysis showed that the loss modulus for both lipid nanoparticle formulations was higher than the storage modulus over the applied frequency range of 10 Hz, demonstrating that they are more elastic than viscous. The crystallinity profiles of both CBD-cSLN (90.41%) and CBD-cNLC (40.18%) were determined. It may justify the obtained encapsulation parameters while corroborating the liquid-like character demonstrated in the rheological analysis. Scanning electron microscopy (SEM) study confirmed the morphology and shape of the developed nanoparticles. The work has proven that the solid nature and morphology of cSLN/cNLC strengthen these particles' potential to modify the CBD delivery profile for several biomedical applications.

Obesity and the Brain.

Innate and adaptive immunity are essential for neurodevelopment and central nervous system (CNS) homeostasis; however, the fragile equilibrium between immune and brain cells can be disturbed by any immune dysregulation and cause detrimental effects. Accumulating evidence indicates that, despite the blood-brain barrier (BBB), overactivation of the immune system leads to brain vulnerability that increases the risk of neuropsychiatric disorders, particularly upon subsequent exposure later in life. Disruption of microglial function in later life can be triggered by various environmental and psychological factors, including obesity-driven chronic low-grade inflammation and gut dysbiosis. Increased visceral adiposity has been recognized as an important risk factor for multiple neuropsychiatric conditions. The review aims to present our current understanding of the topic.

Lipid-Based Nanoparticulate Systems for the Ocular Delivery of Bioactives with Anti-Inflammatory Properties.

The complexity of the eye structure and its physiology turned ocular drug administration into one of the most challenging topics in the pharmaceutical field. Ocular inflammation is one of the most common ophthalmic disorders. Topical administration of anti-inflammatory drugs is also commonly used as a side treatment in tissue repair and regeneration. The difficulty in overcoming the eye barriers, which are both physical and chemical, reduces drug bioavailability, and the frequency of administration must be increased to reach the therapeutic effect. However, this can cause serious side effects. Lipid nanoparticles seem to be a great alternative to ocular drug delivery as they are composed from natural excipients and can encapsulate both hydrophilic and lipophilic drugs of different sources, and their unique properties, as their excellent biocompatibility, safety and adhesion allow to increase the bioavailability, compliance and achieve a sustained drug release. They are also very stable, easy to produce and scale up, and can be lyophilized or sterilized with no significant alterations to the release profile and stability. Because of this, lipid nanoparticles show a great potential to be an essential part of the new therapeutic technologies in ophthalmology to deliver synthetic and natural anti-inflammatory drugs. In fact, there is an increasing interest in natural bioactives with anti-inflammatory activities, and the use of nanoparticles for their site-specific delivery. It is therefore expected that, in the near future, many more studies will promote the development of new nanomedicines resulting in clinical studies of new drugs formulations.

Exudative versus Nonexudative Age-Related Macular Degeneration: Physiopathology and Treatment Options.

Age-related macular degeneration (AMD) is an eye disease typically associated with the aging and can be classified into two types-namely, the exudative and the nonexudative AMD. Currently available treatments for exudative AMD use intravitreal injections, which are associated with high risk of infection that can lead to endophthalmitis, while no successful treatments yet exist for the nonexudative form of AMD. In addition to the pharmacologic therapies administered by intravitreal injection already approved by the Food and Drug Administration (FDA) in exudative AMD, there are some laser treatments approved that can be used in combination with the pharmacological therapies. In this review, we discuss the latest developments of treatment options for AMD. Relevant literature available from 1993 was used, which included original articles and reviews available in PubMed database and also information collected from Clinical Trials Gov website using "age-related macular degeneration" and "antiangiogenic therapies" as keywords. The clinical trials search was limited to ongoing trials from 2015 to date.

How could nanobiotechnology improve treatment outcomes of anti-TNF-α therapy in inflammatory bowel disease? Current knowledge, future directions.

Despite significant advances in therapeutic possibilities for the treatment of inflammatory bowel disease (IBD) in recent years, there is still a big room for improvement. In particular, biological treatment can induce not only clinical remission but also mucosal healing of the gastrointestinal tract. Among these therapeutic molecules, anti-tumor necrosis factor-alpha (anti-TNF-α) antibodies were the first to revolutionize treatment algorithms in IBD. However, due to the parenteral route of administration and systemic mode of action, TNF-α blockers are characterised by high rates of immunogenicity-related loss of response and serious adverse events. Moreover, intravenous or subcutaneous therapy is not considered patient-friendly and requires occasional, direct contact with healthcare centres. To overcome these limitations, several attempts have been made to design oral pharmaceutical formulations of these molecules. It is hypothesized that oral anti-TNF-α antibodies therapy can directly provide a targeted and potent anti-inflammatory effect in the inflamed gastrointestinal tissues without significant systemic exposure, improving long-term treatment outcomes and safety. In this review, we discuss the current knowledge and future perspectives regarding different approaches made towards entering a new era of oral anti-TNF-α therapy, namely, the tailoring of biocompatible nanoparticles with anti-TNF-α antibodies for site-specific targeting to IBD. In particular, we discuss the latest concepts applying the achievements of nanotechnology-based drug design in this area.

Obesity and the Risk of Gastrointestinal Cancers.

Obesity is a risk factor for all major gastrointestinal cancers. With the rapid increase in the prevalence of obesity worldwide, this link could lead to an elevated burden of cancers of the digestive system. Currently, three main mechanisms explaining the link between excess adiposity and gastrointestinal cancer risk are being considered, including altered insulin signaling, obesity-associated chronic low-grade inflammation, and altered sex hormone metabolism, although new potential mechanisms emerge. This review is aimed to present our current knowledge on biological mechanisms involved in adiposity-related gastrointestinal carcinogenesis supported by results collected in epidemiological studies.

C-reactive protein as a diagnostic and prognostic factor in inflammatory bowel diseases.

AIM: The study aimed to evaluate high-sensitivity CRP (hsCRP) as a diagnostic and predictive marker in patients with inflammatory bowel disease (IBD). MATERIAL/METHODS: Medical history of 106 patients with IBD revealed hsCRP concentrations at diagnosis and during the follow-up period. RESULTS: The study showed that the majority of investigated patients had elevated hsCRP concentrations at diagnosis, although the mean concentration was much higher in the group of patients with Crohn's disease (CD) than the group with ulcerative colitis (UC) (P<0.001). The overall decrease in mean hsCRP concentration observed during the follow-up period was larger in the group of CD patients. The analysis showed a correlation between hsCRP concentrations at diagnosis and risk of surgery in the group of CD patients (r=0.408, P=0.002), but not in the group of UC patients. In a logistic regression analysis, surgery in CD patients was associated with age (OR: 0.89, 95% CI: 0.8-1.0, P=0.05) and hsCRP concentration (OR: 1.02, 95% CI: 1.0-1.04, P=0.03) at diagnosis. DISCUSSION: HsCRP might be a useful diagnostic marker in differentiating active IBD from other diseases. Particularly important however seems to be the predictive value of hsCRP at diagnosis in prognosing the clinical outcome of the disease in CD patients.

The microbiome and dermatological diseases.

The human skin harbours hundreds of species of commensal organisms, collectively known as the skin microbiota. The composition of the microbiota can be modified by various factors, such as host genotype, diet, antibiotics, hygiene, and pathogen infections, among others. Changes in these factors can cause microbiome disruption known as dysbiosis, leading to the outgrowth of potential pathogenic bacteria or a decrease in the number of beneficial bacteria. Dysbiosis has been implicated in some dermatological diseases. This mini-review aims to discuss the topic of the skin microbiota and its potential effects on various skin diseases.

Health threat associated with Caucasian giant hogweeds: awareness among doctors and general public in Poland.

CONTEXT: The Caucasian giant hogweeds (Heracleum sosnowskyi and H. mantegazzianum) are aggressive invaders successfully spreading across different parts of Europe. Their sap containing linear furanocoumarins can lead to a persisting cutaneous dermatitis and massive skin necrosis. OBJECTIVE: We aimed to assess the awareness of the giant hogweeds' threat among physicians and general public in Poland. METHODS: The level of awareness was assessed using a short questionnaire given to different groups of physicians: dermatologists (DMs), general practitioners (GPs) and occupational practitioners (OPs). An independent questionnaire was also addressed to the general public. RESULTS: Among the surveyed physician groups, DMs were the best informed, while OPs were the worst informed on health threats associated with the giant hogweeds and treatment methods. Most frequently, application of topical corticosteroids was indicated as a successful method of treatment following the exposure to hogweeds. In the general public, awareness was relatively low with only 57.7% of the surveyed having ever heard about these plants. TV, press and Internet were among the most frequent sources of information in this regard. CONCLUSIONS: Public and medical attention needs to be raised as to the threats associated with giant hogweeds, particularly in countries that are highly infested with these plants.

Biosimilars in dermatology.

Over the last decade the availability of biological drugs for the treatment of psoriasis vulgaris, psoriatic arthritis and many other inflammatory diseases has revolutionized the treatment of these diseases around the world. Due to the high cost of therapy, the search has started for biosimilars. In dermatology the greatest interest in biosimilar medicines concerns inhibitors of tumor necrosis factor a (TNF-α), for use in the treatment of psoriasis vulgaris and psoriatic arthritis (infliximab, etanercept, adalimumab). The most important element of the safety of biologicals is their immunogenicity. Therefore, when discussing biosimilars, attention needs to be paid to the dangers of their immune activity. In view of the fact that the drugs contain and aggregates, produced by living organisms or cultures of living cells, they cannot be compared in any way to low molecular weight synthetic generics (called generics). Biosimilars are authorized for use in patients and treated as equivalent to the reference medicine only after passing a number of studies and assessments. As it is well known, the development of medicine and pharmacology is extremely intense, and the market in biological medicine is developing much faster than that of all other drugs, which underlines their important role in modern medicine. Currently, the subject of biosimilars is one of the most important challenges and topics of discussion around the world, including pharmacovigilance and legal and economic regulatory standards. It seems inevitable that biosimilar products will be introduced for the treatment of diseases with indications corresponding to the original product on which they are based.

Factors affecting response to biologic treatment in psoriasis.

Psoriasis is a chronic, immune-mediated inflammatory skin disease, affecting approximately 2-4% of the population in western countries. Patients with a more severe form of the disease are typically considered for systemic therapy, including biologics. In spite of the overall superiority of biologic agents, the treatment response may differ substantially among individual patients. As with other medical conditions, a range of factors contribute to response heterogeneity observed in psoriasis. Proper identification of these factors can significantly improve the therapeutic decisions. This review focuses on potential genetic and nongenetic factors that may affect the treatment response and outcomes in patients with psoriasis.

Increased apoptosis of regulatory T cells in Crohn's disease.

BACKGROUND/AIMS: Crohn's disease (CD) is characterized by a transmural often granulomatous Th1-driven inflammatory process hallmarked by an increased production of IL-12, TNF-alpha and IFN-gamma. Accumulating evidence suggests that the numerical defect within the regulatory T cell (Tregs) compartment might contribute to this imbalance between pro- and antiinflammatory factors. This study was aimed to investigate whether the numerical defect of Tregs observed in CD resulted from an increased apoptosis of these cells. METHODOLOGY: The cytometric analysis was performed to evaluate the percentage of CD4 + FOXP3 + Tregs in peripheral blood of 55 investigated subjects, as well as to estimate the rate of Treg apoptosis. RESULTS: The cytometric analysis showed a significantly lower percentage of Tregs in peripheral blood of CD patients compared with the healthy control group (P = 0.03) as well as an increased rate of apoptosis within this cell subpopulation (P = 0.000001). Interestingly, a significantly higher rate of Treg apoptosis was observed in female than male CD patients (P = 0.03). DISCUSSION: Current data suggest that CD is associated with a numerical deficiency of the Treg compartment. Presented study indicates that an increased apoptosis might contribute to this numerical deficiency. A higher rate of Tregs apoptosis found in female patients might suggest the involvement of hormonal factors and possibly contribute to the female predominance observed in CD as well as to the tendency of female patients to develop a more severe form of the disease.

[Role of Th17 lymphocytes in pathogenesis of colorectal cancer]. / Rola limfocytów Th17 w patogenezie raka jelita grubego.

Colorectal cancer (CRC) is estimated to be the first leading cause of death from cancer among men and women in the EU. Every year in Poland, 15,254 cases of CRC are diagnosed, and 10,501 patients die of the disease, making it the second leading cause of death from cancer. In more than 90% of cases, the disease begins as adenomatous polyps with epithelial dysplasia as a common feature. Inflammatory bowel diseases (IBD), a group of chronic inflammatory diseases of the gastrointestinal tract characterized by remissions and relapses, constitute an independent risk factor of CRC development. CRC developing in IBD patients, however, has features distinct from sporadic cancer, suggesting the influence of unique factors. The high risk of CRC in IBD patients probably results from chronic inflammation. In most cases, neoplastic lesions arise within the inflamed gastrointestinal mucosa during the process of re-epithelization, which is a healing response to ulceration. The recently discovered Th17 lymphocytes, which demonstrate strong pro-inflammatory capabilities, might link the two diseases. Th17 lymphocytes produce a number of pro-inflammatory cytokines, such as interleukin (IL)-17A, IL-17F, IL-21, IL-22 and tumor necrosis factor (TNF)-a, and play a key role in mucosal defense against various pathogens. Numerous observations suggest that Th17 lymphocytes are involved in pathogenesis of different autoimmune diseases and pathologic inflammatory states. Mounting evidence suggests that Th17 cells contribute to the pathogenesis of IBD and CRC. However, their precise role in both diseases is unknown.

Reactive oxygen species (ROS) production in human peripheral blood neutrophils exposed in vitro to static magnetic field.

The aim of this study was to determine the effect of gradient static magnetic field (SMF) on reactive oxygen species (ROS) production in human neutrophils in peripheral blood in vitro. Blood samples collected from healthy individuals were incubated in an inhomogeneous SMF (in a south or north pole of the field) for 15, 30 or 45 minutes. The maximum value of induction (B max) amounted to ≈ 60 mT. To determine the strength of the ROS production, dihydrorhodamine (123DHR) as fluorophore and phorbol 12-myristate 13-acetate (PMA) as respiratory burst stimulator were used. 123DHR oxidation by ROS was measured by flow cytometry. The exposure of blood samples to SMF induced statistically significant changes in ROS production in unstimulated and PMA-stimulated neutrophils. The observed effects were highly correlated with the exposure time and depended on the orientation of the field. Although intracellular mechanisms underlying such interactions are not thoroughly understood, it could be presumed that SMF affects ROS metabolic oscillations and their formation and inactivation. This study emphasizes the importance of proper adjustment of exposure time to SMF for any potential therapeutic applications.

Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial.

OBJECTIVE: The authors tested whether the anti-interleukin (IL)-17A monoclonal antibody secukinumab was safe and effective for the treatment of active Crohn's disease. DESIGN: In a double-blind, randomised, placebo-controlled proof-of-concept study, 59 patients with moderate to severe Crohn's disease (Crohn's Disease Activity Index (CDAI) ≥220 to ≤450) were assigned in a 2:1 ratio to 2×10 mg/kg intravenous secukinumab or placebo. The primary end point, addressed by bayesian statistics augmented with historical placebo information, was the probability that secukinumab reduces the CDAI by ≥50 points more than placebo at week 6. Ancillary analyses explored associations of 35 candidate genetic polymorphisms and faecal calprotectin response. RESULTS: 59 patients (39 secukinumab, 20 placebo, mean baseline CDAI 307 and 301, respectively) were recruited. 18/59 (31%) patients discontinued prematurely (12/39 (31%) secukinumab, 6/20 (30%) placebo), 10/59 (17%) due to insufficient therapeutic effect (8/39 (21%) secukinumab, 2/20 (10%) placebo). Fourteen serious adverse events occurred in 10 patients (seven secukinumab, three placebo); 20 infections, including four local fungal infections, were seen on secukinumab versus none on placebo. Primary end point analysis estimated <0.1% probability (CDAI (SD) =33.9 (19.7), 95% credible interval -4.9 to 72.9) that secukinumab reduces CDAI by ≥50 points more than placebo. Secondary area under the curve analysis (weeks 4-10) showed a significant difference (mean ΔCDAI=49; 95% CI (2 to 96), p=0.043) in favour of placebo. Post hoc subgroup analysis showed that unfavourable responses on secukinumab were driven by patients with elevated inflammatory markers (CRP≥10 mg/l and/or faecal calprotectin≥200 ng/ml; mean ΔCDAI=62; 95% CI (-1 to 125), p=0.054 in favour of placebo). Absence of the minor allele of tumour necrosis factor-like ligand 1A was strongly associated with lack of response measured by baseline-adjusted changes in calprotectin at week 6 (p=0.00035 Bonferroni-corrected). CONCLUSIONS: Blockade of IL-17A was ineffective and higher rates of adverse events were noted compared with placebo. CLINICAL TRIAL REGISTRATION: This trial was registered at ClinicalTrial.gov with the number NCT01009281.

Upper gastrointestinal bleeding as an unusual manifestation of localized Ménétrier's disease with an underlying lipoma: A case report.

BACKGROUND: Ménétrier's disease is a rare condition characterized by enlarged gastric folds, usually located in the whole body and fundus of the stomach. This report presents an unusual case of localized Ménétrier's disease elevated by a submucosal lipoma and thus looking like a polypoid mass and causing an episode of upper gastrointestinal bleeding. The mass was successfully removed with endoscopic submucosal dissection. CASE SUMMARY: Esophagogastroduodenoscopy was performed on a 76-year-old male patient after an episode of upper gastrointestinal bleeding, manifesting as fatigue and melena. A large polypoid mass (4 cm × 1 cm) with enlarged mucosal folds was found in the body of the stomach, between the lesser curvature and posterior wall. A small ulcer at the distal end of the mass was identified as the source of the bleeding. Biopsy was negative for neoplasia. Computed tomography showed a submucosal lesion beneath the affected mucosa, most likely a lipoma. The mass was removed en bloc with tunneling endoscopic submucosal dissection. Final pathology determined that the mass included Ménétrier's disease and a submucosal lipoma. The patient was scheduled for follow-up esophagogastroduodenoscopy. CONCLUSION: Localized Ménétrier's disease can coexist with a submucosal lipoma creating a polypoid mass with risk of bleeding.

Tocilizumab-coated solid lipid nanoparticles loaded with cannabidiol as a novel drug delivery strategy for treating COVID-19: A review.

Commonly used clinical strategies against coronavirus disease 19 (COVID-19), including the potential role of monoclonal antibodies for site-specific targeted drug delivery, are discussed here. Solid lipid nanoparticles (SLN) tailored with tocilizumab (TCZ) and loading cannabidiol (CBD) are proposed for the treatment of COVID-19 by oral route. TCZ, as a humanized IgG1 monoclonal antibody and an interleukin-6 (IL-6) receptor agonist, can attenuate cytokine storm in patients infected with SARS-CoV-2. CBD (an anti-inflammatory cannabinoid and TCZ agonist) alleviates anxiety, schizophrenia, and depression. CBD, obtained from Cannabis sativa L., is known to modulate gene expression and inflammation and also shows anti-cancer and anti-inflammatory properties. It has also been recognized to modulate angiotensin-converting enzyme II (ACE2) expression in SARS-CoV-2 target tissues. It has already been proven that immunosuppressive drugs targeting the IL-6 receptor may ameliorate lethal inflammatory responses in COVID-19 patients. TCZ, as an immunosuppressive drug, is mainly used to treat rheumatoid arthritis, although several attempts have been made to use it in the active hyperinflammatory phase of COVID-19, with promising outcomes. TCZ is currently administered intravenously. It this review, we discuss the potential advances on the use of SLN for oral administration of TCZ-tailored CBD-loaded SLN, as an innovative platform for managing SARS-CoV-2 and related infections.

Scaffolds for drug delivery and tissue engineering: The role of genetics.

Scaffolds are implants commonly used to deliver cells, drugs, and genes into the body. Their regular porous structure ensures the proper support for cell attachment, proliferation, differentiated function, and migration. Techniques to fabricate a scaffold include leaching, freeze-drying, supercritical fluid technology, thermally induced phase separation, rapid prototyping, powder compaction, sol-gel, and melt molding. Gene delivery from the scaffold represents a versatile approach to influence the environment for managing cell function. Scaffolds can be used for various tissue engineering purposes, e.g. bone formation, periodontal regeneration, cartilage development, artificial corneas, heart valves, tendon repair, or ligament replacement. Moreover, they are also instrumental in cancer therapy, inflammation, diabetes, heart disease, and wound dressings. Scaffolds provide a platform to extend the delivery of drugs and genetic materials at a controlled timeframe, besides potentially being used to prevent infection upon surgery and other chronic diseases, provided that they can be formulated with specific medicines. This review discusses the need to design advanced functional scaffolds with the potential for modified drug delivery and tissue engineering in a synergistic approach. Special attention is given to works published in 2023 to generate the bibliometric map.

Selected cytokine profiles during remission in bipolar patients.

OBJECTIVES: The aim of the study was to examine the cytokine status in bipolar patients during immediate remission after acute episodes of mania or depression and in patients with sustained (≥6 months) remission, compared with healthy controls. METHODS: The study was performed on 121 bipolar patients, of whom 35 were in immediate remission after mania, 41 were in immediate remission after depression, and 45 were in >6-month remission on lithium monotherapy or lithium combined with other drugs. The control group consisted of 78 healthy individuals without any history of psychiatric or immunological illnesses. Serum concentrations of IL-1ß, IL-2, IL-6, IL-10, TNF-α and IFN-γ were determined using the Human Th1/Th2 Cytometric Bead Array method. RESULTS: The concentration of IL-10 was higher in patients in remission after mania and the concentration of IFN-γ was higher in those in remission after depression than in healthy controls. On the other hand, cytokine concentrations in patients with sustained remission were not different from those of healthy subjects. CONCLUSIONS: The results obtained in this study show that sustained remission in bipolar patients achieved mostly by lithium maintenance brings the cytokine status to a level similar to healthy control subjects.

Non-melanoma skin cancers: physio-pathology and role of lipid delivery systems in new chemotherapeutic treatments.

Non-melanoma carcinoma has high incidence rates and has two most common subtypes: basal cell carcinoma and squamous cell carcinoma. This type of carcinoma is usually not fatal; however, it can destroy sensory organs such as the nose, ears, and lips. The treatment of these injuries using non-invasive methods is thus strongly recommended. Some treatments for non-melanoma carcinoma are already well defined, such as surgery, cryosurgery, curettage and electrode section, and radiotherapy; however, these conventional treatments cause inflammation and scarring. In the non-surgical treatment of non-melanoma carcinoma, the topical administration of chemotherapeutic drugs contributes for an effective treatment with reduced side effects. However, the penetration of anticancer drugs in the deeper layers of the skin is required. Lipid delivery systems (liposomes, solid lipid nanoparticles, nanostructured lipid carriers) have been developed to overcome epidermal barrier of the skin and to allow the drugs to reach tumor cells. These lipid nanoparticles contribute to control the release profile of the loaded chemotherapeutic drugs, maintaining their stability and increasing death of tumor cells. In this review, the characteristics of non-melanoma carcinoma will be discussed, describing the main existing treatments, together with the contribution of lipid delivery systems as an innovative approach to increase the effectiveness of topical therapies for non-melanoma carcinomas.