A New Application for Cenicriviroc, a Dual CCR2/CCR5 Antagonist, in the Treatment of Painful Diabetic Neuropathy in a Mouse Model.

The ligands of chemokine receptors 2 and 5 (CCR2 and CCR5, respectively) are associated with the pathomechanism of neuropathic pain development, but their role in painful diabetic neuropathy remains unclear. Therefore, the aim of our study was to examine the function of these factors in the hypersensitivity accompanying diabetes. Additionally, we analyzed the analgesic effect of cenicriviroc (CVC), a dual CCR2/CCR5 antagonist, and its influence on the effectiveness of morphine. An increasing number of experimental studies have shown that targeting more than one molecular target is advantageous compared with the coadministration of individual pharmacophores in terms of their analgesic effect. The advantage of using bifunctional compounds is that they gain simultaneous access to two receptors at the same dose, positively affecting their pharmacokinetics and pharmacodynamics and consequently leading to improved analgesia. Experiments were performed on male and female Swiss albino mice with a streptozotocin (STZ, 200 mg/kg, i.p.) model of diabetic neuropathy. We found that the blood glucose level increased, and the mechanical and thermal hypersensitivity developed on the 7th day after STZ administration. In male mice, we observed increased mRNA levels of Ccl2, Ccl5, and Ccl7, while in female mice, we observed additional increases in Ccl8 and Ccl12 levels. We have demonstrated for the first time that a single administration of cenicriviroc relieves pain to a similar extent in male and female mice. Moreover, repeated coadministration of cenicriviroc with morphine delays the development of opioid tolerance, while the best and longest-lasting analgesic effect is achieved by repeated administration of cenicriviroc alone, which reduces pain hypersensitivity in STZ-exposed mice, and unlike morphine, no tolerance to the analgesic effects of CVC is observed until Day 15 of treatment. Based on these results, we suggest that targeting CCR2 and CCR5 with CVC is a potent therapeutic option for novel pain treatments in diabetic neuropathy patients.

The Obstetrician's Role in Pregnant Women's Decision-Making Process Regarding Influenza and COVID-19 Vaccination.

Pregnant women are considered to be a population vulnerable to influenza and COVID-19 infections, and the latest guidelines consistently recommend that they receive influenza and COVID-19 vaccinations. A cross-sectional questionnaire-based study was conducted among pregnant women in Poland to determine which factors have the greatest impact on their decision to vaccinate against influenza and COVID-19. A total of 515 pregnant women participated in the study. Among them, 38.4% (n = 198) demonstrated a positive attitude toward influenza vaccination, and 64.3% (n = 331) demonstrated a positive attitude toward COVID-19 vaccination. Logistic regression analysis revealed that the strongest influence on positive attitudes toward COVID-19 vaccination is having it recommended by an obstetrician-gynecologist (OR = 2.439, p = 0.025). The obstetrician-gynecologist's recommendation to vaccinate against influenza also significantly influences the decision to vaccinate (OR = 5.323). The study results also show a strong correlation between the obstetrician-gynecologist as a source of information on influenza and vaccination and participants' positive attitudes toward vaccination (OR = 4.163). Obstetricians have a significant influence on pregnant women's decisions regarding vaccinations. Further recommendations to vaccinate and awareness-raising among obstetricians may be needed to increase the vaccination rate of pregnant women in Poland.

Synthetic Opals or Versatile Nanotools-A One-Step Synthesis of Uniform Spherical Silica Particles.

Synthetic opals, a composition of homogeneous silica spheres in the mesoscale size range, have attracted the attention of scientists due to their favorable chemical and physical properties. Their chemical inertness and stability, biocompatibility, homogeneity, elevated specific surface area, and ease of functionalization of their surfaces make them a versatile nanotool. In the present study, the Stöber process was used to investigate the effect of parameters, such as reagent concentration and synthesis temperature, on the resulting silica particle size and structure. The optimal conditions for successfully obtaining homogeneous particles in the mesoscale range with high reproducibility were investigated. Several synthesis procedures and their dependence on the reaction temperature were presented to allow the selection of the assumed diameter of silica spheres. The numerous samples obtained were examined for size, homogeneity, structure, and specific surface area. On the basis of specific surface area measurements and nuclear magnetic resonance studies, the internal hierarchical structure of the spherical silica was confirmed as consisting of a solid core and layers of secondary spheres covered by a solid shell. Structural studies (X-ray Spectroscopy, X-ray Absorption Near-Edge Structure, and nuclear magnetic resonance), together with infrared vibrational spectroscopy, showed no dependence of the structure of the obtained mesospheres on the concentration of reagents and the size of the obtained particles.

Targeting Members of the Chemokine Family as a Novel Approach to Treating Neuropathic Pain.

Neuropathic pain is a debilitating condition that affects millions of people worldwide. Numerous studies indicate that this type of pain is a chronic condition with a complex mechanism that tends to worsen over time, leading to a significant deterioration in patients' quality of life and issues like depression, disability, and disturbed sleep. Presently used analgesics are not effective enough in neuropathy treatment and may cause many side effects due to the high doses needed. In recent years, many researchers have pointed to the important role of chemokines not only in the development and maintenance of neuropathy but also in the effectiveness of analgesic drugs. Currently, approximately 50 chemokines are known to act through 20 different seven-transmembrane G-protein-coupled receptors located on the surface of neuronal, glial, and immune cells. Data from recent years clearly indicate that more chemokines than initially thought (CCL1/2/3/5/7/8/9/11, CXCL3/9/10/12/13/14/17; XCL1, CX3CL1) have pronociceptive properties; therefore, blocking their action by using neutralizing antibodies, inhibiting their synthesis, or blocking their receptors brings neuropathic pain relief. Several of them (CCL1/2/3/7/9/XCL1) have been shown to be able to reduce opioid drug effectiveness in neuropathy, and neutralizing antibodies against them can restore morphine and/or buprenorphine analgesia. The latest research provides irrefutable evidence that chemokine receptors are promising targets for pharmacotherapy; chemokine receptor antagonists can relieve pain of different etiologies, and most of them are able to enhance opioid analgesia, for example, the blockade of CCR1 (J113863), CCR2 (RS504393), CCR3 (SB328437), CCR4 (C021), CCR5 (maraviroc/AZD5672/TAK-220), CXCR2 (NVPCXCR220/SB225002), CXCR3 (NBI-74330/AMG487), CXCR4 (AMD3100/AMD3465), and XCR1 (vMIP-II). Recent research has shown that multitarget antagonists of chemokine receptors, such as CCR2/5 (cenicriviroc), CXCR1/2 (reparixin), and CCR2/CCR5/CCR8 (RAP-103), are also very effective painkillers. A multidirectional strategy based on the modulation of neuronal-glial-immune interactions by changing the activity of the chemokine family can significantly improve the quality of life of patients suffering from neuropathic pain. However, members of the chemokine family are still underestimated pharmacological targets for pain treatment. In this article, we review the literature and provide new insights into the role of chemokines and their receptors in neuropathic pain.

Mirogabalin Decreases Pain-like Behaviors by Inhibiting the Microglial/Macrophage Activation, p38MAPK Signaling, and Pronociceptive CCL2 and CCL5 Release in a Mouse Model of Neuropathic Pain.

Neuropathic pain is a chronic condition that significantly reduces the quality of life of many patients as a result of ineffective pain relief therapy. For that reason, looking for new analgesics remains an important issue. Mirogabalin is a new gabapentinoid that is a specific ligand for the α2σ-1 and α2σ-2 subunits of voltage-gated calcium channels. In the present study, we compared the analgesic effect of pregabalin and mirogabalin in a neuropathic pain chronic constriction injury (CCI) of the sciatic nerve in a mouse model. The main purpose of our study was to determine the effectiveness of mirogabalin administered both once and repeatedly and to explain how the drug influences highly activated cells at the spinal cord level in neuropathy. We also sought to understand whether mirogabalin modulates the selected intracellular pathways (p38MAPK, ERK, JNK) and chemokines (CCL2, CCL5) important for nociceptive transmission, which is crucial information from a clinical perspective. First, our study provides evidence that a single mirogabalin administration diminishes tactile hypersensitivity more effectively than pregabalin. Second, research shows that several indirect mechanisms may be responsible for the beneficial analgesic effect of mirogabalin. This study reports that repeated intraperitoneally (i.p.) mirogabalin administration strongly prevents spinal microglia/macrophage activation evoked by nerve injury, slightly suppresses astroglia and neutrophil infiltration, and reduces the p38MAPK levels associated with neuropathic pain, as measured on Day 7. Moreover, mirogabalin strongly diminished the levels of the pronociceptive chemokines CCL2 and CCL5. Our results indicate that mirogabalin may represent a new strategy for the effective pharmacotherapy of neuropathic pain.

Hypoxia-Inducible Factor-1α (HIF-1α) as a Biomarker for Changes in Microcirculation in Individuals with Systemic Sclerosis.

INTRODUCTION: Systemic sclerosis is an autoimmune disease characterized by tissue fibrosis and microangiopathy. Vascular changes such as a decrease in capillary density diminish blood flow and impair tissue oxygenation. Reliable ways to monitor disease activity and predict disease progression are desired in the process of patient selection for clinical trials and to optimize individual patient outcomes. Hypoxia-inducible factor-1 (HIF-1) is a dimeric protein complex that plays an integral role in the body's response to hypoxia. Our study aimed to investigate the potential abnormalities of HIF-1α plasma concentration and its possible association with disease activity and vascular abnormalities in patients with systemic sclerosis. METHODS: Blood plasma levels of HIF-1α were measured in patients with systemic sclerosis (n = 50) and in healthy individuals (n = 30) using commercially available ELISA test kits. RESULTS: The results showed a marked increase in HIF-1α levels in patients with systemic sclerosis (3.042 ng/ml [2.295-7.749]) compared to the control group (1.969 ng/ml [1.531-2.903] p < 0.01). Patients with diffuse cutaneous SSc (2.803 ng/ml, IQR 2.221-8.799) and limited cutaneous SSc (3.231 ng/ml, IQR 2.566-5.502) exhibited elevated serum HIF-1α levels compared to the control group (p < 0.01). We found a notable increase in HIF-1α plasma concentration in patients with an "active" pattern (6.625 ng/ml, IQR 2.488-11.480) compared to those with either an "early" pattern (2.739, IQR 2.165-3.282, p < 0.05) or a "late" pattern (2.983 ng/ml, IQR 2.229-3.386, p < 0.05). Patients with no history of digital ulcers had significantly higher levels of HIF-1α (4.367 ng/ml, IQR 2.488-9.462) compared to patients with either active digital ulcers (2.832 ng/ml, IQR 2.630-3.094, p < 0.05) or healed digital ulcers (2.668 ng/ml, IQR 2.074-2.983, p < 0.05). CONCLUSIONS: Our results indicate that HIF-1α may serve as a biomarker in assessing microcirculatory changes in individuals with systemic sclerosis.

Phenytoin Decreases Pain-like Behaviors and Improves Opioid Analgesia in a Rat Model of Neuropathic Pain.

Neuropathic pain remains a clinical challenge due to its complex and not yet fully understood pathomechanism, which result in limited analgesic effectiveness of the management offered, particularly for patients with acute, refractory neuropathic pain states. In addition to the introduction of several modern therapeutic approaches, such as neuromodulation or novel anti-neuropathic drugs, significant efforts have been made in the repurposing of well-known substances such as phenytoin. Although its main mechanism of action occurs at sodium channels in excitable and non-excitable cells and is well documented, how the drug affects the disturbed neuropathic interactions at the spinal cord level and how it influences morphine-induced analgesia have not been clarified, both being crucial from a clinical perspective. We demonstrated that single and repeated systemic administrations of phenytoin decreased tactile and thermal hypersensitivity in an animal model of neuropathic pain. Importantly, we observed an increase in the antinociceptive effect on thermal stimuli with repeated administrations of phenytoin. This is the first study to report that phenytoin improves morphine-induced antinociceptive effects and influences microglia/macrophage activity at the spinal cord and dorsal root ganglion levels in a neuropathic pain model. Our findings support the hypothesis that phenytoin may represent an effective strategy for neuropathic pain management in clinical practice, particularly when combination with opioids is needed.

Analgesic Effects of Fisetin, Peimine, Astaxanthin, Artemisinin, Bardoxolone Methyl and 740 Y-P and Their Influence on Opioid Analgesia in a Mouse Model of Neuropathic Pain.

Treatment of neuropathic pain remains a challenge for modern medicine due to the insufficiently understood molecular mechanisms of its development and maintenance. One of the most important cascades that modulate the nociceptive response is the family of mitogen-activated protein (MAP) kinases and phosphatidylinositol-3-kinase (PI3K), as well as nuclear factor erythroid 2-related factor 2 (Nrf2). The aim of this study was to determine the effect of nonselective modulators of MAP kinases-fisetin (ERK1/2 and NFκB inhibitor, PI3K activator), peimine (MAPK inhibitor), astaxanthin (MAPK inhibitor, Nrf2 activator) and artemisinin (MAPK inhibitor, NFκB activator), as well as bardoxolone methyl (selective activator of Nrf2) and 740 Y-P (selective activator of PI3K)-in mice with peripheral neuropathy and to compare their antinociceptive potency and examine their effect on analgesia induced by opioids. The study was performed using albino Swiss male mice that were exposed to chronic constriction injury of the sciatic nerve (CCI model). Tactile and thermal hypersensitivity was measured using von Frey and cold plate tests, respectively. Single doses of substances were administered intrathecally on day 7 after CCI. Among the tested substances, fisetin, peimine, and astaxanthin effectively diminished tactile and thermal hypersensitivity in mice after CCI, while artemisinin did not exhibit analgesic potency in this model of neuropathic pain. Additionally, both of the activators tested, bardoxolone methyl and 740 Y-P, also showed analgesic effects after intrathecal administration in mice exposed to CCI. In the case of astaxanthin and bardoxolone methyl, an increase in analgesia after combined administration with morphine, buprenorphine, and/or oxycodone was observed. Fisetin and peimine induced a similar effect on tactile hypersensitivity, where analgesia was enhanced after administration of morphine or oxycodone. In the case of 740 Y-P, the effects of combined administration with each opioid were observed only in the case of thermal hypersensitivity. The results of our research clearly indicate that substances that inhibit all three MAPKs provide pain relief and improve opioid effectiveness, especially if they additionally block NF-κB, such as peimine, inhibit NF-κB and activate PI3K, such as fisetin, or activate Nrf2, such as astaxanthin. In light of our research, Nrf2 activation appears to be particularly beneficial. The abovementioned substances bring promising results, and further research on them will broaden our knowledge regarding the mechanisms of neuropathy and perhaps contribute to the development of more effective therapy in the future.

Pharmacological Modulation of the MIP-1 Family and Their Receptors Reduces Neuropathic Pain Symptoms and Influences Morphine Analgesia: Evidence from a Mouse Model.

Neuropathic pain pathophysiology is not fully understood, but it was recently shown that MIP-1 family members (CCL3, CCL4, and CCL9) have strong pronociceptive properties. Our goal was to examine how pharmacological modulation of these chemokines and their receptors (CCR1 and CCR5) influence hypersensitivity after nerve injury in Albino Swiss male mice. The spinal changes in the mRNA/protein levels of the abovementioned chemokines and their receptors were measured using RT-qPCR and ELISA/Western blot techniques in a mouse model of chronic constriction injury of the sciatic nerve. Behavioral studies were performed using the von Frey and cold plate tests after pharmacological treatment with neutralizing antibodies (nAbs) against chemokines or antagonists (CCR1-J113863, CCR5-TAK-220/AZD-5672) alone and in coadministration with morphine on Day 7, when the hypersensitivity was fully developed. Our results showed enhanced protein levels of CCL3 and CCL9 1 and 7 days after nerve injury. The single intrathecal administration of CCL3 or CCL9 nAb, J113863, TAK-220, or AZD-5672 diminished neuropathic pain symptoms and enhanced morphine analgesia. These findings highlight the important roles of CCL3 and CCL9 in neuropathic pain and additionally indicate that these chemokines play essential roles in opioid analgesia. The obtained results suggest CCR1 and CCR5 as new, interesting targets in neuropathy treatment.

The Pathogen Isolates in Chronic Wound Infections in Poland.

Chronic wound infection is one of the factors that hinder or prevent its healing. The incidence of infection may vary depending on the type of wound. It is estimated that clinically significant infection in diabetic foot syndrome occurs in up to 30% of patients. Accurate diagnosis of infection features and proper microbiological tests are crucial for introducing of appropriate local and often systemic treatment. The aim of the study was a comparative analysis of the microbiota found in infected chronic wounds in patients from Poland, consulted on an outpatient basis at a wound care center in 2013-2021. The indication for microbiology culture tests was the detection of local signs of infection, and sampling was preceded by appropriate wound debridement. The standard culture technique was a deep-tissue biopsy. Material for the study was collected from 1,199 patients. Overall, 3,917 results of microbiological tests were subjected to retrospective analysis. The paper presents the results in the form of the number of cultured microorganisms and their relative incidence as percentages, considering the division into the types of wounds from which the material was obtained. The most frequently isolated microorganisms in the analyzed group were Staphylococcus aureus (14.3% of this group were MRSA - methicillin-resistant Staphylococcus aureus) and Enterococcus faecalis (2.4% of this group were VRE - vancomycin-resistant Enterococcus). Further analysis of such an extensive database, especially regarding drug susceptibility of isolated microorganisms, seems crucial to elaborate new recommendations for empirical antibacterial treatment of infected chronic wounds.

Effect of pharmacological modulation of the kynurenine pathway on pain-related behavior and opioid analgesia in a mouse model of neuropathic pain.

Dysfunction of the central nervous system are accompanied by changes in tryptophan metabolism, with the kynurenine pathway (KP) being the main route of its catabolism. Recently, KP metabolites, which are collectively called kynurenines, have become an area of intense research due to their ability to directly and indirectly affect a variety of classic neurotransmitter systems. However, the significance of KP in neuropathic pain is still poorly understood. Therefore, we designed several experiments to verify changes in the mRNA levels of KP enzymes in parallel with other factors related to this metabolic route after chronic constriction injury of the sciatic nerve (CCI model) in mice. The analysis revealed an increase in, Kmo, Kynu and Haoo mRNA levels in the spinal cord on the 7th day after CCI, while Kat1, Kat2, Tdo2, Ido2 and Qprt mRNA levels remain unchanged. Subsequent pharmacological studies provided evidence that modulation of KP by single intrathecal administration of 1-D-MT, UPF468 or L-kynurenine attenuates mechanical and thermal hypersensitivity and increases the effectiveness of selected opioids in mice as measured on day 7 after CCI. Moreover, our results provide the first evidence that the injection of L-kynurenine preceded by UPF468 (KMO inhibitor) is more effective at reducing hypersensitivity in animals with neuropathic pain. Importantly, L-kynurenine also exerts an analgesic effect after intravenous injections, which is enhanced by the administration of minocycline, an inhibitor of microglial activation. Additionally, L-kynurenine administered intrathecally and intravenously enhances analgesia evoked by all tested opioids (morphine, buprenorphine and oxycodone). Overall, our results indicate that the modulation of KP at different levels might be a new pharmacological tool in neuropathy management.

Promising anticonvulsant and/or analgesic compounds among 5-chloro-2- or 5-chloro-4-methyl derivatives of xanthone coupled to aminoalkanol moieties-Design, synthesis and pharmacological evaluation.

A series of 10 aminoalkanol derivatives of 5-chloro-2- or 5-chloro-4-methylxanthone was synthetized and evaluated for anticonvulsant properties (MES test, mice, intraperitoneal) and compared with neurotoxicity rotarod test (NT, mice, i.p.). The best results both in terms of anticonvulsant activity and protective index value were obtained for 3: 5-chloro-2-([4-hydroxypiperidin-1-yl]methyl)-9H-xanthen-9-one hydrochloride. Compounds: 1-3, 7 and 10 revealed ED50 values in MES test: 42.78, 31.64, 25.76, 46.19 and 52.50 mg/kg b.w., respectively. 3 showed 70% and 72% of inhibition control specific binding of sigma-1 (σ1) and sigma-2 (σ2) receptor, respectively. 3 exhibited also antinociceptive activity at dose 2 mg/kg b.w. after chronic constriction injury in mice. 1, 3, 7 and 10 were evaluated on gastrointestinal flora and proved safe. In genotoxicity test (UMU-Chromotest) compounds 1, 7 and 10 proved safe at dose 150-300 µg/ml. The pharmacokinetic analysis showed rapid absorption of all studied molecules from the digestive tract (tmax  = 5-30 min). The bioavailability of the compounds ranged from 6.6% (1) to 16% (10). All studied compounds penetrate the blood-brain barrier with brain to plasma ratios varied from 4.15 (3) to 7.6 (compound 7), after i.v. administration, and from 1 (7) to 5.72 (3) after i.g. administration.

CC Chemokine Receptor 4 (CCR4) as a Possible New Target for Therapy.

Chemokines and their receptors participate in many biological processes, including the modulation of neuroimmune interactions. Approximately fifty chemokines are distinguished in humans, which are classified into four subfamilies based on the N-terminal conserved cysteine motifs: CXC, CC, C, and CX3C. Chemokines activate specific receptors localized on the surface of various immune and nervous cells. Approximately twenty chemokine receptors have been identified, and each of these receptors is a seven-transmembrane G-protein coupled receptor. Recent studies provide new evidence that CC chemokine receptor 4 (CCR4) is important in the pathogenesis of many diseases, such as diabetes, multiple sclerosis, asthma, dermatitis, and cancer. This review briefly characterizes CCR4 and its ligands (CCL17, CCL22, and CCL2), and their contributions to immunological and neoplastic diseases. The review notes a significant role of CCR4 in nociceptive transmission, especially in painful neuropathy, which accompanies many diseases. The pharmacological blockade of CCR4 seems beneficial because of its pain-relieving effects and its influence on opioid efficacy. The possibilities of using the CCL2/CCL17/CCL22/CCR4 axis as a target in new therapies for many diseases are also discussed.

The Etiology of Community-Acquired Pneumonia Correlates with Serum Inflammatory Markers in Children.

Community-acquired pneumonia (CAP) severely affects pediatric hospitalizations. This study assessed the contribution of CAP to hospitalizations, its etiology in relationship with age, and the inflammatory markers. Between 2013 and 2018, 1064 CAP patients were hospitalized and diagnosed with bacterial/possibly bacterial pneumonia (BP), viral/possibly viral pneumonia (VP) and atypical pneumonia (AP). The etiology was confirmed using blood/pleural fluid culture/polymerase chain reaction (PCR), rapid antigen test/PCR in nasopharyngeal swabs, or serological studies. CAP accounted for 9.9% of hospitalizations and 14.8% of patient days. BP was diagnosed in 825 (77.5%), VP in 190 (17.9%), and AP in 49 (4.6%) cases; the confirmed etiology (n = 209; 20%) included mostly influenza (39%; n = 82), respiratory syncytial virus (RSV, 35%; n = 72), and Mycoplasma pneumoniae (19%; n = 39). VP frequency decreased with age (41% in < 3 mo to 9% in ≥ 60 mo), in contrast to AP (13% in ≥ 60 mo). Among the analyzed parameters, the best differentiating potential was shown by: C-reactive protein (CRP, AUCBP-VP = 0.675; 95% CI: 0.634−0.715), procalcitonin (AUCBP-AP = 0.73; 95% CI: 0.67−0.794), and CRP/procalcitonin (AUCAP-VP = 0.752; 95% CI: 0.67−0.83); a good positive predictive value (88.8%, 98.3%, and 91.6%, respectively) but a low negative predictive value (29.5%, 13.1%, and 40.7%, respectively) was observed. CAP influences hospital patient days more than the crude number of patients would suggest. On a clinical basis, BP is mainly recognized, although viral pneumonia is confirmed most often. RSV and influenza are responsible for a huge percentage of hospitalized cases, as well as M. pneumoniae in children aged ≥ 5 years. Serum inflammatory markers may help differentiate etiological factors.

Pregnant Women's Knowledge of and Attitudes towards Influenza Vaccination during the COVID-19 Pandemic in Poland.

Pregnant women are more susceptible to influenza virus infections due to the immunological and physiological changes in the course of pregnancy. Vaccination during pregnancy is a safe and effective method for protecting both the mothers and the infants from influenza and its complications. This study was conducted in order to determine the knowledge and attitudes of Polish pregnant women towards influenza vaccination during the COVID-19 pandemic. A questionnaire-based and self-administered study was carried out fully online and a total of 515 women participated. A total of 52% (n = 268) of surveyed women answered that vaccination against influenza during pregnancy was safe. However, only 21% (n = 108) were vaccinated against influenza during their current pregnancy and 17.5% (n = 90) intended to be vaccinated. The participants indicated many concerns about getting vaccinated during pregnancy, but also many benefits that come with the vaccination. General knowledge about influenza, its complications, and vaccination was quite high in the study group.

Future Treatment Options in Systemic Sclerosis-Potential Targets and Ongoing Clinical Trials.

Systemic sclerosis is an autoimmune connective tissue disease characterized by vasculopathy and fibrosis of the skin and internal organs. The pathogenesis of systemic sclerosis is very complex. Mediators produced by immune cells are involved in the inflammatory processes occurring in the tissues. The currently available therapeutic options are often insufficient to halt disease progress. This article presents an overview of potential therapeutic targets and the pipeline of possible future therapeutic options. It is based on research of clinical trials involving novel, unestablished methods of treatment. Increasing knowledge of the processes and mediators involved in systemic scleroderma has led to the initiation of drug trials with therapeutic targets of CD28-CD80/86, CD19, CCL24, CD20, CD30, tumor necrosis factor (TNF), transforming growth factor ß (TGF-ß), B-cell activating factor (BAFF), lysophosphatidic acid receptor 1 (LPA1 receptor), soluble guanylate cyclase (sGC), Janus kinases (JAK), interleukin 6 (IL-6), endothelin receptor, and autotaxin. Data from clinical trials on these drugs indicate a significant potential for several new therapeutic options for systemic sclerosis in the upcoming future.

Mirogabalin Decreases Pain-like Behaviours and Improves Opioid and Ketamine Antinociception in a Mouse Model of Neuropathic Pain.

Neuropathic pain remains a difficult clinical challenge due to its diverse aetiology and complex pathomechanisms, which are yet to be fully understood. Despite the variety of available therapies, many patients suffer from ineffective pain relief; hence, the search for more efficacious treatments continues. The new gabapentinoid, mirogabalin has recently been approved for clinical use. Although its main mechanism of action occurs at the α2σ-1 and α2σ-2 subunits of calcium channels and is well documented, how the drug affects the disturbed neuropathic interactions at the spinal cord level has not been clarified, which is crucial information from a clinical perspective. The findings of our study suggest that several indirect mechanisms may be responsible for the beneficial analgesic effect of mirogabalin. This is the first study to report that mirogabalin enhances the mRNA expression of spinal antinociceptive factors, such as IL-10 and IL-18BP, and reduces the concentration of the pronociceptive substance P. Importantly, mirogabalin improves the morphine-, buprenorphine-, oxycodone-, and ketamine-induced antinociceptive effects in a neuropathic pain model. Our findings support the hypothesis that enhancing opioid and ketamine analgesia by combining these drugs with mirogabalin may represent a new strategy for the effective pharmacotherapy of neuropathic pain.

The impact of COVID-19 pandemic on reproductive intentions among the Polish population.

OBJECTIVES: The study was conducted in order to determine the impact of the COVID-19 pandemic on the fertility intentions among the Polish population. MATERIAL AND METHODS: A cross-sectional, questionnaire-based online study was carried out among Polish adults in order to determine the impact of the COVID-19 pandemic on the reproductive plans of the Polish society. A total of 984 participants correctly completed the survey. RESULTS: The pandemic has affected the reproductive intentions of 22% (n = 216) of the respondents, most of them want to have a child later than they previously planned (74.1%). The relationship between the change in reproductive intentions and the concerns about the pandemic was found. Most of those who changed their plans were afraid that the access to prenatal care and delivery services could be limited (86.6%) or were afraid about giving birth at the hospital (81%). More than half (51.9%) of those who changed reproductive plans were afraid of losing their income and 40.3% had already experienced a decrease in their income. The change in partner's emotional relationships was also observed. More than half of respondents (56.7%) admitted that during the pandemic they had developed a deeper emotional relationship with their partners or felt more emotionally supported (56.6%). Most participants responded that the frequency of their sexual intercourses was not affected (66.7%) and that they had not experienced limited access to contraceptives (95.1%) during the pandemic. CONCLUSIONS: The COVID-19 pandemic has affected Polish people's reproductive intentions. Concerns related to healthcare access and the economic difficulties have the most significant impact.

New insights into the analgesic properties of the XCL1/XCR1 and XCL1/ITGA9 axes modulation under neuropathic pain conditions - evidence from animal studies.

Recent studies have indicated the involvement of chemokine-C-motif ligand 1 (XCL1) in nociceptive transmission; however, the participation of its two receptors, canonical chemokine-C-motif receptor 1 (XCR1) and integrin alpha-9 (ITGA9), recently recognized as a second receptor, has not been clarified to date. The aim was to explore by which of these receptors XCL1 reveals its pronociceptive properties and how the XCL1-XCR1 and XCL1-ITGA9 axes blockade/neutralization influence on pain-related behavior and opioid analgesia in the model of neuropathic pain. In our studies we used Albino Swiss mice which were exposed to the unilateral sciatic nerve chronic constriction injury (CCI) as a neuropathic pain model. Animals received single intrathecal (i.t.) injection of XCL1, XCL1 neutralizing antibodies, antagonist of XCR1 (vMIP-II) and neutralizing antibodies of ITGA9 (YA4), using lumbar puncture technique. Additionally we performed i.t. co-administration of abovementioned neutralizing antibodies and antagonists with single dose of morphine/buprenorphine. To assess pain-related behavior the von Frey and cold plate tests were used. To measure mRNA and protein level the RT-qPCR and Western Blot/Elisa/immunofluorescence techniques were performed, respectively. Statistical analysis was conducted using ANOVA with a Bonferroni correction. Presented studies have shown time-dependent upregulation of the mRNA and/or protein expression of XCL1 in the spinal cord after nerve injury as measured on day 1, 4, 7, 14, and 35. Our immunofluorescence study showed that XCL1 is released by astroglial cells located in the spinal cord, despite the neural localization of its receptors. Our results also provided the first evidence that the blockade/neutralization of both receptors, XCR1 and ITGA9, reversed hypersensitivity after intrathecal XCL1 administration in naive mice; however, neutralization of ITGA9 was more effective. In addition, the results proved that the XCL1 neutralizing antibody and, similarly, the blockade of XCR1 and neutralization of ITGA9 diminished thermal and mechanical hypersensitivity in nerve injury-exposed mice after 7 days. Additionally, neutralization of XCL1 improves morphine analgesia. Moreover, blockade of XCR1 positively influences buprenorphine effectiveness, and neutralization of ITGA9 enhances not only buprenorphine but also morphine analgesia. Therefore, blockade of the XCL1-ITGA9 interaction may serve as an innovative strategy for the polypharmacotherapy of neuropathic pain in combination with opioids.

Pharmacological Evidence of the Important Roles of CCR1 and CCR3 and Their Endogenous Ligands CCL2/7/8 in Hypersensitivity Based on a Murine Model of Neuropathic Pain.

Neuropathic pain treatment remains a challenging issue because the therapies currently used in the clinic are not sufficiently effective. Moreover, the mechanism of neuropathy is still not entirely understood; however, much evidence indicates that chemokines are important factors in the initial and late phases of neuropathic pain. To date, the roles of CCR1, CCR3 and their endogenous ligands have not been extensively studied; therefore, they have become the subject of our research. In the present comprehensive behavioral and biochemical study, we detected significant time-dependent and long-lasting increases in the mRNA levels of CCR1 and/or CCR3 ligands, such as CCL2/3/4/5/6/7/8/9, in the murine spinal cord after chronic constriction injury of the sciatic nerve, and these increases were accompanied by changes in the levels of microglial/macrophage, astrocyte and neutrophil cell markers. ELISA results suggested that endogenous ligands of CCR1 and CCR3 are involved in the development (CCL2/3/5/7/8/9) and persistence (CCL2/7/8) of neuropathic pain. Moreover, intrathecal injection of CCL2/3/5/7/8/9 confirmed their possible strong influence on mechanical and thermal hypersensitivity development. Importantly, inhibition of CCL2/7/8 production and CCR1 and CCR3 blockade by selective/dual antagonists effectively reduced neuropathic pain-like behavior. The obtained data suggest that CCL2/7/8/CCR1 and CCL7/8/CCR3 signaling are important in the modulation of neuropathic pain in mice and that these chemokines and their receptors may be interesting targets for future investigations.