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Background: Available therapeutic options are currently limited by their modest efficacy. As a result, novel pharmacotherapeutic treatments with different mechanisms have recently attracted empirical attention. Magnesium, a divalent cation, is postulated to provide analgesic and anti-nociceptive effect through its action at the N-methyl-D-aspartate (NMDA) receptor. Objective: Considering the evidence surrounding magnesium's potential as a therapeutic modality for chronic pain, we conducted a narrative review on the evidence of magnesium's therapeutic effects in chronic pain. Methods: A review of the PubMed, and Google scholar databases was undertaken in May 2022 to identify completed studies that investigated the effectiveness of magnesium in the treatment of chronic pain from database inception to May 2022. Results: A total of 33 studies were included in the narrative review, out of which 26 were randomized controlled trials. Findings on available studies suggest that intravenous infusion of magnesium is an emerging and promising option that may alleviate pain in some clinical populations. Our narrative synthesis showed that evidence for intravenous magnesium is currently equivocal for a variety of chronic pain syndrome. Findings indicate that evidence for efficacy is poor or equivocal for: CRPS, neuropathic pain, chronic low back pain, and migraine prophylaxis. However, there is good evidence supporting the efficacy of intravenous magnesium for treating renal colic pain and pelvic pain related to endometriosis. Conclusion: Magnesium may be a promising pharmacologic solution for chronic pain. Future investigation is warranted on elucidating the neurobiological mechanisms of magnesium in attenuating pain signaling pathways.

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OBJECTIVE: To investigate the anticaries effects of graphene oxide (GO) and graphene quantum dots (GQDs) combined with casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) on enamel in a biofilm-challenged environment. MATERIAL AND METHODS: GO and GQDs were synthesised using citric acid. The antibiofilm and biofilm inhibition effects for Streptococcus mutans were evaluated by scanning electron microscopy (SEM), confocal laser scanning microscopy (CLSM), and colony-forming units (CFU). Remineralisation ability was determined by assessing mineral loss, calcium-to-phosphorus ratio, and surface morphology. To create a biofilm-challenged environment, enamel blocks were immersed in S. mutans to create the lesion and then subjected to artificial saliva/biofilm cycling for 7 days. Anticaries effects of GO, GQDs, GQDs@CPP-ACP, GO@CPP-ACP, and CPP-ACP were determined by broth pH and mineral changes after 7-day pH cycling. Biocompatibility was tested using a Cell Counting Kit-8 (CCK8) assay for human gingival fibroblasts (HGF-1). RESULTS: GQDs and GO presented significant antibiofilm and biofilm inhibition effects compared to the CPP-ACP and control groups (P < 0.05). The enamel covered by GQDs and GO showed better crystal structure formation and less mineral loss (P < 0.05) than that covered by CPP-ACP alone. After 7 days in the biofilm-challenged environment, the GO@CPP-ACP group showed less lesion depth than the CPP-ACP and control groups (P < 0.05). GO and GQDs showed good biocompatibility compared to the control group by CCK8 (P > 0.05) within 3 days. CONCLUSION: GO and GQDs could improve the anti-caries effects of CPP-ACP, and CPP-ACP agents with GO or GQDs could be a potential option for enamel lesion management. CLINICAL SIGNIFICANCE: GO and GQDs have demonstrated the potential to significantly enhance the anticaries effects of CPP-ACP. Incorporating these nanomaterials into CPP-ACP formulations could provide innovative and effective options for the management of enamel lesions, offering improved preventive and therapeutic strategies in dental care.

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Background: White spot lesions (WSLs) are frequently linked with low microhardness and mineral content changes. several strategies have been employed to deal with these problems. This investigation aimed to analyze the microhardness and mineral content changes after remineralization with bioactive glass (BAG) and casein phospho-peptide-amorphous calcium phosphate with fluoride (CPP-ACPF). Methods: Twenty sound maxillary first premolars extracted were used to obtain a total of one hundred enamel samples. forty enamel slabs were split into four experimental groups (n = 10 each): Group I, BAG; Group II, BAG+CPP-ACPF; Group III, CPP-ACPF varnish; and Group IV, artificial saliva (negative control). To create artificial WSLs, all samples were preserved in a prepared demineralizing agent for 72 h before treatment with remineralizing agents. Vickers microhardness test was performed. Additionally, 60 enamel samples were selected for analysis using energy dispersive spectroscopy (EDX) and assigned to six experimental groups; the first four groups were similar to that used in the microhardness test along with Group V: WSLs, and Group VI: baseline. The statistical analyses employed in this study included Tukey's HSD (p<0.05), one-way ANOVA, and Shapiro-Wilk. Result: Regarding surface microhardness, the BAG+CPP-ACPF group showed the most favorable recovery, which was better than the outcomes of the BAG and CPP-ACPF groups. A statistically significant change (p <0.05) was not observed between them. Similarly, for mineral content change, the BAG+CPP-ACPF group demonstrated the greatest result, The BAG group came next, and the CPP-ACPF group came last. Conclusion: The BAG+CPP-ACPF group might be regarded as the best course of treatment for enhancing both the surface microhardness and mineral content (Ca, P), while the control group (Artificial saliva) showed the least satisfactory results in comparison. After demineralization, mineral content and microhardness decreased in all samples. Therefore, BAG+CPP-ACPF significantly improved the surface microhardness and mineral content.

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Acute stimulation of M1 or M4 muscarinic cholinergic receptors reduces cocaine abuse-related effects in mice and rats. The combined activation of these receptor subtypes produces synergistic effects on some behavioural endpoints in mice. M1 and M1 + M4 receptor stimulation in a cocaine vs. food choice assay in rats and microdialysis in rats showed delayed and lasting "anticocaine effects". Here, we tested whether these putative lasting neuroplastic changes are sufficient to occlude the reinforcing effects of cocaine at the behavioural level in mice. Mice were pre-treated with the M1 receptor partial agonist VU0364572, M4 receptor positive allosteric modulator VU0152100, or VU0364572 + VU0152100 two weeks prior to acquisition of cocaine intravenous self-administration (IVSA). Male C57BL/6JRj mice received vehicle, VU0364572, VU0152100, or VU0364572 + VU0152100. Female mice were tested with two VU0364572 + VU0152100 dose combinations or vehicle. To attribute potential effects to either reduced rewarding effects or increased aversion to cocaine, we tested VU0364572 alone and VU0364572 + VU0152100 in acquisition of cocaine-conditioned place preference (CPP) in male mice using an unbiased design. The acquisition of cocaine IVSA was drastically reduced and/or slowed in male and female mice receiving VU0364572 + VU0152100, but not either drug alone. Food-maintained operant behaviour was unaffected, indicating that the treatment effects were cocaine-specific. No treatment altered the acquisition of cocaine-CPP, neither in the post-test, nor in a challenge 14 days later. The cocaine IVSA findings confirm unusual long-lasting "anticocaine" effects of muscarinic M1 + M4 receptor stimulation. Thus, in mice, simultaneous stimulation of both receptor subtypes seems to produce potential neuroplastic changes that yield lasting effects.

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Advancements in medicine and pharmacology have led to the development of systems that deliver biologically active molecules inside cells, increasing drug concentrations at target sites. This improves effectiveness and duration of action and reduces side effects on healthy tissues. Cell-penetrating peptides (CPPs) show promise in this area. While traditional medicinal chemistry methods have been used to develop CPPs, machine learning techniques can speed up and reduce costs in the search for new peptides. A predictive algorithm based on machine learning models was created to identify novel CPP sequences using molecular descriptors using a combination of algorithms like k-nearest neighbors, gradient boosting, and random forest. Some potential CPPs were found and tested for cytotoxicity and penetrating ability. A new low-toxicity CPP was discovered from the Rhopilema esculentum venom proteome through this study.

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The diterpene ent-copalol is an important precursor to the synthesis of andrographolide and is found only in green chiretta (Andrographis paniculata). De novo biosynthesis of ent-copalol has not been reported, because the catalytic activity of ent-copalyl diphosphate synthase (CPS) is very low in microorganisms. In order to achieve the biosynthesis of ent-copalol, Saccharomyces cerevisiae was selected as the chassis strain, because its endogenous mevalonate pathway and dephosphorylases could provide natural promotion for the synthesis of ent-copalol. The strain capable of synthesizing diterpene geranylgeranyl pyrophosphate was constructed by strengthening the mevalonate pathway genes and weakening the competing pathway. Five full-length ApCPSs were screened by transcriptome sequencing of A. paniculata and ApCPS2 had the best activity and produced ent-CPP exclusively. The peak area of ent-copalol was increased after the ApCPS2 saturation mutation and its configuration was determined by NMR and ESI-MS detection. By appropriately optimizing acetyl-CoA supply and fusion-expressing key enzymes, 35.6 mg/L ent-copalol was generated. In this study, de novo biosynthesis and identification of ent-copalol were achieved and the highest titer ever reported. It provides a platform strain for the further pathway analysis of andrographolide and derivatives and provides a reference for the synthesis of other pharmaceutical intermediates.

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Introduction Incorporation of remineralizing agents with fluoride-releasing bracket adhesives may prevent the development of white spot lesions (WSL) or reverse the established WSL in patients undergoing fixed orthodontic treatment. We aimed to find out how effectively casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) and fluoride varnish (FV) can remineralize teeth when mixed with fluoride-releasing orthodontic adhesive. Materials and methods We randomly assigned a total of 60 premolar teeth, therapeutically extracted for orthodontic purposes, into two equal groups. Group I (n = 30) utilized fluoride-releasing adhesive (FR), and Group II (n = 30) bonded with non-fluoride adhesive (NFR). Based on the applied remineralizing agent, we further divided each of the two groups into three equal subgroups of 10: Group IA (FR+FV), Group IB (FR+CPP-ACP), Group IC (control-only FR), Group IIA (NFR+FV), Group IIB (NFR+CPP-ACP), and Group IIC (control-only NFR). Following bonding procedures, all the samples underwent pH cycling for 28 days, where the enamel samples were immersed in 20 ml of demineralizing solution for three hours, followed by immersion in 30 ml of remineralizing solution for 17 hours. The samples were analyzed for shear bond strength (SBS) on a universal testing machine and hardness values (HV) by the Vickers microhardness test (VMT) using the indentation method. We also evaluated the adhesive remnant index (ARI) scores to determine the site of bracket failure. Statistical analysis The shear bond strength (SBS) and hardness value (HV) were expressed as the mean, standard deviation (SD), and median for each subgroup. We used the non-parametric Kruskal-Wallis test to analyze the SBS and HV, followed by the Dunn-Bonferroni test for intra-pair differences. The ARI score was expressed as the frequency of the percentage distribution, and the difference in the distribution of ARI scores between the groups was assessed by the Cochran chi-square test. The probability (p) value equal to or less than 0.05 was considered statistically significant. Results The results show that Group IB, bonded with a fluoride-releasing adhesive and a CPP-ACP remineralizing agent surface treatment, has the highest HV of 300.23 units. Group IIC (only NFR) has the lowest hardness of 153.3 units, which is statistically significant (p < 0.001). However, the ARI scores are not statistically significant between the groups tested. Conclusion The bond strength of the adhesive and the surface hardness of the enamel increased with the addition of fluoride varnish and CPP-ACP to both the fluoride-releasing and non-fluoride-releasing adhesives.

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Chondrosarcoma (CS) is a rare malignant bone sarcoma that primarily affects cartilage cells in the femur and pelvis. While most subtypes exhibit slow growth with a very good prognosis, some aggressive subtypes have a poorer overall survival. CS is known for its resistance to chemotherapy and radiotherapy, leaving surgery as the sole effective therapeutic option. Cold physical plasma (CPP) has been explored in vitro as a potential therapy, demonstrating positive anti-tumor effects on CS cells. This study investigated the synergistic effects of combining CPP with cytostatics on CS cells. The chemotherapeutic agents cisplatin, doxorubicin, and vincristine were applied to two CS cell lines (CAL-78 and SW1353). After determining their IC20 and IC50, they were combined with CPP in both cell lines to assess their impact on the cell proliferation, viability, metabolism, and apoptosis. This combined approach significantly reduced the cell proliferation and viability while increasing the apoptosis signals compared to cytostatic therapy alone. The combination of CPP and chemotherapeutic drugs shows promise in targeting chemoresistant CS cells, potentially improving the prognosis for patients in clinical settings.

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OBJECTIVE: This study aimed to assess the remineralization efficacy of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP), silver diamine fluoride/potassium iodide (SDF/KI), and sodium fluoride with functionalized tricalcium phosphate (NaF/fTCP) on artificial early enamel lesion using laser fluorescence and micro-CT analysis. METHODOLOGY: On extracted impacted third molars, artificial enamel lesions were prepared. Twenty-eight specimens were randomly assigned to four groups (n = 7 per group): a control group (artificial saliva), CPP-ACP (GC Tooth Mousse), SDF/KI (Riva Star), and NaF/fTCP (Clinpro White varnish). Following the manufacturer's instructions, the remineralization agents were applied to demineralized surfaces. Laser fluorescence and micro-CT were used to evaluate the remineralization efficacy of the agents and analyzes were performed during four stages: before demineralization, after demineralization, 1st day of remineralization and 30th day of remineralization. Shapiro-Wilk test, repeated measures two-way ANOVA, and Spearman correlation tests were used for statistical analysis. A significant level of p < 0.05 was established. RESULTS: SDF/KI significantly reduced the lesion area and lesion volume on the demineralized enamel surface after 30 days of remineralization. In the T3 period, SDF/KI increased the mineral density statistically significantly compared to the T1 period. The laser fluorescence values for all three remineralizing agents exhibited a linear decrease. A significant correlation between the fluorescence values and the mineral density was found (p = 0.01). CONCLUSION: All three investigated agents were showed positive remineralization efficacy on artificial enamel lesion. However, SDF/KI, containing silver diamine fluoride and potassium iodide exhibited superior than other agents in promoting remineralization. CLINICAL SIGNIFICANCE: Although all three remineralization agents showed positive remineralization efficacy on artificial enamel lesions, SDF had higher remineralization performance over the other two agents. SDF has potential to prevent progression of demineralization in treating children with high caries risk in the long-term.

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Codonopsis pilosula polysaccharides (CPP), the main active ingredient of Codonopsis pilosula, has gained significant attention as a liver-protective agent. Previous studies have demonstrated that CPP could alleviate gut microbiota dysbiosis in colitis or obese mice. However, the effects of CPP on mycotoxin-induced liver injury and gut microbiota dysbiosis are still poorly understood. In this study, we aimed to investigate the protective effects of CPP on sterigmatocystin (STC)-induced liver injury, as well as its regulatory effects on gut microbiota. Our results revealed that CPP intervention significantly alleviated STC-induced liver injury, as evidenced by decreased liver index, reduced liver histopathological changes, and modulation of related molecular markers. Additionally, we found that CPP could alleviate liver injury by reducing liver inflammation and oxidative stress, inhibiting hepatocyte apoptosis, and regulating lipid metabolism. Notably, we also observed that CPP could alleviate STC-induced gut microbiota dysbiosis by modulating the diversity and richness of gut microbiota, suggesting that gut microbiota modulation may also serve as a mechanism for CPP-mediated remission of liver injury. In summary, our study not only provided a new theoretical basis for understanding the hepatotoxicity of STC and the protective effects of CPP against STC-induced liver injury, but also provided new perspectives for the application of CPP in the fields of food, healthcare products, and medicine.

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Neuroadaptive changes in the hippocampus underlie addictive-like behaviors in humans or animals chronically exposed to cocaine. miR-181a, which is widely expressed in the hippocampus, acts as a regulator for synaptic plasticity, while its role in drug reinstatement is unclear. In this study, we found that miR-181a regulates the reinstatement of cocaine conditioned place preference(CPP), and altered miR-181a expression changes the complexity of hippocampal neurons and the density and morphology of dendritic spines. By using a luciferase gene reporter, we found that miR-181a targets PRKAA1, an upstream molecule in the mTOR pathway. High miR-181a expression reduced the expression of the PRKAA1 mRNA and promoted mTOR activity and the reinstatement of cocaine CPP. These results indicate that miR-181a is involved in neuronal structural plasticity induced by reinstatement of cocaine CPP, possibly through the activation of the mTOR signaling pathway. This study provides new microRNA targets and a theoretical foundation for the prevention of cocaine-induced reinstatement.

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Elevated intracranial pressure (ICP) in patients with cerebral lesions has garnered considerable attention in research. It often manifests as a common symptom in conditions such as intracranial tumors, intracerebral hemorrhage, and cerebral edema. This paper provides an overview of ICP concepts, discusses the advantages and disadvantages of traditional monitoring methods, explores the physiological and anatomical aspects of the optic nerve sheath, examines the utility of ultrasound measurement of optic nerve sheath diameter (ONSD) in both nervous system and nonnervous system disorders, and outlines the cutoff values and normal ranges for assessing elevated ICP using ultrasound measurement of ONSD. The review underscores ultrasound measurement of ONSD as a promising noninvasive, safe, straightforward, and repeatable examination technique for various diseases. Nevertheless, the lack of standardized cutoff values for elevated ICP remains a challenge. Summarizing studies on optic nerve sheaths is crucial for enhancing the efficacy of ultrasound measurement of ONSD in assessing ICP.

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The primary hurdles for small interference RNA (siRNA) in clinical use are targeted and cytosolic delivery. To overcome both challenges, we have established a novel platform based on phage display, called NNJA. In this approach, a lysosomal cathepsin substrate is engineered within the flexible loops of PIII, that is displaying a unique random sequence at its N-terminus. NNJA library selection targeting cell-expressed targets should yield specific peptides localized in the cytoplasm. That is because phage internalization and subsequent localization to lysosome, upon peptide binding to the cell expressed target, will result in cleavage of PIII, rendering phage non-infective. Such phage will be eliminated from the selected pool and only peptide-phage that escapes lysosomes will advance to the next round. Proof of concept studies with the NNJA library demonstrated cytosolic localization of selected peptide-phage and peptide-siRNA, confirmed through confocal microscopy. More importantly, conjugation of siHPRT to monomeric or multimeric NNJA peptides resulted in significant reduction in HPRT mRNA in various cell types without significant cytotoxicity. Sequence similarity and clustering analysis from NGS dataset provide insights into sequence composition facilitating cell penetration. NNJA platform offers a highly efficient peptide discovery engine for targeted delivery of oligonucleotides to cytosol.

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Natural killer (NK) cells make only a small fraction of immune cells in the human body, however, play a pivotal role in the fight against cancer by the immune system. They are capable of eliminating abnormal cells via several direct or indirect cytotoxicity pathways in a self-regulating manner, which makes them a favorable choice as a cellular therapy against cancer. Additionally, allogeneic NK cells, unlike other lymphocytes, do not or only minimally cause graft-versus-host diseases opening the door for an off-the-shelf therapy. However, to date, the production of NK cells faces several difficulties, especially because the critical process parameters (CPPs) influencing the critical quality attributes (CQAs) are difficult to identify or correlate. There are numerous different cultivation platforms available, all with own characteristics, benefits and disadvantages that add further difficulty to define CPPs and relate them to CQAs. Our goal in this contribution was to summarize the current knowledge about NK cell expansion CPPs and CQAs, therefore we analyzed the available literature of both dynamic and static culture format experiments in a systematic manner. We present a list of the identified CQAs and CPPs and discuss the role of each CPP in the regulation of the CQAs. Furthermore, we could identify potential relationships between certain CPPs and CQAs. The findings based on this systematic literature research can be the foundation for meaningful experiments leading to better process understanding and eventually control.

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This study evaluated the probable relevance of a non-covalent conjugate of imatinib with TP10 in the context of a neuroprotective effect in Parkinson's disease. Through the inhibition of c-Abl, which is a non-receptor tyrosine kinase and an indicator of oxidative stress, imatinib has shown promise in preclinical animal models of this disease. The poor distribution of imatinib within the brain tissue triggered experiments in which a conjugate was obtained by mixing the drug with TP10, which is known for exhibiting high translocation activity across the cell membrane. The conjugate was tested on the HT-22 cell line with respect to its impact on MPP+-induced oxidative stress, apoptosis, necrosis, cytotoxicity, and mortality. Additionally, it was checked whether the conjugate activated the ABCB1 protein. The experiments indicated that imatinib+PEG4+TP10 reduced the post-MPP+ oxidative stress, apoptosis, and mortality, and these effects were more prominent than those obtained after the exposition of the HT-22 cells to imatinib alone. Its cytotoxicity was similar to that of imatinib itself. In contrast to imatinib, the conjugate did not activate the ABCB1 protein. These favorable qualities of imatinib+PEG4+TP10 make it a potential candidate for further in vivo research, which would confirm its neuroprotective action in PD-affected brains.

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BACKGROUND/AIM: Cold physical plasma (CPP) has emerged as an effective therapy in oncology by inducing cytotoxic effects in various cancer cells, including chondrosarcoma (CS), Ewing's sarcoma (ES), and osteosarcoma (OS). The current study investigated the impact of CPP on cell motility in CS (CAL-78), ES (A673), and OS (U2-OS) cell lines, focusing on the actin cytoskeleton. MATERIALS AND METHODS: The CASY Cell Counter and Analyzer was used to study cell proliferation and determine the optimal concentrations of fetal calf serum to maintain viability without stimulation of cell proliferation. CellTiter-BlueCell viability assay was used to determine the effects of CPP on the viability of bone sarcoma cells. The Radius assay was used to determine cell migration. Staining for Deoxyribonuclease I, G-actin, and F-actin was used to assay for the effects on the cytoskeleton. RESULTS: Reductions in cell viability and motility were observed across all cell lines following CPP treatment. CPP induced changes in the actin cytoskeleton, leading to decreased cell motility. CONCLUSION: CPP effectively reduces the motility of bone sarcoma cells by altering the actin cytoskeleton. These findings underscore CPP's potential as a therapeutic tool for bone sarcomas and highlight the need for further research in this area.

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The requirement for clinically effective treatments to remineralize early enamel caries lesions is dictated by the principles of minimally invasive dentistry. Numerous studies outlined the significance of treating early carious lesions with different remineralizing agents. This study aimed to evaluate and compare the remineralization potential of topical cream containing casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) and CPP-ACP with fluoride in remineralizing artificial carious lesions on enamel. Forty-five freshly extracted human premolar teeth were selected as samples. These samples were divided into three groups: Group I-regular toothpaste without specific remineralizing agent; Group II-topical cream containing CPP-ACP and Group III topical cream containing CPP-ACP with fluoride. All the samples were viewed under scanning electron microscope (SEM) to assess the topographical pictures of the enamel surface and also subjected to energy dispersing X-ray analysis (EDX) for quantitative estimation of minerals, calcium (Ca), and phosphorous (P). In the result of the study, Group I does not show any increase in the Ca and P after applying toothpaste without any remineralizing agent but Group II and Group III showed a net increase in Ca and P- values after applying concerned remineralizing agents. Intergroup comparison showed Group III yielded higher net Ca and P- values than Group II. Two remineralizing agents showed remineralization potential on samples. Descriptive statistics were used to calculate the mean and standard deviation. Mann-Whitney test was used. The level of significance was set at 0.05. CPP-ACP containing fluoride showed better remineralizing potential than CPP-ACP. Hence, CPP-ACP containing fluoride can be considered the material of choice in remineralizing early enamel carious lesions.

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Calcium pyrophosphate deposition disease is categorized into radiographic chondrocalcinosis, acute calcium pyrophosphate arthritis, chronic calcium pyrophosphate arthritis, and osteoarthritis with calcium pyrophosphate deposition. These entities collectively are characterized by the deposition of calcium into joints, which then may cause localized and systemic inflammation, resulting in pain and swelling in the affected joints. Patients with the ANKH gene are more susceptible to the development of CPP arthritis as are those with primary hyperparathyroidism, hypomagnesemia, and hemochromatosis. Radiographic chondrocalcinosis is asymptomatic. Acute calcium pyrophosphate arthritis results in self-limited periods of joint pain and swelling in the affected joint. Along with localized inflammation, there may also be systemic inflammation characterized by fever and elevated inflammatory markers. Chronic calcium pyrophosphate arthritis results in periods of quiescence interrupted by flares that are identical to acute periods of disease. Osteoarthritis associated calcium pyrophosphate arthritis presents with chronic pain well described in osteoarthritis with periods of acute flares. In 2023, a joint effort by the American College of Rheumatology and the European League Against Rheumatism developed guidelines meant to aid in the recognition of calcium pyrophosphate deposition diseases. The diagnosis is made if there is proof of either crowned dens syndrome or synovial fluid analysis demonstrating calcium pyrophosphate crystals or when more than 56 points are summed utilizing the criteria described in the guidelines. Radiographic chondrocalcinosis requires no therapy. Acute calcium pyrophosphate arthritis is treated with the goal of aborting the flare. Treatment options include nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, oral corticosteroids, parenteral corticosteroids, intraarticular corticosteroids, IL-1 inhibitors, or parenteral adrenocorticotropic hormone (ACTH). The goal in treatment for chronic calcium pyrophosphate arthritis is the suppression of acute flares. The drugs used for acute flare treatment may be given as maintenance therapy with the additional options of methotrexate and hydroxychloroquine.

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Chlamydia psittaci pneumonia (CPP) is a lung disease caused by the infection with the Chla-mydia psittaci bacterium, which can lead to severe acute respiratory distress syndrome and systemic symptoms. This study explored the specific mechanisms underlying the impact of reactive oxygen species (ROS) on the Th17/Treg balance in CPP. The levels of ROS and the differentiation ratio of Th17/Treg in the peripheral blood of healthy individuals and CPP patients were measured using ELISA and flow cytometry, respectively. The association between the ROS levels and Th17/Treg was assessed using Pearson correlation analysis. The ROS levels and the Th17/Treg ratio were measured in CD4+ T cells following H2O2 treatment and NLRP3 inhibition. The effects of H2O2 treatment and NLRP3 inhibition on the NLRP3/IL-1ß/caspase-1 pathway were observed using immunoblotting. Compared to the healthy group, the CPP group exhibited increased levels of ROS in the peripheral blood, an elevated ratio of Th17 differentiation, and a decreased ratio of Treg differentiation. ROS levels were positively correlated with the Th17 cell proportion but negatively correlated with the Treg cell proportion. The ROS levels and NLRP3/IL-1ß/caspase-1 expression were up-regulated in CD4+ T cells after H2O2 treatment. Furthermore, there was an increase in Th17 differentiation and a decrease in Treg differentiation. Conversely, the NLRP3/IL-1ß/caspase-1 pathway inhibition reversed the effects of H2O2 treatment, with no significant change in the ROS levels. ROS regulates the Th17/Treg balance in CPP, possibly through the NLRP3/IL-1ß/caspase-1 pathway. This study provides a new perspective on the development of immunotherapy for CPP.

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BACKGROUND: Genetic and environmental factors are implicated in many developmental processes. Recent evidence, however, has suggested that epigenetic changes may also influence the onset of puberty or the susceptibility to a wide range of diseases later in life. The present study aims to investigate changes in genomic DNA methylation profiles associated with pubertal onset analyzing human peripheral blood leukocytes from three different groups of subjects: 19 girls with central precocious puberty (CPP), 14 healthy prepubertal girls matched by age and 13 healthy pubertal girls matched by pubertal stage. For this purpose, the comparisons were performed between pre- and pubertal controls to identify changes in normal pubertal transition and CPP versus pre- and pubertal controls. RESULTS: Analysis of methylation changes associated with normal pubertal transition identified 1006 differentially methylated CpG sites, 86% of them were found to be hypermethylated in prepubertal controls. Some of these CpG sites reside in genes associated with the age of menarche or transcription factors involved in the process of pubertal development. Analysis of methylome profiles in CPP patients showed 65% and 55% hypomethylated CpG sites compared with prepubertal and pubertal controls, respectively. In addition, interestingly, our results revealed the presence of 43 differentially methylated genes coding for zinc finger (ZNF) proteins. Gene ontology and IPA analysis performed in the three groups studied revealed significant enrichment of them in some pathways related to neuronal communication (semaphorin and gustation pathways), estrogens action, some cancers (particularly breast and ovarian) or metabolism (particularly sirtuin). CONCLUSIONS: The different methylation profiles of girls with normal and precocious puberty indicate that regulation of the pubertal process in humans is associated with specific epigenetic changes. Differentially methylated genes include ZNF genes that may play a role in developmental control. In addition, our data highlight changes in the methylation status of genes involved in signaling pathways that determine the migration and function of GnRH neurons and the onset of metabolic and neoplastic diseases that may be associated with CPP in later life.

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