Notes

VITRECTOMY Regarding REFRACTORY MACULAR Gap.
Parametric test (chi-square) was performed to compare the results of the questionnaire between the two groups using STATA statistical software. All patients correctly filled and returned the questionnaire. Significantly higher proportions of patients of test group reported no bad taste, pain, and limited activity, (24/26, 13/26, and 25/26, respectively) respect to control. Postoperative pain with VAS score was significantly lower in the test group on day 1, 2, and 3 as compared to control. CGF positively influenced QoL when associated with implant rehabilitation of mandibular molars, minimizing post-operative discomfort.The route of transmission of SARS-CoV-2 has been understood thanks to the knowledge of previously identified human coronaviruses. According to these studies, the transmission of the virus occurs mainly between humans at close range, through respiratory droplets produced during conversation or coughing, as well as through direct contact of the hands then placed on the mucous membranes or mouth. From the final analysis of studies carried out on protective systems, the validity of plexiglass as a material to be used for the construction of protective devices could be affirmed. The plexiglass, in fact, would seem able to isolate the diffusion of aerosol particles dispersed by infected subjects and in different environments.Numerous studies have been published aiming to investigate the relationship between sagittal craniofacial pattern and the dimensions of upper airway, but with controversial results. The aim of the study is to verify if an association exists between a specific sagittal cranio-facial pattern and smaller dimensions of upper airway, leading so to a possible risk indicator for OSAS development. Ninety-nine cone-beam computed tomographies (CBCT) were selected from adult patients (48 males, 51 females, age range 18- 65 years). Patients were divided into 3 groups, with 33 patients each, according to their skeletal class (I 13; III ANB less then 1). The CBCT data were imported into Simplant O&O software as Dicom files. Borders for the oropharynx and for the hypopharynx of which the volumes were calculated, and the total length (L) were defined. Finally, the average cross-sectional area (a-CSA) was defined as the ratio between total volume and total length for each patient. All data were statistically analyzed using GraphPad Software. A significant difference was found between groups for oropharynx, hypopharynx, and total volume, with Class II having smaller airway dimensions. In a gender-based comparison, there was a statistically significant difference between female and male patients of the same group, and between the same gender in different groups. Regarding the total length and the a-CSA, there was a statistically significant difference between the groups. These results indicate that class II and female patients have smaller dimensions of upper airway leading to a possible risk indicator for OSAS development.The aim of this retrospective case series was to evaluate the clinical and radiographic outcomes of the patients that underwent implant surgery with a modification of the sinus lift summers protocol. Forty healthy patients in need for oral rehabilitation with dental implants were included in this study. Inclusion criterion was the need for extraction of one compromised tooth due to persistent abscess/ periodontitis/cyst in the atrophic posterior maxilla region. The treatment consisted of two stage surgery for all patients. In the first stage, after tooth extraction, the sockets were preserved with allogenic bone graft and equine collagen membrane. After 4-5 months, 40 implants with a sandblasted surface, were inserted with osseodensification technique and a modification of the Summers sinus lift protocol for fracturing the sinus floor. The implant survival rate was the primary outcome. Intra- and postoperative complications were additional criteria for success. The mean follow-up from implant surgery was 28.0±7.3 (standard deviation) months (range 17.8-43.4 months). One implant was lost before the delivery of the prosthesis. The overall implant survival rate was 97.5%. The overall mean peri-implant marginal bone level change after 6 and 12 months of function was, respectively, 0.26±0.24 mm (95% CI 0.19, 0.34 mm) and 0.71±0.36 mm (95% CI 0.60, 0.82 mm). Marginal bone loss was statistically significant at both time frames respect to implant placement, and also the difference between 6 and 12 months was significant (p less then 0.001 in both cases). No biological nor mechanical complications were recorded throughout the observation period. As a conclusion, the technique presented in this cohort study can be an effective and safe alternative to standard maxillary sinus floor augmentation procedures and immediate implant insertion protocol, especially in cases of periodontitis and infected sites, which can represent a high risk for implant failure in patients with atrophic posterior maxilla.The objective of the research was to evaluate the location, size, variability, and morphologic features of mental foramen (MF) and the inferior alveolar nerve canal (IAN) on cone-beam CT. We evaluated the morphologic findings of mental foramen (MF) and inferior alveolar nerve (IAN) canal of 88 mandibular hemiarches of 65 Caucasian subjects (35 males, 30 females; age range 25-75 years) using cone beam CT. The most common horizontal position of MF was type 3 (53.4%), followed by type 4 (39.8%), type 1 (2.3%), type 2 (2.3%), and type 5 (2.3%). Regarding the vertical position, in 71.6% of cases (63/88) we found type 3 position, followed by type 2 (22.7%) and type 1 (5.7%). MF presented as oval in 51.1% and round in 42%, with double oval and triple foramens having been observed in 5.7% and 1.1% respectively. In 36.9% of cases, we found an anterior loop of the IAN. The mean depth of MF was 6.12±1.65mm; width and height were 3.7±0.83mm and 3.14±0.78mm. Width and height of the IAN distal to MF were 2.27±0.53mm and 2.74±0.51mm, while those of the incisive nerve canal mesial to MF were 1.37±0.44mm and 1.54±0.58mm, respectively. An increase in the width of MF was correlated to oval shape (r=0.45; P less then 0.01), and there was a low but significant correlation (r=0.23; P less then 0.05) between the round shape of MF and the size of the IAN. MF shape appears to be correlated to MF width and size of the IAN. The individual anatomical variability of this structure is a factor that must be considered when dealing with mandibular surgery.Bibliometric Analysis researches and analyses the quantitative data derived from scientific publications through the empirical evidence of scientific activity generated by collaborating authors through the final product of their research the scientific article. In scientific society, the concept of impact factor is probably the most widely used in bibliometric construction. To assess the scientometrics of three high-impact factor periodontal journals and identify the contribution of India in these most productive journals over three years (Jan 2018 - Dec 2020) and to know the most influential topics researched. A retrospective observational study was conducted for the Journal of Clinical Periodontology, Journal of Periodontology, and Journal of Periodontal Research. All issues of 2018, 2019, and 2020 were electronically and hand searched for the following parameters Number of papers, affiliated organizations, and countries, topics reported, and contribution of Indian authors. The data were organized and analyzed with descriptive statistics using SPSS software (version 21.0). In total 469 articles were published by Journal of Periodontology, followed by 454 articles in Journal of Clinical Periodontology and 287 articles in Journal of Periodontal Research. In all the three journals, China had the maximum contributions, succeeded by USA. India has published maximum number of articles in the Journal of Periodontal Research. When analysed, although less as compared to the western counterparts, an increasing trend in the publications is seen in case of India.Grape seed extract (GSE), a naturally producing polyphenolic compound, is found to be a potent hostmodulatory agent and considered for management of periodontal disease. Its anti-bacterial, antioxidant, and anti-inflammatory property may aid in achieving periodontal health. To assess the clinical efficacy of GSE in adjunct to scaling and root planing (SRP) in healing of periodontal pockets. The present study was a longitudinal, parallel design, randomized clinical trial. Seventy-two patients (mean age 39.2±8.6 years) with periodontal pockets were randomly divided into two groups; Test group received intra-pocket delivery of GSE with SRP and Control group received SRP alone. The clinical parameters like Plaque Index (PI), Gingival Index (GI), Probing Depth (PD) and Relative Attachment Level (RAL) were recorded at baseline and 3 months. 64 patients completed the study. Test group at the end of 3 months had statistically significant reduced PD (p=0.002) and RAL (p=0.01). No significant difference was observed for PI and GI at the end of 3 months. Intra-pocket application of GSE with SRP could be beneficial in management of periodontal pockets.In the last decades, the presence of peri-implant diseases (PD) has increased. One of the therapies currently used is probiotics with Lactobacillus reuteri (LR). The aim of this article is to determinate, through a systematic review and meta-analysis, the clinical effectiveness of LR in the treatment of PD. We searched the literature until January 2021, in the biomedical databases Pubmed, Embase, Scielo, Science Direct, Scopus, SIGLE, LILACS, Google Scholar and Cochrane Central Registry of Clinical Trials. The selection criteria of the studies were randomized controlled clinical trials, without language and time restriction, reporting the clinical effects (depth to probing, plaque index and bleeding index) of the LR in the PD treatment. The risk of study bias was analyzed through the Cochrane tool for randomized studies using Review Manager software. The search strategy resulted in 6 articles of which four investigated peri-implantitis and three peri-implant mucositis. All studies reported that there was a difference in the depth of the probing in the treatment of PD, in favor of the group using LR, though not always achieving significance. The use of LR can be clinically effective in terms of pocket depth reduction in the treatment of PD.The objective of this study was to establish the significance of probiotic usage, both as a preventive as well as a therapeutic strategy for the management of periodontal disease. It also substantiates the existing studies of single/combined bacterial strain for exhibiting variable ecological impact on oral bacteria. Data sources included literature searches of PubMed (MEDLINE), Scopus, Embase, CENTRAL and Web of science databases for placebo controlled randomized clinical trials of SRP with orally administered probiotics in any form as an adjunct. Data extraction was conducted and information from the included studies was tabulated according to the study designs, form of drug delivery, main outcomes, and clinical parameters. Data collected were based on the focused question outlined for the present systematic review. The reviewers cross-checked all extracted data. CAL and PD were assessed as the primary outcome to compare the effectiveness of adjunctive probiotic therapy in addition to SRP. Fourteen clinical studies were included and demonstrated efficacy in reducing periodontal probing depth (PPD) and gaining clinical attachment level (CAL), between probiotics and SRP/placebo. Adjunctive probiotic therapy in addition to SRP leads to decrease in probing depth and clinical attachment gain in chronic periodontitis patients. However, further high-quality randomized clinical trials with microbiological outcomes are required to fortify the conclusion.Radiotherapy to head and neck has always been considered as a risk factor for rehabilitation with dental implants. Nevertheless, recent data suggest that overall, 5-year implant survival in irradiated patients can be greater than 90%. The purpose of this review was to compare the implant survival rates of irradiated and non-radiated head and neck cancer sites, and discuss the outcomes, through a systematic review approach of prospective and retrospective studies. Electronic searches were performed in the EMBASE, Cochrane, and PubMed/Medline databases up to 2019 Dec, to identify retrospective and prospective clinical studies addressing the subject. This systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The primary variables collected from the studies were the site of tumor, age and sex of the patient, site of implant placement, radiation dosage, frequency and duration of radiotherapy, follow-up duration, implant survival and staes is challenging and often warrants protocol modifications. Although statistically the survival rates at irradiated sites were lower in comparison to non-radiated sites, a strict inclusion criterion in patient selection, timing of implant placement after radiotherapy, radiation dosage and regular oral hygiene maintenance could minimize the chances of implant failure in irradiated patients.The aim of this retrospective case series was to evaluate the clinical and radiographic outcomes of the patients that underwent implant surgery in all indication classes, with a follow-up of at least 9 years. 121 healthy patients in need for oral rehabilitation with dental implants were included in this study. 196 implants (160 conical, 73 cylindric design implants) were inserted. The implant survival rate was the primary outcome. Intra- and postoperative complications were additional criteria for success. The mean follow-up of the patients was 12.29 years (SD 1.39). Mean age of the study population was 51.0 years (SD 12.7). The mean bone loss around implants after at least 9 years of loading was measured as 2.0 mm (SD 0.73 mm). Intra-operative complications were seen in 5 patients. Post-operative complications included 5 mucositis,1 dehiscence, 2 screw loosening, 1 infection at site and 1 nonintegrated implant. Two implants were lost in two patients. The overall implant survival rate was 99.1%. As a conclusion, oral rehabilitation with dental implant-supported prostheses can be accepted as a safe procedure with relevantly high survival rates of oral implants and successful aesthetic and functional outcomes.Although arthrocentesis is an accepted safe treatment modality for the management of temporomandibular disorders (TMD) in symptomatic patients, the benefit of hyaluronic acid (HA) injections remains uncertain. The aim of this study was to evaluate whether intra-articular HA injections adjunctive to arthrocentesis can be more effective than other medications for the improvement of TMD associated symptoms. Additionally, the impact of HA injections on quality of life of TMD patients was assessed with SF-36® questionnaire in a cohort of patients. An electronic search of Medline, Scopus and Cochrane databases was performed up to March 2020. The following search terms were used "arthrocentesis", "hyaluronic acid", "intra-articular injections", "visco-supplementation", "temporomandibular disorders". Prospective and retrospective studies that reported the application of HA injections compared to other intra-articular drugs for the treatment of temporomandibular disorders were included. Systematic or narrative reviewsing results. In conclusion, there is no consensus in the literature that HA injections shows better results in comparison with other treatment modalities. According to the results of the present clinical study, HA injections with/without arthrocentesis seems to be beneficial in terms of clinical symptoms and quality of life of the TMD patients.The aim of the present study is to describe a new technique through which it is possible to complete the maxillary sinus lift procedure even in case of severe damage or complete removal of the sinus mucosa using the PRGF-Endoret® platelet concentrate. Eighteen patients (ratio FM=45; average age 58.2 years; DS 8.85 years) with severe perforation (more than 10 millimetres of diameter) of the sinus mucosa during the maxillary sinus lift procedure were selected. Normally the procedure is interrupted due to impossible stabilization of the graft material inside the subantral cavity. On the contrary, our protocol foreseen the sealing of the perforation using the PRGF autologous gel membranes or the creation of a new sinus pseudomembrane through which the graft material was covered. The PRGF-Endoret were obtained according to the protocol developed by BTI (Biotechnology Institute - Vitoria, Spain). In 14 cases out of 18 implant fixtures were concurrently inserted while in 4 cases the fixture insertion was postponed ad favouring bone regeneration.The relationship between occlusion and posture has been and is still strongly debated. This study examines 40 male and female healthy subjects, (11 males and 29 females, average age 26.27 years, st dv 3.03) aged between 21 and 32. The baropodometric evaluation was performed with the subject in rest position and in usual centric occlusion. The results obtained were analyzed using a baropodometric platform and Freesteps software (Sensor Medica srl, Rome - Italy) analyzing the podalic load, the foot axis and the foot angles. The values reported show that 80% of subjects in rest position (p-value 0.01) and 70% of subjects in centric occlusion (p-value 0.05) have a greater foot load in the contralateral foot compared to the chewing side; moreover, the foot axis values are statistically significant because 77% of subjects in rest position and 72% in centric occlusion have a foot axis more open on the same side than the chewing one. The foot angles values are not significant. These results could be understood analyzing the activation of the body muscular chains on the chewing side there is an increase of the activity of the flexion chain with side bending of the trunk. This induces a change of the body barycenter compensated by an outer rotation of the homolateral leg and foot; moreover, the body bending creates a false short leg on the same side, explaining the excess of podalic load on the other side. These values show that the hypothesis of a correlation appears to be likely, although obviously it still needs confirmation and further analysis.
Due to low incidence, epidemiologic data of Ewing sarcoma in the Asian population are scarce. We aimed to examine the incidence pattern and outcome of patients with Ewing sarcoma in the Republic of Korea.

Data of patients with Ewing sarcoma diagnosed between 1999 and 2017 were obtained from the Korea Central Cancer Registry (KCCR). Incidence, clinical characteristics, and survival rates were analyzed and compared between different age groups.

There were 788 cases (459 male, 329 female), with a median age at diagnosis of 20 years. The age-standardized rate of Ewing sarcoma was 1.01. The number of cases and incidence rates in each age group were as follows children, 1.6; adolescents and young adults, 0.93; adults, 0.44; and elderly, 0.53. There were more male cases in children and the adolescents and young adults (AYA) group (p<0.001). Extraskeletal tumors (p=0.0007), primary sites other than extremity (P=0.0069), and presence of metastasis at diagnosis (p=0.0314) were more frequent in the adults and eove the outcome of Ewing sarcoma in low-incidence populations.
Sarcopenia is an independent prognostic factor of liver cirrhosis (LC). However, the association between LC-related systemic inflammation and sarcopenia is unclear.

Sprague-Dawley rats were treated with thioacetamide (TAA) or saline as a control. Rifaximin was administered to TAA-induced rats. ELISA was performed to measure inflammatory mediators in rat serum. RT-PCR was performed to measure the molecular expression in tissues. Hematoxylin and eosin (H&E) staining and immunohistochemistry were performed to investigate tissue pathology. Serum tumor necrosis factor-α (TNF-α) levels, liver stiffness (LS), and the L3 skeletal muscle index (L3SMI) were measured in 60 patients with chronic liver disease (CLD).

LC and sarcopenia were successfully induced by TAA. Serum TNF-α levels were increased in LC rats and correlated with myostatin expression, muscle weight, and myofiber diameter. The expression of intestinal occludin and ZO-1 was reduced in LC rats and was associated with serum TNF-α levels and sarcopenia. In patients with LS≥7 kPa or sarcopenia, serum TNF-α levels were significantly increased, which was also confirmed when we raised the LS cutoff to 10 kPa. The value of the L3SMI was inversely correlated with serum TNF-α levels in patients with LS≥7 kPa. TNF-α was reduced by rifaximin, which might have resulted in reduced expression of muscular MuRF1 and myostatin and improvements in myofiber diameters within muscle tissues.

These results suggest that TNF-α is associated with LC-related sarcopenia. Rifaximin might be effective in reducing TNF-α levels and improving sarcopenia in LC, but these results need to be validated in future studies.
These results suggest that TNF-α is associated with LC-related sarcopenia. Rifaximin might be effective in reducing TNF-α levels and improving sarcopenia in LC, but these results need to be validated in future studies.Hepatitis B virus (HBV) affects approximately 250 million patients worldwide, resulting in the progression to cirrhosis and hepatocellular carcinoma, which are serious public health problems. Although universal vaccination programs exist, they are only prophylactic and not curative. In the HBV life cycle, HBV forms covalently closed circular DNA (cccDNA), which is the viral minichromosome, in the nuclei of human hepatocytes and makes it difficult to achieve a complete cure with the current nucleos(t)ide analogs and interferon therapies. Current antiviral therapies rarely eliminate cccDNA; therefore, lifelong antiviral treatment is necessary. Recent trials for antiviral treatment of chronic hepatitis B have been focused on establishing a functional cure, defined by either the loss of hepatitis B surface antigen, undetectable serum HBV DNA levels, and/or seroconversion to hepatitis B surface antibody. Novel therapeutic targets and molecules are in the pipeline for early clinical trials aiming to cure HBV infection. The ideal strategy for achieving a long-lasting functional or complete cure might be using combination therapies targeting different steps of the HBV life cycle and immunomodulators. This review summarizes the current knowledge about novel treatments and combination treatments for a complete HBV cure.Macrophages are one of the most important cells of the innate immune system and are known for their ability to engulf and digest foreign substances, including cellular debris and tumor cells. They can convert into tumor-associated macrophages (TAMs) when mature macrophages are recruited into the tumor microenvironment. Their role in cancer progression, metastasis, and therapy failure is of special note. The aim of this review is to understand how the presence of TAMs are both advantageous and disadvantageous in the immune system.Cancer is one of the deadliest illness globally. Searching for new solutions in cancer treatments is essential because commonly used mixed, targeted and personalized therapies are sometimes not sufficient or are too expensive for common patients. Sugar fatty acid esters (SFAEs) are already well-known as promising candidates for an alternative medical tool. The manuscript brings the reader closer to methods of obtaining various SFAEs using combined biological, chemical and enzymatic methods. It presents how modification of SFAE's hydrophobic chains can influence their cytotoxicity against human skin melanoma and prostate cancer cell lines. The compound's cytotoxicity was determined by an MTT assay, which followed an assessment of SFAEs' potential metastatic properties in concentrations below IC50 values. Despite relatively high IC50 values (63.3-1737.6 μM) of the newly synthesized SFAE, they can compete with other sugar esters already described in the literature. The chosen bioactives caused low polymerization of microtubules and the depolymerization of actin filaments in nontoxic levels, which suggest an apoptotic rather than metastatic process. Altogether, cancer cells showed no propensity for metastasis after treating them with SFAE. They confirmed that lactose-based compounds seem the most promising surfactants among tested sugar esters. This manuscript creates a benchmark for creation of novel anticancer agents based on 3-hydroxylated fatty acids of bacterial origin.The dynamic evolution of mitochondrial gene and intron content has been reported across the angiosperms. However, a reference mitochondrial genome (mitogenome) is not available in Rubiaceae. The phylogenetic utility of mitogenome data at a species level is rarely assessed. Here, we assembled mitogenomes of six Damnacanthus indicus (Rubiaceae, Rubioideae) representing two varieties (var. indicus and var. microphyllus). The gene and intron content of D. indicus was compared with mitogenomes from representative angiosperm species and mitochondrial contigs from the other Rubiaceae species. Mitogenome structural rearrangement and sequence divergence in D. indicus were analyzed in six individuals. The size of the mitogenome in D. indicus varied from 417,661 to 419,435 bp. Comparing the number of intact mitochondrial protein-coding genes in other Gentianales taxa (38), D. indicus included 32 genes representing several losses. The intron analysis revealed a shift from cis to trans splicing of a nad1 intron (nad1i728) in D. indicus and it is a shared character with the other four Rubioideae taxa. Two distinct mitogenome structures (type A and B) were identified. Two-step direct repeat-mediated recombination was proposed to explain structural changes between type A and B mitogenomes. The five individuals from two varieties in D. indicus diverged well in the whole mitogenome-level comparison with one exception. Collectively, our study elucidated the mitogenome evolution in Rubiaceae along with D. indicus and showed the reliable phylogenetic utility of the whole mitogenome data at a species-level evolution.Plasmodium falciparum's resistance to available antimalarial drugs highlights the need for the development of novel drugs. Pyrimidine de novo biosynthesis is a validated drug target for the prevention and treatment of malaria infection. P. falciparum dihydroorotate dehydrogenase (PfDHODH) catalyzes the oxidation of dihydroorotate to orotate and utilize ubiquinone as an electron acceptor in the fourth step of pyrimidine de novo biosynthesis. PfDHODH is targeted by the inhibitor DSM265, which binds to a hydrophobic pocket located at the N-terminus where ubiquinone binds, which is known to be structurally divergent from the mammalian orthologue. In this study, we screened 40,400 compounds from the Kyoto University chemical library against recombinant PfDHODH. These studies led to the identification of 3,4-dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine and its derivatives as a new class of PfDHODH inhibitor. Moreover, the hit compounds identified in this study are selective for PfDHODH without inhibition of the human enzymes. Finally, this new scaffold of PfDHODH inhibitors showed growth inhibition activity against P. falciparum 3D7 with low toxicity to three human cell lines, providing a new starting point for antimalarial drug development.Several recent studies have shown that citric acid/citrate (CA) can confer abiotic stress tolerance to plants. Exogenous CA application leads to improved growth and yield in crop plants under various abiotic stress conditions. Improved physiological outcomes are associated with higher photosynthetic rates, reduced reactive oxygen species, and better osmoregulation. Application of CA also induces antioxidant defense systems, promotes increased chlorophyll content, and affects secondary metabolism to limit plant growth restrictions under stress. In particular, CA has a major impact on relieving heavy metal stress by promoting precipitation, chelation, and sequestration of metal ions. This review summarizes the mechanisms that mediate CA-regulated changes in plants, primarily CA's involvement in the control of physiological and molecular processes in plants under abiotic stress conditions. We also review genetic engineering strategies for CA-mediated abiotic stress tolerance. Finally, we propose a model to explain how CA's position in complex metabolic networks involving the biosynthesis of phytohormones, amino acids, signaling molecules, and other secondary metabolites could explain some of its abiotic stress-ameliorating properties. This review summarizes our current understanding of CA-mediated abiotic stress tolerance and highlights areas where additional research is needed.
We developed and phenotyped a pigmented knockout rat model for lecithin retinol acyltransferase (LRAT) using CRISPR/Cas9. The introduced mutation (c.12delA) is based on a patient group harboring a homologous homozygous frameshift mutation in the
gene (c.12delC), causing a dysfunctional visual (retinoid) cycle.

The introduced mutation was confirmed by DNA and RNA sequencing. The expression of
was determined on both the RNA and protein level in wildtype and knockout animals using RT-PCR and immunohistochemistry. The retinal structure and function, as well as the visual behavior of the

and control rats, were characterized using scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT), electroretinography (ERG) and vision-based behavioral assays.

Wildtype animals had high
mRNA expression in multiple tissues, including the eye and liver. In contrast, hardly any expression was detected in

animals. LRAT protein was abundantly present in wildtype animals and absent in

animals.

animals showed progressively reduced ERG potentials compared to wildtype controls from two weeks of age onwards. Vison-based behavioral assays confirmed reduced vision. Structural abnormalities, such as overall retinal thinning, were observed in

animals. The retinal thickness in knockout rats was decreased to roughly 80% by four months of age. No functional or structural differences were observed between wildtype and heterozygote animals.

Our

rat is a new animal model for retinal dystrophy, especially for the
-subtype of early-onset retinal dystrophies. This model has advantages over the existing mouse models and the RCS rat strain and can be used for translational studies of retinal dystrophies.
Our Lrat-/- rat is a new animal model for retinal dystrophy, especially for the LRAT-subtype of early-onset retinal dystrophies. This model has advantages over the existing mouse models and the RCS rat strain and can be used for translational studies of retinal dystrophies.Diabetic retinopathy (DR) is a common complication of diabetes that causes severe visual impairment globally. The pathogenesis of DR is related to oxidative stress and chronic inflammation. The fibroblast growth factor type 1 (FGF-1) mitogen plays crucial roles in cell function, development, and metabolism. FGF-1 is involved in blood sugar regulation and exerts beneficial antioxidative and anti-inflammatory effects on various organ systems. This study investigated the antioxidative and anti-inflammatory neuroprotective effects of FGF-1 on high-glucose-induced retinal damage. The results revealed that FGF-1 treatment significantly reversed the harmful effects of oxidative stress and inflammatory mediators in retinal tissue in a streptozotocin-induced diabetic rat model. These protective effects were also observed in the in vitro model of retinal ARPE-19 cells exposed to a high-glucose condition. We demonstrated that FGF-1 attenuated p38 mitogen-activated protein kinase and nuclear factor-κB pathway activation under the high-glucose condition. Our results indicated that FGF-1 could effectively prevent retinal injury in diabetes. The findings of this study could be used to develop novel treatments for DR that aim to reduce the cascade of oxidative stress and inflammatory signals in neuroretinal tissue.Norepinephrine (NE) neurons and extracellular NE exert some protective effects against a variety of insults, including methamphetamine (Meth)-induced cell damage. The intimate mechanism of protection remains difficult to be analyzed in vivo. In fact, this may occur directly on target neurons or as the indirect consequence of NE-induced alterations in the activity of trans-synaptic loops. Therefore, to elude neuronal networks, which may contribute to these effects in vivo, the present study investigates whether NE still protects when directly applied to Meth-treated PC12 cells. Meth was selected based on its detrimental effects along various specific brain areas. The study shows that NE directly protects in vitro against Meth-induced cell damage. The present study indicates that such an effect fully depends on the activation of plasma membrane β2-adrenergic receptors (ARs). Evidence indicates that β2-ARs activation restores autophagy, which is impaired by Meth administration. This occurs via restoration of the autophagy flux and, as assessed by ultrastructural morphometry, by preventing the dissipation of microtubule-associated protein 1 light chain 3 (LC3) from autophagy vacuoles to the cytosol, which is produced instead during Meth toxicity. These findings may have an impact in a variety of degenerative conditions characterized by NE deficiency along with autophagy impairment.Sjögren's syndrome (SS), a chronic inflammatory disease involving the salivary and lacrimal glands, presents symptoms of sicca as well as systemic manifestations such as fatigue and musculoskeletal pain. Only a few treatments have been successful in management of SS; thus treatment of the disease is challenging. Metformin is the first-line agent for type 2 diabetes and has anti-inflammatory potential. Its immunomodulatory capacity is exerted via activation of 5' adenosine monophosphate-activated protein kinase (AMPK). Metformin inhibits mitochondrial respiratory chain complex I which leads to change in adenosine mono-phosphate (AMP) to adenosine tri-phosphate (ATP) ratio. This results in AMPK activation and causes inhibition of mammalian target of rapamycin (mTOR). mTOR plays an important role in T cell differentiation and mTOR deficient T cells differentiate into regulatory T cells. In this manner, metformin enhances immunoregulatory response in an individual. mTOR is responsible for B cell proliferation and germinal center (GC) differentiation. Thus, reduction of B cell differentiation into antibody-producing plasma cells occurs via downregulation of mTOR. Due to the lack of suggested treatment for SS, metformin has been considered as a treatment strategy and is expected to ameliorate salivary gland function.Progressive diabetic nephropathy (DN) in diabetes leads to major morbidity and mortality. The major pathological alterations of DN include mesangial expansion, extracellular matrix alterations, tubulointerstitial fibrosis, and glomerular sclerosis. Polygoni avicularis is widely used in traditional oriental medicine and has long been used as a diuretic, astringent, insecticide and antihypertensive. However, to the best of the authors' knowledge, the effects of the ethanolic extract from rhizome of Polygoni avicularis (ER-PA) on DN have not yet been assessed. The present study aimed to identify the effect of ER-PA on renal dysfunction, which has been implicated in DN in human renal mesangial cells and db/db mice and investigate its mechanism of action. The in vivo experiment was performed using Polygoni avicularis-ethanol soluble fraction (ER-PA) and was administrated to db/db mice at 10 and 50 mg/kg dose. For the in vitro experiments, the human renal mesangial cells were induced by high glucose (HG, 25 mM). The ER-PA group showed significant amelioration in oral glucose tolerance, and insulin resistance index. ER-PA significantly improved the albumin excretion and markedly reduced plasma creatinine, kidney injury molecule-1 and C-reactive protein. In addition, ER-PA significantly suppressed inflammatory cytokines. Histopathologically, ER-PA attenuated glomerular expansion and tubular fibrosis in db/db mice. Furthermore, ER-PA suppressed the expression of renal fibrosis biomarkers (TGF and Collagen IV). ER-PA also reduced the NLR family pyrin domain containing 3 inflammatory factor level. These results suggest that ER-PA has a protective effect against renal dysfunction through improved insulin resistance as well as the inhibition of nephritis and fibrosis in DN.β-thalassaemia is a rare genetic condition caused by mutations in the β-globin gene that result in severe iron-loading anaemia, maintained by a detrimental state of ineffective erythropoiesis (IE). The role of multiple mechanisms involved in the pathophysiology of the disease has been recently unravelled. The unbalanced production of α-globin is a major source of oxidative stress and membrane damage in red blood cells (RBC). In addition, IE is tightly linked to iron metabolism dysregulation, and the relevance of new players of this pathway, i.e., hepcidin, erythroferrone, matriptase-2, among others, has emerged. Advances have been made in understanding the balance between proliferation and maturation of erythroid precursors and the role of specific factors in this process, such as members of the TGF-β superfamily, and their downstream effectors, or the transcription factor GATA1. The increasing understanding of IE allowed for the development of a broad set of potential therapeutic options beyond the current standard of care. Many candidates of disease-modifying drugs are currently under clinical investigation, targeting the regulation of iron metabolism, the production of foetal haemoglobin, the maturation process, or the energetic balance and membrane stability of RBC. Overall, they provide tools and evidence for multiple and synergistic approaches that are effectively moving clinical research in β-thalassaemia from bench to bedside.Urinary acrolein adduct levels have been reported to be increased in both habitual smokers and type-2 diabetic patients. The impairment of glucose transport in skeletal muscles is a major factor responsible for glucose uptake reduction in type-2 diabetic patients. The effect of acrolein on glucose metabolism in skeletal muscle remains unclear. Here, we investigated whether acrolein affects muscular glucose metabolism in vitro and glucose tolerance in vivo. Exposure of mice to acrolein (2.5 and 5 mg/kg/day) for 4 weeks substantially increased fasting blood glucose and impaired glucose tolerance. The glucose transporter-4 (GLUT4) protein expression was significantly decreased in soleus muscles of acrolein-treated mice. The glucose uptake was significantly decreased in differentiated C2C12 myotubes treated with a non-cytotoxic dose of acrolein (1 μM) for 24 and 72 h. Acrolein (0.5-2 μM) also significantly decreased the GLUT4 expression in myotubes. Acrolein suppressed the phosphorylation of glucose metabolic signals IRS1, Akt, mTOR, p70S6K, and GSK3α/β. Over-expression of constitutive activation of Akt reversed the inhibitory effects of acrolein on GLUT4 protein expression and glucose uptake in myotubes. These results suggest that acrolein at doses relevant to human exposure dysregulates glucose metabolism in skeletal muscle cells and impairs glucose tolerance in mice.Atopic dermatitis (AD) is a prototypic inflammatory disease that presents with intense itching. The pathophysiology of AD is multifactorial, involving environmental factors, genetic susceptibility, skin barrier function, and immune responses. A recent understanding of pruritus transmission provides more information about the role of pruritogens in the pathogenesis of AD. There is evidence that pruritogens are not only responsible for eliciting pruritus, but also interact with immune cells and act as inflammatory mediators, which exacerbate the severity of AD. In this review, we discuss the interaction between pruritogens and inflammatory molecules and summarize the targeted therapies for AD.Cold shock Y-box binding protein-1 (YB-1) coordinates several molecular processes between the nucleus and the cytoplasm and plays a crucial role in cell function. Moreover, it is involved in cancer progression, invasion, and metastasis. As trophoblast cells share similar characteristics with cancer cells, we hypothesized that YB-1 might also be necessary for trophoblast functionality. In samples of patients with intrauterine growth restriction, YB-1 mRNA levels were decreased, while they were increased in preeclampsia and unchanged in spontaneous abortions when compared to normal pregnant controls. Studies with overexpression and downregulation of YB-1 were performed to assess the key trophoblast processes in two trophoblast cell lines HTR8/SVneo and JEG3. Overexpression of YB-1 or exposure of trophoblast cells to recombinant YB-1 caused enhanced proliferation, while knockdown of YB-1 lead to proliferative disadvantage in JEG3 or HTR8/SVneo cells. The invasion and migration properties were affected at different degrees among the trophoblast cell lines. Trophoblast expression of genes mediating migration, invasion, apoptosis, and inflammation was altered upon YB-1 downregulation. Moreover, IL-6 secretion was excessively increased in HTR8/SVneo. Ultimately, YB-1 directly binds to NF-κB enhancer mark in HTR8/SVneo cells. Our data show that YB-1 protein is important for trophoblast cell functioning and, when downregulated, leads to trophoblast disadvantage that at least in part is mediated by NF-κB.(1) Background Autophagy, the major cytoplasmic process of substrate turnover, declines with age, contributing to proteostasis decline, accumulation of harmful protein aggregates, damaged mitochondria and to ROS production. Accordingly, abnormalities in the autophagic flux may contribute to many different pathophysiological conditions associated with ageing, including neurodegeneration. Recent data have shown that extra-virgin olive oil (EVOO) polyphenols stimulate cell defenses against plaque-induced neurodegeneration, mainly, through autophagy induction. (2) Methods We carried out a set of in vitro experiments on SH-SY5Y human neuroblastoma cells exposed to toxic Aβ1-42 oligomers to investigate the molecular mechanisms involved in autophagy activation by two olive oil polyphenols, oleuropein aglycone (OleA), arising from the hydrolysis of oleuropein (Ole), the main polyphenol found in olive leaves and drupes and its main metabolite, hydroxytyrosol (HT). (3) Results Our data show that the mixture of the two polyphenols activates synergistically the autophagic flux preventing cell damage by Aβ1-42 oligomers., in terms of ROS production, and impairment of mitochondria. (4) Conclusion Our results support the idea that EVOO polyphenols act synergistically in autophagy modulation against neurodegeneration. These data confirm and provide the rationale to consider these molecules, alone or in combination, as promising candidates to contrast ageing-associated neurodegeneration.Osteoarthritis (OA) is hallmarked by a progressive degradation of articular cartilage. One major driver of OA is inflammation, in which cytokines such as IL-6, TNF-α and IL-1β are secreted by activated chondrocytes, as well as synovial cells-including macrophages. Intra-articular injection of blood products-such as citrate-anticoagulated plasma (CPRP), hyperacute serum (hypACT), and extracellular vesicles (EVs) isolated from blood products-is gaining increasing importance in regenerative medicine for the treatment of OA. A co-culture system of primary OA chondrocytes and activated M1 macrophages was developed to model an OA joint in order to observe the effects of EVs in modulating the inflammatory environment. Primary OA chondrocytes were obtained from patients undergoing total knee replacement. Primary monocytes obtained from voluntary healthy donors and the monocytic cell line THP-1 were differentiated and activated into proinflammatory M1 macrophages. EVs were isolated by ultracentrifugation and characterized by nanoparticle tracking analysis and Western blot. Gene expression analysis of chondrocytes by RT-qPCR revealed increased type II collagen expression, while cytokine profiling via ELISA showed lower TNF-α and IL-1β levels associated with EV treatment. In conclusion, the inflammation model provides an accessible tool to investigate the effects of blood products and EVs in the inflammatory context of OA.The aim of this research was to analyze the heterologous expression, purification, and immunoregulatory activity of recombinant YGP40 (rYGP40), the potential precursor of the yolkin peptide complex. The ygp40 coding sequence was codon optimized, successfully expressed in the E. coli system, and purified from inclusion bodies with a yield of about 1.1 mg/L of culture. This study showed that the protein exhibits immunomodulatory activity, expressed by the stimulation of TNF-α and IL-10 production and nitric oxide induction at a level comparable to that of the natural yolkin peptide complex obtained by other authors from hen egg yolk. At the highest dose of 100 µg/mL, rYGP40 also caused the up-regulation of iNOS expression in murine bone marrow-derived macrophages (BMDM). Moreover, no cytotoxic effects of rYGP40 on the BMDM cell line were observed.Extracellular vesicles (EVs) are membranous, rounded vesicles released by prokaryotic and eukaryotic cells in their normal and pathophysiological states. These vesicles form a network of intercellular communication as they can transfer cell- and function-specific information (lipids, proteins and nucleic acids) to different cells and thus alter their function. Fungi are not an exception; they also release EVs to the extracellular space. The vesicles can also be retained in the periplasm as periplasmic vesicles (PVs) and the cell wall. Such fungal vesicles play various specific roles in the lives of these organisms. They are involved in creating wall architecture and maintaining its integrity, supporting cell isolation and defence against the environment. In the case of pathogenic strains, they might take part in the interactions with the host and affect the infection outcomes. The economic importance of fungi in manufacturing high-quality nutritional and pharmaceutical products and in remediation is considerable. The analysis of fungal EVs opens new horizons for diagnosing fungal infections and developing vaccines against mycoses and novel applications of nanotherapy and sensors in industrial processes.Human estrogens prescribed for hormone replacement therapy (HRT) are known to be potent carcinogens. To find safer estrogens, several chlorinated estrogens were synthesized and their carcinogenic potential were determined. A pellet containing either 2-chloro-17β-estradiol (2-ClE2) or 4-chloro-17β-estradiol (4-ClE2) was implanted subcutaneously for 52 weeks into August Copenhagen Irish (ACI) rats, a preferred animal model for human breast cancer. 17β-Estradiol (E2) frequently induced mammary tumors while both 2-ClE2 and 4-ClE2 did not. Their 17α-ethinyl forms, thought to be orally active estrogens, were also synthesized. Neither 2-chloro-17α-ethinylestradiol (2-ClEE2) nor 4-chloro-17α-ethinylestradiol (4-ClEE2) induced tumors. The less carcinogenic effects were supported by histological examination of mammary glands of ACI rats treated with the chlorinated estrogens. A chlorine atom positioned at the 2- or 4-position of E2 may prevent the metabolic activation, resulting in reducing the carcinogenicity. 2-ClE2 and 4-ClE2 administered subcutaneously and 2-ClEE2 and 4-ClEE2 given orally to ovariectomized rats all showed uterotrophic potency, albeit slightly weaker than that of E2. Our results indicate that less carcinogenic chlorinated estrogens retaining estrogenic potential could be safer alternatives to the carcinogenic estrogens now in use for HRT.It has been recognized that serotonin 2A receptor (5-HT2A) agonist 2,5-dimethoxy-4-iodo-amphetamine (DOI) impairs serotonergic homeostasis. However, the mechanism of DOI-induced serotonergic behaviors remains to be explored. Moreover, little is known about therapeutic interventions against serotonin syndrome, although evidence suggests that ginseng might possess modulating effects on the serotonin system. As ginsenoside Re (GRe) is well-known as a novel antioxidant in the nervous system, we investigated whether GRe modulates 5-HT2A receptor agonist DOI-induced serotonin impairments. We proposed that protein kinase Cδ (PKCδ) mediates serotonergic impairments. Treatment with GRe or 5-HT2A receptor antagonist MDL11939 significantly attenuated DOI-induced serotonergic behaviors (i.e., overall serotonergic syndrome behaviors, head twitch response, hyperthermia) by inhibiting mitochondrial translocation of PKCδ, reducing mitochondrial glutathione peroxidase activity, mitochondrial dysfunction, and mitochondrial oxidative stress in wild-type mice. These attenuations were in line with those observed upon PKCδ inhibition (i.e., pharmacologic inhibitor rottlerin or PKCδ knockout mice). Furthermore, GRe was not further implicated in attenuation mediated by PKCδ knockout in mice. Our results suggest that PKCδ is a therapeutic target for GRe against serotonergic behaviors induced by DOI.Muscular dystrophies (MDs) are a group of inherited degenerative muscle disorders characterized by a progressive skeletal muscle wasting. Respiratory impairments and subsequent hypoxemia are encountered in a significant subgroup of patients in almost all MD forms. In response to hypoxic stress, compensatory mechanisms are activated especially through Hypoxia-Inducible Factor 1 α (HIF-1α). In healthy muscle, hypoxia and HIF-1α activation are known to affect oxidative stress balance and metabolism. Recent evidence has also highlighted HIF-1α as a regulator of myogenesis and satellite cell function. However, the impact of HIF-1α pathway modifications in MDs remains to be investigated. Multifactorial pathological mechanisms could lead to HIF-1α activation in patient skeletal muscles. In addition to the genetic defect per se, respiratory failure or blood vessel alterations could modify hypoxia response pathways. Here, we will discuss the current knowledge about the hypoxia response pathway alterations in MDs and address whether such changes could influence MD pathophysiology.Hypertrophic cardiomyopathy (HCM) is the most common monogenic cardiac disease with a highly variable phenotypic expression, ranging from asymptomatic to drug refractory heart failure (HF) presentation. Pharmacological therapy is the first line of treatment, but options are currently limited to nonspecific medication like betablockers or calcium channel inhibitors, with frequent suboptimal results. While being the gold standard practice for the management of drug refractory HCM patients, septal reduction therapy (SRT) remains an invasive procedure with associated surgical risks and it requires the expertise of the operating centre, thus limiting its accessibility. It is therefore with high interest that researchers look for pharmacological alternatives that could provide higher rates of success. With new data gathering these past years as well as the development of a new drug class showing promising results, this review provides an up-to-date focused synthesis of existing medical treatment options and future directions for HCM pharmacological treatment.
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