Isokinetic training of lower extremity during the early stage promote functional restoration in elder patients with disability after Total knee replacement (TKR) - a randomized control trial.

BACKGROUND: Transient progressive weakness and disability of lower limb during the early stage after TKR will increase the risk of fall, but the superior postoperative strength training mode have not been elucidated for functional restoration. This study aimed to compare whether the isokinetic lower limb training is superior to either isotonic or home isometric exercise during early stage after TKR in older people. METHODS: A total of 43 recruited old participants (mean age, 68.40 years old) receiving TKR were divided randomly based on the different four-week training modes into three groups including isokinetic, isotonic, and home isometric exercise (control group). The primary outcome was set as functional performance in terms of Timed Up and Go (TUG) test and the secondary outcomes include the peak torque of knee at 60 and 120 degree/ second, Short-Form 36 Health Survey (SF-36), and Western Ontario and McMaster Universities Arthritis index (WOMAC). RESULTS: All of the peak torque measurements of the knee improved significantly in both the isokinetic and the isotonic group, but not in the control group. Although isotonic training resulted in more strength gains, a significant enhancement in TUG test was observed in the isokinetic group only (p = 0.003). However, there were no significantly improvement of TUG test after training in other two groups. SF-36 and WOMAC improved after training in all three groups, with no significant difference in the degree of improvement between groups. CONCLUSION: Isokinetic training for 4 weeks following TKR effectively improved all the outcome parameters in this study, including the TUG test, lower limb strength, and functional scores. However, both isokinetic and isotonic training modes could be recommended after TKR because of no significant difference in the degree of improvement between these two groups. TRIAL REGISTRATION: Clinical trial registration number: NCT02938416. LEVEL OF EVIDENCE: I.

De Novo Noninversion Variants Implicated in Sporadic Hemophilia A: A Variant Origin and Timing Study.

Sporadic hemophilia A (HA) enables the persistence of HA in the population. F8 gene inversion originates mainly in male germ cells during meiosis. To date, no studies have shown the origin and timing of HA sporadic noninversion variants (NIVs); herein, we assume that HA-sporadic NIVs are generated as a de novo variant. Of the 125 registered families with HA, 22 were eligible for inclusion. We conducted a linkage analysis using F8 gene markers and amplification refractory mutation system-quantitative polymerase chain reaction to confirm the origin of the sporadic NIVs (~0% mutant cells) or the presence of a mosaic variant, which requires further confirmation of the origin in the parent. Nine mothers, four maternal grandmothers, and six maternal grandfathers were confirmed to be the origin of sporadic NIVs, which most likely occurred in the zygote within the first few cell divisions and in single sperm cells, respectively. Three mothers had mosaic variants, which most likely occurred early in postzygotic embryogenesis. All maternal grandparents were free from sporadic NIV. In conclusion, F8 NIVs in sporadic HA were found to be caused primarily by de novo variants. Our studies are essential for understanding the genetic pathogenesis of HA and improving current genetic counseling.

Does positive feedback or appraisal about medical providers increase patients' trust and lead to better treatment outcomes? A double-blind randomized control trial.

[Purpose] Trust among patients and clinical suppliers is the foundation for achieving appropriate treatment. This double-blind randomized control trial aimed to determine whether providing patients a pre-treatment physical therapists' introductions and positive appraisal can enhance the trust of patients in therapists. [Participants and Methods] This study included patients diagnosed with lumbar spine spondylosis or non-acute lower back muscle strain who were divided into intervention and control groups. The previously recorded video informed the intervention group patients that they were assigned to our best therapist because of their participation. The primary outcome was evaluated twice, once before and once after the treatment, and the secondary outcome was measured using the second time pain inventory evaluation. [Results] A total of 32 patients participated in this study. No significant difference was found in patients' trust in therapists between the two groups, and a lower successful treatment rate with a higher pain influence level to daily life was noted in the intervention group. [Conclusion] Doctors who offer introductions with a positive assessment of physical therapists cannot change the trust of patients on therapists. Furthermore, this action may risk worse treatment outcomes.

Origin and timing of de novo variants implicated in type 2 von Willebrand disease.

Very few studies have shown the real origin and timing of de novo variants (DNV) implicated in von Willebrand disease (VWD). We investigated four families with type 2 VWD. First, we conducted linkage analysis using single nucleotide variant genotyping to recognize the possible provenance of DNV. Second, we performed amplification refractory mutation system-quantitative polymerase chain reaction to confirm the real origin of variant (~0% mutant cells) or presence of a genetic mosaic variant (0%-50% mutant cells) in three embryonic germ layer-derived tissues and sperm cells. Then, three possible timings of DNV were categorized based on the relative likelihood of occurrence according to the number of cell divisions during embryogenesis. Two each with type 2B VWD (proband 1 p.Arg1308Cys, proband 4 p.Arg1306Trp) and type 2A VWD (proband 2 p.Leu1276Arg, proband 3 p.Ser1506Leu) were identified. Variant origins were identified for families 1, 2 and 3 and confirmed to originate from the mother, father and father, respectively. However, the father of family 4 was confirmed to have isolated germline mosaicism with 2.2% mutant sperm cells. Further investigation confirmed the paternal grandfather to be the origin of variant. Thus, we proposed that DNV originating from the two fathers most likely occurred at the single sperm cell, the one originating from the mother occurred at the zygote during the first few cellular divisions; alternatively, in family 4, the DNV most likely occurred at the early postzygotic development in the father. Our findings are essential for understanding genetic pathogenesis and providing accurate genetic counselling.

Curbing COVID-19 progression and mortality with traditional Chinese medicine among hospitalized patients with COVID-19: A propensity score-matched analysis.

BACKGROUND: Viral- and host-targeted traditional Chinese medicine (TCM) formulae NRICM101 and NRICM102 were administered to hospitalized patients with COVID-19 during the mid-2021 outbreak in Taiwan. We report the outcomes by measuring the risks of intubation or admission to intensive care unit (ICU) for patients requiring no oxygen support, and death for those requiring oxygen therapy. METHODS: This multicenter retrospective study retrieved data of 840 patients admitted to 9 hospitals between May 1 and July 26, 2021. After propensity score matching, 302 patients (151 received NRICM101 and 151 did not) and 246 patients (123 received NRICM102 and 123 did not) were included in the analysis to assess relative risks. RESULTS: During the 30-day observation period, no endpoint occurred in the patients receiving NRICM101 plus usual care while 14 (9.27%) in the group receiving only usual care were intubated or admitted to ICU. The numbers of deceased patients were 7 (5.69%) in the group receiving NRICM102 plus usual care and 27 (21.95%) in the usual care group. No patients receiving NRICM101 transitioned to a more severe status; NRICM102 users were 74.07% less likely to die than non-users (relative risk= 25.93%, 95% confidence interval 11.73%-57.29%). CONCLUSION: NRICM101 and NRICM102 were significantly associated with a lower risk of intubation/ICU admission or death among patients with mild-to-severe COVID-19. This study provides real-world evidence of adopting broad-spectrum oral therapeutics and shortening the gap between outbreak and effective response. It offers a new vision in our preparation for future pandemics.

Intermittent parathyroid hormone treatment affects the bone structural parameters and mechanical strength of the femoral neck after ovariectomy-induced osteoporosis in rats.

BACKGROUND: Menopause-induced decline in estrogen levels in women is a main factor leading to osteoporosis. The objective of this study was to investigate the effect of intermittent parathyroid hormone (PTH) on bone structural parameters of the femoral neck in ovariectomized rats, in addition to correlations of maximum fracture force. METHODS: Fifteen female Wister rats were divided into three groups: (1) control group; (2) ovariectomized (OVX) group; and (3) OVX + PTH group. All rats were then killed and the femurs extracted for microcomputed tomography scanning to measure volumetric bone mineral density (vBMD) and bone structural parameters of the femoral neck. Furthermore, the fracture forces of femoral neck were measured using a material testing system. RESULTS: Compared with the control and OVX + PTH groups, the OVX group had significantly lower aBMD, bone parameter, and mechanical strength values. A comparison between OVX and OVX + PTH groups indicated that PTH treatment increased several bone parameters. However, the OVX + PTH groups did not significantly differ with the control group with respect to the bone structural parameters, except for trabecular bone thickness of cancellous bone, which was greater. In addition, among the bone structural parameters, the CSA and BSI of cortical bone were significantly correlated with the maximum fracture force of the femoral neck, with correlations of, respectively, 0.682 (p = 0.005) and 0.700 (p = 0.004). CONCLUSION: Intermittent PTH helped treat ovariectomy-induced osteoporosis of cancellous bone and cortical bone in the femoral necks of rats. The ability of the femoral neck to resist fracture was highly correlated with the two parameters, namely cross-sectional area (CSA) and bone strength index (= vBMD × CSA), of cortical bone in the femoral neck and was less correlated with aBMD or other bone structural parameters.

The Protective Effects of n-Butylidenephthalide on Retinal Ganglion Cells during Ischemic Injury.

Clinically, acute ischemic symptoms in the eyes are one of the main causes of vision loss, with the associated inflammatory response and oxidative stress being the key factors that cause injury. Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common type of ischemic optic neuropathy (ION); however, there are still no effective or safe treatment options to date. In this study, we investigated the neuroprotective effects of n-butylidenephthalide (BP) treatment in an experimental NAION rodent model (rAION). BP (10 mg/kg) or PBS (control group) were administered on seven consecutive days in the rAION model. Rats were evaluated for visual function by flash visual evoked potentials (FVEPs) at 4 weeks after NAION induction. The retina and optic nerve were removed for histological examination after the rats were euthanized. The molecular machinery of BP treatment in the rAION model was analyzed using Western blotting. We discovered that BP effectively improves retinal ganglion cell survival rates by preventing apoptotic processes after AION induction and reducing the inflammatory response through which blood-borne macrophages infiltrate the optic nerve. In addition, BP significantly preserved the integrity of the myelin sheath in the rAION model, demonstrating that BP can prevent the development of demyelination. Our immunoblotting results revealed the molecular mechanism through which BP mitigates the neuroinflammatory response through inhibition of the NF-κB signaling pathway. Taken together, these results demonstrate that BP can be used as an exceptional neuroprotective agent for ischemic injury.

Hydroxygenkwanin Improves the Efficacy of Cytotoxic Drugs in ABCG2-Overexpressing Multidrug-Resistant Cancer Cells.

Hydroxygenkwanin, a flavonoid isolated from the leaves of the Daphne genkwa plant, is known to have pharmacological properties; however, its modulatory effect on multidrug resistance, which is (MDR) mediated by ATP-binding cassette (ABC) drug transporters, has not been investigated. In this study, we examine the interaction between hydroxygenkwanin, ABCB1, and ABCG2, which are two of the most well-characterized ABC transporters known to contribute to clinical MDR in cancer patients. Hydroxygenkwanin is not an efflux substrate of either ABCB1 or ABCG2. We discovered that, in a concentration-dependent manner, hydroxygenkwanin significantly reverses ABCG2-mediated resistance to multiple cytotoxic anticancer drugs in ABCG2-overexpressing multidrug-resistant cancer cells. Although it inhibited the drug transport function of ABCG2, it had no significant effect on the protein expression of this transporter in cancer cells. Experimental data showing that hydroxygenkwanin stimulates the ATPase activity of ABCG2, and in silico docking analysis of hydroxygenkwanin binding to the inward-open conformation of human ABCG2, further indicate that hydroxygenkwanin sensitizes ABCG2-overexpressing cancer cells by binding to the substrate-binding pocket of ABCG2 and attenuating the transport function of ABCG2. This study demonstrates the potential use of hydroxygenkwanin as an effective inhibitor of ABCG2 in drug combination therapy trials for patients with tumors expressing higher levels of ABCG2.

The Effects of Lycium chinense, Cuscuta chinensis, Senna tora, Ophiopogon japonicus, and Dendrobium nobile Decoction on a Dry Eye Mouse Model.

Background and objective: Dry eye disease (DED) is a relatively common disorder associated with abnormal tear film and the ocular surface that causes ocular irritation, dryness, visual impairment, and damage to the cornea. DED is not a life-threatening disease but causes discomfort and multifactorial disorders in vision that affect daily life. It has been reported that all traditional medicinal plants exhibit anti-inflammatory effects on several diseases. We hypothesized that the decoction ameliorated ocular irritation and decreased cytokine expression in the cornea. This study aimed to investigate the molecular mechanisms of DED and discover a therapeutic strategy to reduce corneal inflammation. Material and Methods: We used a DED mouse model with extraorbital lacrimal gland (ELG) excision and treated the mice with a decoction of five traditional medicines: Lycium chinense, Cuscuta chinensis, Senna tora, Ophiopogon japonicus, and Dendrobium nobile for 3 months. The tear osmolarity and the ocular surface staining were evaluated as indicators of DED. Immunohistochemistry was used to detect the level of inflammation on the cornea. Results: After treatment with the decoction for three months, epithelial erosions and desquamation were reduced, the intact of corneal endothelium was maintained, and tear osmolarity was restored in the eyes. The IL-1ß-associated inflammatory response was reduced in the cornea in the DED model. Conclusions: These data suggested that a mixture of traditional medicines might be a novel therapy to treat DED.

Recent advances in functional conservation and divergence of recombinase RAD51 and DMC1.

Meiosis is a specialized cell division that occurs in reproductive cells during sexual reproduction. It contains once DNA replication following nucleus division twice, thus producing haploid gametes. Fusion of male and female gametes restores genome to the diploid level, which not only ensures the genome stability between generations during sexual reproduction, but also leads to genetic diversity among offspring. Meiosis homologous recombination (HR) is one of the crucial events during meiotic prophase I, and it not only ensures the subsequently faithful segregation of homologous chromosomes (homologs), but also exchanges genetic information between homologs with greatly increasing the genetic diversity of progeny. RAD51 (RADiation sensitive 51) and DMC1 (disruption Meiotic cDNA 1) are essential recombinases for the HR process, and have certain commonalities and differences. In this review, we summarize and compare the conserved and differentiated features of RAD51 and DMC1 in terms of origin, evolution, structure, and function, we also provide an outlook on future research directions to further understand and study the molecular mechanisms in regulation of meiotic recombination.

Delineation of molecular findings by whole-exome sequencing for suspected cases of paediatric-onset mitochondrial diseases in the Southern Chinese population.

BACKGROUND: Mitochondrial diseases (MDs) are a group of clinically and genetically heterogeneous disorders characterized by defects in oxidative phosphorylation. Since clinical phenotypes of MDs may be non-specific, genetic diagnosis is crucial for guiding disease management. In the current study, whole-exome sequencing (WES) was performed for our paediatric-onset MD cohort of a Southern Chinese origin, with the aim of identifying key disease-causing variants in the Chinese patients with MDs. METHODS: We recruited Chinese patients who had paediatric-onset MDs and a minimum mitochondrial disease criteria (MDC) score of 3. Patients with positive target gene or mitochondrial DNA sequencing results were excluded. WES was performed, variants with population frequency ≤ 1% were analysed for pathogenicity on the basis of the American College of Medical Genetics and Genomics guidelines. RESULTS: Sixty-six patients with pre-biopsy MDC scores of 3-8 were recruited. The overall diagnostic yield was 35% (23/66). Eleven patients (17%) were found to have mutations in MD-related genes, with COQ4 having the highest mutation rate owing to the Chinese-specific founder mutation (4/66, 6%). Twelve patients (12/66, 18%) had mutations in non-MD-related genes: ATP1A3 (n = 3, two were siblings), ALDH5A1, ARX, FA2H, KCNT1, LDHD, NEFL, NKX2-2, TBCK, and WAC. CONCLUSIONS: We confirmed that the COQ4:c.370G>A, p.(Gly124Ser) variant, was a founder mutation among the Southern Chinese population. Screening for this mutation should therefore be considered while diagnosing Chinese patients suspected to have MDs. Furthermore, WES has proven to be useful in detecting variants in patients suspected to have MDs because it helps to obtain an unbiased and precise genetic diagnosis for these diseases, which are genetically heterogeneous.

Ultrasound Shear Wave Elastography for Evaluation of Diaphragm Stiffness in Patients with Stable COPD: A Pilot Trial.

OBJECTIVES: Skeletal muscle dysfunction is one of the most common comorbidities in chronic obstructive pulmonary disease (COPD). The occurrence of respiratory failure in COPD is common and leads to the patient's death. The diaphragm is the most important muscle in the respiratory system and plays a key role in the onset of respiratory failure. This study explores the feasibility of ultrasound shear wave elastography (SWE) to measure diaphragmatic stiffness and evaluates its changes in COPD patients. METHODS: In total, 77 participants (43 patients with stable COPD and 34 healthy controls) were enrolled. All subjects underwent complete diaphragmatic ultrasound SWE measurements and pulmonary function tests. The diaphragmatic stiffness was indicated via diaphragmatic shear wave velocity (SWV) at functional residual capacity (FRC). A trained operator performed the ultrasound SWE examinations of the first 15 healthy controls thrice to assess the reliability of diaphragmatic SWE. RESULTS: A good to excellent reliability was found in diaphragmatic SWV at FRC (ICC = 0.93, 95%CI 0.82-0.98). As compared to the control group, the diaphragmatic SWV at FRC was considerably high in the COPD group (median 2.5 m/s versus 2.1 m/s, P = .008). Diaphragmatic SWV at FRC was linked to forced expiratory volume in one second (r = -0.30, P = .009), forced vital capacity (r = -0.33, P = .003), modified Medical Research Council score (r = 0.30, P = .001), and COPD assessment test score (r = 0.48, P < .001). CONCLUSIONS: Ultrasound SWE may be employed as an effective tool for quantitative evaluation of diaphragm stiffness and can help in personalized management of COPD, such as treatment guidance and follow-up monitoring.

Association of osteoporosis and varus inclination of the tibial plateau in postmenopausal women with advanced osteoarthritis of the knee.

BACKGROUND: Although varus inclination of the tibial plateau has increasingly been recognized as a major risk factor in the progression of Osteoarthritis of the knee (OA knee), little attention has been placed on the development of the varus inclination of the tibial plateau. Osteoporosis is a disease characterized by low bone mass and may increase the risk of a stress fracture in the proximal tibia. To date, risk factors for varus inclination of the tibial plateau are rarely reported. In this study, we investigated Bone Mineral Density (BMD) as a risk factor of varus inclination of the tibial plateau in postmenopausal women with advanced OA knee. METHODS: A total of 90 postmenopausal women with varus OA knee who had received a total knee arthroplasty in our department between January 2016 and December 2019 were reviewed. Certain factors may correlate to inclination of the tibial plateau (Medial Tibial Plateau Angle, MTPA), including age, operation side, Kellgren-Lawrence grade of OA knee, BMD, Body Mass Index (BMI), Lateral Distal Femur Angle (LDFA), lower extremity alignment (Hip-Knee-Ankle angle, HKAA), and history of both spinal compression fracture and hip fracture were collected and analyzed. RESULTS: Osteoporosis, lower extremity varus malalignment and age were significantly associated with varus inclination of the tibial plateau (MTPA) (P = 0.15, 0.013 and 0.033 respectively). For patients with a lower extremity varus malalignment (HKAA < 175°), osteoporosis (T-score ≤ -2.5) was significantly associated with inclination of the tibial plateau. For patients with a normal lower extremity alignment (HKAA ≥ 175°), no significant association was found between osteoporosis (T-score ≤ -2.5) and varus inclination of the tibial plateau. CONCLUSIONS: Osteoporosis, lower extremity varus malalignment and age are major risk factors for inclination of the tibial plateau in postmenopausal women with OA knee. More attention needs to be given to the progression of varus OA knee in postmenopausal women who simultaneously has osteoporosis and lower extremity varus malalignment.

Handgrip strength: a reliable predictor of postoperative early ambulation capacity for the elderly with hip fracture.

BACKGROUNDS: A common sequela of hip fracture is loss of ambulation capacity. Prediction of postoperative ambulation capacity is important for surgical and rehabilitation decision making. Handgrip strength is a quick and convenient tool for evaluating postoperative functional ability and outcome in variety of clinical conditions for the elderly and is associated with the use of walking aids. We propose that handgrip strength may be a good predictor for postoperative early ambulation. The purpose of our study was to investigate the contribution of handgrip strength in the prediction of postoperative early ambulation capacity in elderly hip fracture patients. METHODS: Clinical data of patients with low-energy hip fractures who received surgery from Jan 2018 to Dec 2019 were prospectively collected. The correlations of ambulation time with complication rate, age, gender, injured side, fracture classifications, surgical procedure, body mass index (BMI), and handgrip strength were analyzed. RESULTS: Sixty-three hip fracture patients were included in this study. Patients whose ambulation time was less than 3 days after the operation had significantly fewer postoperative complications (P = 0.006). Handgrip strength showed the strongest correlation with postoperative early ambulation capacity (P = 0.004). The handgrip strength threshold value for early ambulation was found to be 20.5 kg for male patients and 11.5 kg for female patients. CONCLUSION: Handgrip strength testis a quick and convenient tool for predicting postoperative early ambulation capacity. In elderly Asians, male patients with a handgrip strength above 20.5 kg and female patients with a handgrip strength above 11.5 kg suggest a high likelihood of early postoperative ambulation and a lower risk of complications after the hip surgery.

Superficial Temporal Artery Arteriovenous Fistula and Pseudoaneurysm: The Yin-Yang Sign.

Online supplemental material is available for this article.

4-(Phenylsulfanyl) Butan-2-One Attenuates the Inflammatory Response Induced by Amyloid-ß Oligomers in Retinal Pigment Epithelium Cells.

Age-related macular degeneration (AMD) is a progressive eye disease that causes irreversible impairment of central vision, and effective treatment is not yet available. Extracellular accumulation of amyloid-beta (Aß) in drusen that lie under the retinal pigment epithelium (RPE) has been reported as one of the early signs of AMD and was found in more than 60% of Alzheimer's disease (AD) patients. Extracellular deposition of Aß can induce the expression of inflammatory cytokines such as IL-1ß, TNF-α, COX-2, and iNOS in RPE cells. Thus, finding a compound that can effectively reduce the inflammatory response may help the treatment of AMD. In this research, we investigated the anti-inflammatory effect of the coral-derived compound 4-(phenylsulfanyl) butan-2-one (4-PSB-2) on Aß1-42 oligomer (oAß1-42) added to the human adult retinal pigment epithelial cell line (ARPE-19). Our results demonstrated that 4-PSB-2 can decrease the elevated expressions of TNF-α, COX-2, and iNOS via NF-κB signaling in ARPE-19 cells treated with oAß1-42 without causing any cytotoxicity or notable side effects. This study suggests that 4-PSB-2 is a promising drug candidate for attenuation of AMD.

Optic nerve head width and retinal nerve fiber layer changes are proper indexes for validating the successful induction of experimental anterior ischemic optic neuropathy.

Reproducible skills are essential for successful induction of a rat model of anterior ischemic optic neuropathy (rAION). We established an in vivo validation index by measuring the natural course of optic nerve head (ONH) width and retinal nerve fiber layer (RNFL) thickness in the rAION model using optical coherence tomography (OCT). The rAION model was induced by photodynamic operations. We measured the ONH width, RNFL, Inner Plexiform layer (IPL) and Ganglion cell complex (GCC) thickness in the acute stage (<3 days), subacute stage (day-7 to day-14) and later stage (day-14 to day-28) post-infarct by OCT. Retinal layers were measured by hematoxylin and eosin stain (HE) to confirm the OCT findings. The RGCs survival rate was determined by retrograde Fluoro-gold labeling, and the visual function was assessed with flash visual-evoked potentials (FVEPs) 4 weeks post-infarct. We observed significant thinning in GCC, IPL, and RNFL at day-14 and day-28 but only RNFL showed significant thinning between day-14 and day-28. The ONH showed significant swelling in the acute stage which correlated at a greater extent with RNFL than GCC and IPL. Further RNFL correlated at a greater extent at with GCC than IPL. HE-stained retina cross sections also showed IPL and RNFL thinning, which further confirmed our OCT findings. The RGC density and P1-N2 amplitude were significantly reduced in rAION. Our data suggest that Swelling, reduction of swelling, and atrophy of RNFL in acute, sub-acute, and later stage, respectively and ONH swelling in the acute stage are essential events for confirming the successful induction of rAION.

Isorhamnetin ameliorates inflammatory responses and articular cartilage damage in the rats of monosodium iodoacetate-induced osteoarthritis.

Context: Osteoarthritis (OA) is a degenerative joint disease with damage to the articular cartilage. Active production of inflammatory cytokine/chemokine and matrix metalloproteinases may be found during the progression of OA. Isorhamnetin had the effects of anti-inflammatory, antioxidant, anti-ischemia, anti-atherosclerotic hepatoprotective and anticancer activities. Objective: Our study was focused on the effects of isorhamnetin treatment in OA. Materials and methods: We used monosodium iodoacetate (MIA)-induced OA rats to evaluate the effects of isorhamnetin related anti-inflammatory process. The rats in all groups were sacrificed on four weeks post-MIA injection. The measurements of knee joint swelling, histological analysis, serum inflammatory biomarkers and western blot were evaluated. Results: We found that isorhamnetin may reduce MIA-induced knee swelling by significantly reduction of articular cartilage damage.in rats. Suppression of pro-inflammatory cytokines production was found after isohamnetin treatment. Isorhamnetin inhibited the production of NO and PGE2, and the expression of iNOS and COX-2. The production of COMP, CTX-II and osteopontin (OPN) were also inhibited in MIA-induced OA rats. Discussion and conclusions: Isorhamnetin may modulate the inflammatory progression of OA in MIA-induced OA rats. The prevention of cartilage damage was found in OA after adequate isorhamnetin treatment. Isorhamnetin may serve as a potential agent for the management of OA.

Identifying Key Networks Linked to Light-Independent Photoreceptor Degeneration in Visual Arrestin 1 Knockout Mice.

When visual arrestin 1 (ARR1, S-antigen, 48 KDa protein) was genetically knocked out in mice (original Arr1 -/- , designated Arr1 -/-A ), rod photoreceptors degenerated in a light-dependent manner. Subsequently, a light-independent cone dystrophy was identified with minimal rod death in ARR1 knockout mice (Arr1 -/-A Arr4 +/+, designated Arr1 -/-B ), which were F2 littermates from breeding the original Arr1 -/-A and cone arrestin knockout 4 (Arr4 -/- ) mice. To resolve the genetic and phenotypic differences between the two ARR1 knockouts, we performed Affymetrix™ exon array analysis to focus on the potential differential gene expression profile and to explore the molecular and cellular pathways leading to this observed susceptibility to cone dystrophy in Arr1 -/-B compared to Arr1 -/-A or control Arr1 +/+ Arr4 +/+ (wild type [WT]). Only in the Arr1 -/-B retina did we observe an up-regulation of retinal transcripts involved in the immune response, inflammatory response and JAK-STAT signaling molecules, OSMRß and phosphorylation of STAT3. Of these responses, the complement system was significantly higher, and a variety of inflammatory responses by complement regulation and anti-inflammatory cytokine or factors were identified in Arr1 -/-B retinal transcripts. This discovery supports that Arr1 -/-B has a distinct genetic background from Arr1 -/-A that results in alterations in its retinal phenotype leading to susceptibility to cone degeneration induced by inappropriate inflammatory and immune responses.

Downregulations of AKT/mTOR Signaling Pathway for Salmonella-Mediated Suppression of Matrix Metalloproteinases-9 Expression in Mouse Tumor Models.

The roles of Matrix MetalloProteinases (MMPs), such as MMP-9, in tumor metastasis are well studied, and this in turns stimulates the development of MMP inhibitors as antitumor agents. Previously, Salmonella accumulation was observed in the metastatic nodules of the lungs after systemic administration. Salmonella significantly enhanced the survival of the pulmonary metastatic tumor-bearing mice. Based on our previous observation, we hypothesized that Salmonella could affect metastasis-related protein expression. The treatment of Salmonella clearly reduced the expression of MMP-9. Meanwhile, the MMP-9 related signaling pathways, including Phosph-Protein Kinase B (P-AKT) and Phosph-mammalian Targets Of Rapamycin (P-mTOR) were decreased after a Salmonella treatment. The Salmonella inhibited tumor cell migration by wound-healing and Transwell assay. The anti-metastatic effects of Salmonella were evaluated in mice bearing experimental metastasis tumor models. Consequently, Salmonella inhibited the expression of MMP-9 by reducing the AKT/mTOR pathway and metastatic nodules in vivo.