Osteoimmunology: The correlation between osteoclasts and the Th17/Treg balance in osteoporosis.

Osteoporosis is a bone disease that is caused by disorder of the skeletal microenvironment, and it characterized by a high disability rate and the occurrence of low energy fractures. Studies on osteoporosis and related treatment options have always been hot spots in the field of bone biology. In the past, the understanding of osteoporosis has been rather limited; research has only shown that osteoporosis involves the imbalance of bone resorption and bone formation, and recent studies have not provided cutting-edge theories of the basic understanding of osteoporosis. Recent studies have shown crosstalk between bone and immune responses. RANKL, an essential factor for osteoclasts (OCs), is associated with the immune system. T helper (Th17)/regulatory T (Treg) cells are two different kinds of T cells that can self-interact and regulate the differentiation and formation of OCs. Therefore, understanding the correlation between the skeletal and immune systems and further revealing the roles and the cooperation between RANKL and the Th17/Treg balance will help to provide new insights for the treatment of osteoporosis.

Influence of cement-augmented pedicle screws with different volumes of polymethylmethacrylate in osteoporotic lumbar vertebrae over the adjacent segments: a 3D finite element analysis.

BACKGROUND: Polymethylmethacrylate (PMMA) is commonly used for cement-augmented pedicle screw instrumentation (CAPSI) to improve the fixation stability and reduce the risk of screw loosening in the osteoporotic thoracolumbar spine. Biomechanical researches have shown that various dose of cement (1-3 ml) can be injected to enhance screw stability. To date, there have been no studies on the relationship between adjacent segment degeneration and the volume of PMMA. This study aimed to explore the influence of CAPSI with different volumes of PMMA in osteoporotic lumbar vertebrae over adjacent segments by using finite element analysis. METHODS: Seven different finite element models were reconstructed and simulated under different loading conditions, including (1) an intact model, (2) three single-level CAPSI models with different volumes of PMMA (1, 1.73, and 2.5 ml), and (3) three double-level CAPSI models with different volumes of PMMA (1, 1.73, and 2.5 ml). To improve the accuracy of the finite element analysis, the models of the injectable pedicle screw and bone cement were created by using a three-dimensional scanning machine and the CAPSI patient's CT data, respectively. The range of motion (ROM), the stress of intervertebral discs, and the stress of facet in the adjacent segment were comparatively analyzed among the different models. RESULTS: The ROMs of the different segments were compared with experimental data, with good agreement under the different load conditions (21.3°, 13.55°, 13.99°, and 6.11° in flexion, extension, bending, and rotation at L3-S1 level, respectively). Compared with the intact model, the ROM, disc stresses, and facet stress in adjacent segments were found to be higher in the six operative models. Otherwise, with a larger volume of PMMA injected, the ROM, disc stresses, and facet stress slightly increased at the adjacent segment. However, the differences were insignificant with the biggest difference less than 3.8%. CONCLUSIONS: CAPSI could increase the incidence of disk degeneration in the adjacent segment, while within a certain range, different volumes of PMMA provided an approximate impact over the adjacent segment degeneration.

Nrf2 protects human lens epithelial cells against H2O2-induced oxidative and ER stress: The ATF4 may be involved.

Our previous study has shown heme oxygenase-1 (HO-1) protects human lens epithelial cells (LECs) against H2O2-induced oxidative stress and apoptosis. Nrf2, the major regulator of HO-1, is triggered during the mutual induction of oxidative stress and ER stress. In response to ER stress, unfolded protein response (UPR) serves as a program of transcriptional and translational regulation mechanism with PERK involved. Both Nrf2 and ATF4 are activated as the downstream effect of PERK signaling coordinating the convergence of dual stresses. However, the ways in which Nrf2 interacting with ATF4 regulates deteriorated redox state have not yet been fully explored. Here, the transfected LECs with Nrf2 overexpression illustrated enhanced resistance in morphology and viability upon H2O2 treatment condition. Intracellular ROS accumulation arouses ER stress, initiating PERK dependent UPR and inducing the downstream signal Nrf2 and ATF4 auto-phosphorylation. Further, converging at target promoters, ATF4 facilitates Nrf2 with the expression of ARE-dependent phase II antioxidant and detoxification enzymes. According to either Nrf2 or ATF4 gene modification, our data suggests a novel interaction between Nrf2 and ATF4 under oxidative and ER stress, thus drives specific enzymatic and non-enzymatic reactions of antioxidant mechanisms maintaining redox homeostasis. Therapies that restoring Nrf2 or ATF4 expression might help to postpone LECs aging and age-related cataract formation.

N-methylthioacetylation of RYYRIK-NH2 with enhanced specific binding affinity and high antagonist activity for nociceptin ORL1 receptor.

Antagonists of the neuropeptide nociceptin are expected to be potential analgesic and antineuropathic drugs acting on ORL1 GPCR receptors. The peptide library-based antagonist Ac-RYYRIK-NH2 inhibits the nociceptin activity mediated through ORL1, but preserves a considerably high level of agonist activity. We previously reported that the N-terminal acyl group is important for interaction with specific receptors, and developed isovarelyl-RYYRIK-NH2, which exhibits strong antagonist activity with negligible agonist activity. In the present study, in order to obtain a more potent antagonist, we further modified the isovarelyl group by replacing its Cß atom with an oxygen, nitrogen, or sulfur atom to give the methyl group improved interaction ability. The methyl group bound to such heteroatoms was expected to enhance the hydrophobic interaction between the peptide and the ORL1 receptor. The RYYRIK-NH2 peptide with a methylthioacetyl group, CH3SCH2CO, revealed a higher receptor-binding affinity with strong antagonist activity, and the results suggested the presence of a receptor aromatic group as a complementary residue of this CH3S group.

Tritium-labelled isovaleryl-RYYRIK-NH2 as potential antagonist probe for ORL1 nociceptin receptor.

IsoVa-RYYRIK-NH2 is a highly specific antagonist ligand of the opioid receptor-like 1 (ORL1) receptor, an endogenous ligand of which is 17-mer peptide nociceptin. ORL1 antagonists have potential for clinical use as analgesic and antineuropathic drugs, and thus information on the receptor-binding characteristics of antagonists is very important for rational drug design. In the present study, we prepared tritium-labelled isova-RYYRIK-NH2 from its precursor with the 3-methylcrotonyl (CH3)2CCHCO group by a catalytic reduction using tritium gas. The resulting [(3)H]isoVa-RYYRIK-NH2 was evaluated in a saturation binding assay using the COS-7 cell membrane preparations of transiently expressed ORL1. It exhibited more than 90% specific binding with a dissociation constant of 1.21±0.03nM. From the mutual heterologous binding assays using [(3)H]isoVa-RYYRIK-NH2 and [(3)H]nociceptin, isoVa-RYYRIK-NH2 and nociceptin were found to share the receptor-binding site, but each also had a separate specific binding site of its own. They differentiated the two different binding states or conformations of ORL1, which might represent the agonist-active and antagonist-inactive conformations of ORL1. [(3)H]isoVa-RYYRIK-NH2 is thus a key tracer to uncover the amino acid residues important for receptor inactivation.

Effect of Chitosan and Hyperbranched Poly-L-Lysine Treatment on Quality of Cucumber (Cucumis sativus L.) during Storage.

To enhance the storage time of cucumbers, this research investigated the impact of chitosan (CS) and hyperbranched poly-L-lysine (HBPL) on the quality and nutritional attributes of cucumbers when stored at a temperature of 25 °C. The results demonstrated that sensory evaluation scores for cucumbers treated with a CS-HBPL combination were significantly higher than the control (CK), CS, and HBPL groups. On the 18th day of storage, cucumbers in the CK group exhibited significant decay and softening; however, there was a decrease in hardness observed in the CS-HBPL group and no decay or noticeable sour taste was detected. Furthermore, compared to the CK group, treatment with CS-HBPL effectively delayed cucumber decay and weight loss rate while significantly inhibiting decreases in cucumber hardness and growth of surface microorganisms. Additionally, it substantially reduced losses of soluble protein content as well as vitamin C (Vc), reducing sugars, and total phenolic compounds within cucumbers, which were 4.7 mg/g, 4.7 mg/g, 0.94 mg/g, and 0.52 mg/kg, respectively. Moreover, compared to the CK group, combined treatment with CS-HBPL significantly inhibited malondialdehyde (MDA) accumulation and reducing relative electrolyte permeability within cucumbers, which were 1.45 µmol·g-1FW and 29.82%. Furthermore, it notably enhanced activities of superoxide dismutase (SOD) and catalase (CAT), while exerting a significant inhibitory effect on polyphenol oxidase (PPO). In summary, the combined CS-HBPL treatment successfully prolonged cucumber shelf life at room temperature, enabling new possibilities for extending cucumber shelf life.

Ginsenoside Rb2 exhibits therapeutic value for male osteoporosis in orchiectomy mice by suppressing osteoclastogenesis and modulating NF-κB/MAPK signaling pathways.

Osteoporosis (OP) is a systemic disorder characterized by decreased bone mass as well as deteriorated microarchitecture. Although OP in men is common, it has received much less attention than that in women. Ginseng, a famous traditional herb in Asia, is used to strengthen and repair bones by invigorating vital bioenergy and maintaining body homeostasis in dietary intake and clinical applications. However, there is currently no study investigating the impact of ginseng and its active compounds on male osteoporosis. In this study, RNA sequencing and bioinformatic analysis were conducted to reveal the influence of Ginsenoside-Rb2 on RAW264.7 cells and its underlying signaling pathways. The potential anti-osteoporosis effects of Rb2 as well as its molecular mechanisms were elucidated in RAW264.7 cells and BMMs by TRAP staining, F-actin belt staining, qRT-PCR and WB. Moreover, orchiectomy (ORX) was utilized to demonstrate the influence of Rb2 on bone mass loss in vivo by micro-CT scanning, and H&E, TRAP, and IHC staining. The results suggested that Rb2 suppressed osteoclastogenesis and mitigated bone loss in orchiectomy mice through NF-κB/MAPK signaling pathways. These findings indicate that ginseng as well as its active component Rb2 have potential therapeutic value in the management of osteoporosis in men.

Outcomes of vitrectomy, complete pan-retinal photocoagulation, and endoscopic cyclophotocoagulation surgery after anti-VEGF treatment in neovascular glaucoma.

Purpose: To establish a comprehensive treatment strategy and evaluate the efficacy of combination of anti-vascular endothelial growth factor (VEGF) injection, pars plana vitrectomy (PPV), endoscopic pan-retinal photocoagulation (PRP), and endoscopic cyclophotocoagulation (ECP) surgery for neovascular glaucoma (NVG) patients. Methods: This retrospective study included 30 patients (30 eyes) who were suffering from NVG and treated with PPV & PRP & ECP (ECP group, 16 eyes), or Ahmed glaucoma valve implantation (Ahmed group, 14 eyes). The intraocular pressure (IOP), number of postoperative anti-glaucoma medications, best-corrected visual acuity (BCVA), successful rate of surgery, and postoperative complications were recorded and statistically analyzed at the time points of preoperative, 1-day, 1-month, 3-months, 6-months, and 12-months after operation. Results: An obvious reduction in IOP and number of postoperative anti-glaucoma medications were observed in both the ECP group and Ahmed group after operation (P â€‹< â€‹0.05), and the ECP group showed a significantly lower IOP compared to the Ahmed group at the 6-months (P â€‹= â€‹0.014) and 12-months (P â€‹= â€‹0.047) postoperative time points, while there was no significant difference of medication number between the two groups except for 1-day after surgery. The BCVA showed no marked difference between the two groups preoperatively and postoperatively (P â€‹> â€‹0.05), while it was significantly improved in ECP group at 3-months (P â€‹= â€‹0.001), 6-months (P â€‹= â€‹0.004), and 12-months (P â€‹= â€‹0.010) time points comparing with preoperative BCVA. The surgical success rates in ECP group were also slightly higher than Ahmed group. And the complications after operation showed no marked differences. Conclusions: The comprehensive treatment of PPV, endoscopic PRP, and ECP surgery for NVG patients after anti-VEGF injection can control IOP effectively and be friendly to patients' BCVA without obvious serious complications throughout a 12-months follow-up period.

UV-ARTP-DES compound mutagenesis breeding improves natamycin production of Streptomyces natalensis HW-2 and reveals transcriptional changes by RNA-seq.

Natamycin is widely used in food, medical and health, agriculture, and animal husbandry. In this study, Streptomyces natalensis HW-2 was used as the research object, and a mutant DES-26 with stable genetic characters was selected by UV-ARTP-DES compound mutation. The natamycin yield was 1.64 g/L, 86.36% higher than original strain. Differential expression genes were analyzed by transcriptomics, and results showed that 295 and 860 genes were significantly differentially expressed at fermentation for 48 h and 72 h. GO and KEGG analysis showed that compound mutagenesis had a significant impact on glycolysis, pentose phosphate, TCA cycle, fatty acid metabolism pathways, and several key enzyme genes in the pathways were up-regulated, and genes related to natamycin biosynthesis (pimB-pimI) and transcriptional regulator (pimR) were also up-regulated. qRT-PCR results confirmed that expression levels of these genes were consistent with transcriptional changes of RNA-Seq. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-022-01191-z.

Carbon Monoxide Releasing Molecule-3 Alleviates Oxidative Stress and Apoptosis in Selenite-Induced Cataract in Rats via Activating Nrf2/HO-1 Pathway.

PURPOSE: This study investigated the protective effect of carbon monoxide releasing molecule-3 (CORM-3), the classical donor of carbon monoxide, on selenite-induced cataract in rats and explore its possible mechanism. METHODS: Sprague-Dawley rat pups treated with sodium selenite (Na2SeO3) were chosen as the cataract model. Fifty rat pups were randomly divided into 5 groups: Control group, Na2SeO3 (3.46 mg/kg) group, low-dose CORM-3 (8 mg/kg/d) + Na2SeO3 group, high-dose CORM-3 (16 mg/kg/d) + Na2SeO3 group, and inactivated CORM-3 (iCORM-3) (8 mg/kg/d) + Na2SeO3 group. The protective effect of CORM-3 was tested by lens opacity scores, hematoxylin and eosin staining, TdT-mediated dUTP nick-end labeling assay, and enzyme-linked immunosorbent assay. Besides, quantitative real-time PCR and western blotting were used for mechanism validation. RESULTS: Na2SeO3 induced nuclear cataract rapidly and stably, and the achievement ratio of Na2SeO3 group was 100%. CORM-3 alleviated lens opacity of selenite-induced cataract and attenuated the morphological changes of the rat lens. The levels of antioxidant enzymes GSH and SOD in rat lens were also increased by CORM-3 treatment. CORM-3 significantly reduced the ratio of apoptotic lens epithelial cells, besides, CORM-3 decreased the expression of Cleaved Caspase-3 and Bax induced by selenite and increased the expression of Bcl-2 in rat lens inhibited by selenite. Moreover, Nrf-2 and HO-1 were upregulated and Keap1 was downregulated after CORM-3 treatment. While iCORM-3 did not exert the same effect as CORM-3. CONCLUSIONS: Exogenous CO released from CORM-3 alleviates oxidative stress and apoptosis in selenite-induced rat cataract via activating Nrf2/HO-1 pathway. CORM-3 may serve as a promising preventive and therapeutic strategy for cataract.

Development and Validation of a Prediction Model for Nd:YAG Laser Capsulotomy: A Retrospective Cohort Study of 9768 eyes.

INTRODUCTION: Posterior capsular opacification (PCO) is the most common complication of cataract surgery. In this study, we develop a model to quantitatively predict the probability of Nd:YAG laser capsulotomy for vision-threatening PCO to improve the life quality of postoperative patients. METHODS: A registry analysis of cataract procedures performed between the years 2010 and 2021. Following the screening of 16,802 patients (25,883 eyes), 9768 patients (eyes) were enrolled. The cohort was randomly divided into two groups: training (n = 6838) and validation (n = 2930). To identify relevant risk factors, univariate, multivariate, and Least Absolute Shrinkage and Selection Operator (LASSO) algorithm Cox regression analysis were employed, and a nomogram was created to demonstrate the prediction result. RESULTS: At 5 years, the overall cumulative incidence of Nd:YAG laser capsulotomy was 12.0% (1169/9768). The following variables were included in the prediction model: sex [hazard ratio (HR) = 1.53, 95% CI 1.32-1.76], age (HR = 0.71, 95% CI 0.56-0.88), intraocular lens (IOL) material (HR = 2.65, 95% CI 2.17-3.24), high myopia (HR = 2.28, 95% CI 1.90-2.75), and fibrinogen (HR = 0.79, 95% CI 0.72-0.88). In the validation cohort, the area under the curve (AUC) of 1-, 3-, and 5-year predictions for Nd:YAG laser capsulotomy were 0.702, 0.691, and 0.688, respectively. For a subgroup of patients with high myopia, the protective effect of hydrophobic IOL disappeared (HR = 0.68, 95% CI 0.51-1.12, P = 0.127). CONCLUSION: This model could predict the probability of Nd:YAG laser capsulotomy for vision-threatening PCO after cataract surgery by taking into account factors such as age, gender, IOL material, high myopia, and fibrinogen. Meanwhile, implantation of a hydrophobic IOL in individuals with high myopia did not demonstrate a protective impact against vision-threatening PCO.

Effect of Combined Chitosan and Hyperbranched Poly-L-Lysine Based Coating on Prolonging the Shelf Life of Oyster Mushroom (Pleurotus ostreatus).

To extend the shelf life of oyster mushroom (Pleurotus ostreatus), the effects of chitosan (CS) and hyperbranched poly-L-lysine (HBPL) combined treatment on quality characteristics, nutritional quality, storage characteristics, and enzyme activity of oyster mushroom during postharvest storage at 4 °C were investigated. The results showed that CS-HBPL combined treatment could significantly reduce rot degree and weight loss and significantly inhibit the browning of oyster mushroom. At the same time, the loss of reducing sugar, vitamin C, soluble protein, and total phenolic was significantly reduced. Compared with the control, CS-HBPL combined treatment could also significantly inhibit an increase in malondialdehyde (MDA) and significantly decrease the relative electrolyte leakage of oyster mushroom. In addition, the activities of catalase (CAT), superoxide dismutase (SOD), phenylalnine ammonialyase (PAL), and peroxidase (POD) were significantly improved, and the activity of polyphenol oxidase (PPO) was significantly inhibited in oyster mushroom. In conclusion, CS-HBPL combined treatment had a good protective effect on the membrane permeability damage of oyster mushroom and could effectively delay the oxidation of phenolic substances and browning of oyster mushroom. Therefore, CS-HBPL combined treatment can be used as a potential strategy to extend the storage time of oyster mushroom.

Biliverdin/Bilirubin Redox Pair Protects Lens Epithelial Cells against Oxidative Stress in Age-Related Cataract by Regulating NF-κB/iNOS and Nrf2/HO-1 Pathways.

Age-related cataract (ARC) is the leading cause of vision impairment globally. It has been widely accepted that excessive reactive oxygen species (ROS) accumulation in lens epithelial cells (LECs) is a critical risk factor for ARC formation. Biliverdin (BV)/bilirubin (BR) redox pair is the active by-product of heme degradation with robust antioxidative stress and antiapoptotic effects. Thus, we purpose that BV and BR may have a therapeutic effect on ARC. In the present study, we determine the expression levels of enzymes regulating BV and BR generation in human lens anterior capsule samples. The therapeutic effect of BV/BR redox pair on ARC was assessed in hydrogen peroxide (H2O2)-damaged mouse LECs in vitro. The NF-κB/inducible nitric oxide synthase (iNOS) and nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathways were evaluated to illustrate the molecular mechanism. The results revealed that the mRNA expressions of Nrf2, HO-1, and biliverdin reductase A (BVRA) were all decreased in human samples of age-related nuclear cataract. BV/BR redox pair pretreatment protected LECs against H2O2 damage by prohibiting NF-κB p65 nuclear trafficking, ameliorating iNOS expression, reducing intracellular and mitochondrial ROS levels, and restoring glutathione (GSH) and superoxide dismutase (SOD) levels. BV and BR pretreatment also regulated the expression of apoptotic molecules (Bax, Bcl-2, and cleaved caspase-3), thus decreasing the apoptosis of LECs. In addition, BV/BR pair promoted Nrf2 nuclear accumulation and HO-1 induction, whereas the knockdown of BVRA counteracted the effect of BV on activating Nrf2/HO-1 pathway and antiapoptosis. These findings implicated that BV/BR redox pair protects LECs against H2O2-induced apoptosis by regulating NF-κB/iNOS and Nrf2/HO-1 pathways. Moreover, BVRA is responsible for BV-mediated cytoprotection by reductive conversion of BV to BR. This trial is registered with ChiCTR2000036059.

Protective Effects of Piceatannol against Selenite-Induced Cataract and Oxidative Damage in Rats.

PURPOSE: This study aimed to investigate the protective effects of piceatannol (PIC) on selenite-induced cataracts in Sprague-Dawley rats and explore its therapeutic effects as an antioxidant. METHODS: Thirty-two eight-day-old rat pups were randomly divided into four groups, with eight pups in each of them. Group 1, as the control group, was injected with the same amount of saline, while Groups 2-4 were administered with sodium selenite (3.46 mg/kg) subcutaneously into the neck on postpartum day 10 for cataract induction. Without further treatment, Group 2 served as the control model, while Groups 3 and 4 (low- and high-dose PIC-treated) had intraperitoneal piceatannol from day 8 to day 17 at doses of 10 mg/kg and 20 mg/kg, respectively. On postpartum day 17, after the last injection, the rat pups were examined for cataract grade by slit lamp, and the lenses of every group were isolated for oxidative damage indicators and further analysis. SRA01/04 cells were exposed to 600 µM H2O2 for 24 hours with or without pretreatment with 10µÐœ piceatannol. Cell viability was tested by CCK-8 assay and cell apoptosis was evaluated by AnnexinV-PE/7AAD assay. RESULTS: This study determined that compared with the model group, the degree of lens opacity was significantly reduced in PIC-treated groups. The histopathological damage of the lenses in the PIC-treated groups improved compared to the model group. There were fewer signs of lesions, such as vacuoles and atrophy. The biochemical results indicated that malondialdehyde (MDA) content of the PIC-treated groups were downregulated and the antioxidant enzyme activities (GSH and catalase) and antioxidant status (SOD) were upregulated compared with the model group. In vitro, piceatannol significantly restored cell viability and cell apoptosis under H2O2 injury. CONCLUSION: Pretreatment with piceatannol may achieve a protective effect on cataract development through upregulating antioxidant enzyme activity.

Biliverdin Reductase A Protects Lens Epithelial Cells against Oxidative Damage and Cellular Senescence in Age-Related Cataract.

Age-related cataract (ARC) is the common cause of blindness globally. Reactive oxygen species (ROS), one of the greatest contributors to aging process, leads to oxidative damage and senescence of lens epithelial cells (LECs), which are involved in the pathogenesis of ARC. Biliverdin reductase A (BVRA) has ROS-scavenging ability by converting biliverdin (BV) into bilirubin (BR). However, little is known about the protective effect of BVRA against ARC. In the present study, we measured the expression level of BVRA and BR generation in human samples. Then, the antioxidative property of BVRA was compared between the young and senescent LECs upon stress condition. In addition, we evaluated the effect of BVRA on attenuating H2O2-induced premature senescence in LECs. The results showed that the mRNA expression level of BVRA and BR concentration were decreased in both LECs and lens cortex of age-related nuclear cataract. Using the RNA interference technique, we found that BVRA defends LECs against oxidative stress via (i) restoring mitochondrial dysfunction in a BR-dependent manner, (ii) inducing heme oxygenase-1 (HO-1) expression directly, and (iii) promoting phosphorylation of ERK1/2 and nuclear delivery of nuclear factor erythroid 2-related factor 2 (Nrf2). Intriguingly, the antioxidative effect of BVRA was diminished along with the reduced BR concentration and repressed nuclear translocation of BVRA and Nrf2 in senescent LECs, which would be resulted from the decreased BVRA activity and impaired nucleocytoplasmic trafficking. Eventually, we confirmed that BVRA accelerates the G1 phase transition and prevents against H2O2-induced premature senescence in LECs. In summary, BVRA protects LECs against oxidative stress and cellular senescence in ARC by converting BV into BR, inducing HO-1 expression, and activating the ERK/Nrf2 pathway. This trial is registered with ChiCTR2000036059.

A Novel RANKL-Targeted Furoquinoline Alkaloid Ameliorates Bone Loss in Ovariectomized Osteoporosis through Inhibiting the NF-κB Signal Pathway and Reducing Reactive Oxygen Species.

Dysregulation of osteoclast-osteoblast balance, resulting in abnormal bone remodeling, is responsible for postmenopausal osteoporosis (PMOP) or other secondary forms of osteoporosis. We demonstrated that dictamnine (DIC), a novel RANKL-targeted furoquinoline alkaloid, inhibits osteoclastogenesis by facilitating the activities of reactive oxygen species (ROS), NF-κB, and NFATc1 in vitro and prevents the development of OVX-induced osteoporosis mouse models in vivo. Methods. The docking mechanism of DIC and RANKL was initially identified by protein-ligand molecular docking. RNA sequencing was performed and analyzed to reveal the potential mechanism and signaling pathway of the antiosteoporosis effects of DIC. To verify the sequencing results, we examined the impact of DIC on RANKL-induced osteoclast differentiation, bone resorption, F-actin ring production, ROS generation, and NF-κB activation in osteoclasts in vitro. Moreover, a luciferase assay was performed to determine the binding and transcriptional activity of Nrf2 and NF-κB. The in vivo efficacy of DIC was assessed with an ovariectomy- (OVX-) induced osteoporosis model, which was analyzed using micro-CT and bone histomorphometry. Results. The molecular docking results indicated that DIC could bind particularly to RANKL. RNA-seq confirmed that DIC could regulate the osteoclast-related pathway. DIC suppressed osteoclastogenesis, bone resorption, F-actin belt formation, osteoclast-specific gene expression, and ROS activity by preventing NFATc1 expression and affecting NF-κB signaling pathways in vitro. The luciferase assay showed that DIC not only suppressed the activity of Nrf2 but also contributed to the combination of Nrf2 and NF-κB. Our in vivo study indicated that DIC protects against OVX-induced osteoporosis and preserves bone volume by inhibiting osteoclast activity and function. Conclusions. DIC can ameliorate osteoclast formation and OVX-induced osteoporosis and therefore is a potential therapeutic treatment for osteoporosis.

A prediction model for worsening diabetic retinopathy after panretinal photocoagulation.

BACKGROUND: As one of the severe complications of diabetes mellitus, diabetic retinopathy (DR) is the leading cause of blindness in the working age worldwide. Although panretinal photocoagulation (PRP) was standard treatment, PRP-treated DR still has a high risk of progression. Hence, this study aimed to assess the risk factors and establish a model for predicting worsening diabetic retinopathy (DR-worsening) within five years after PRP. METHODS: Patients who were diagnosed with severe non-proliferative diabetic retinopathy or proliferative diabetic retinopathy and treated with PRP were included, and those patients were randomly assigned to either a training or validation cohort. The multivariate logistic regression analysis was used to screen potential risk factors for DR-worsening in the training cohort. Then the model was established after including significant independent risk factors and further validated using discrimination and calibration. RESULTS: A total of 271 patients were included, and 56.46% of patients had an outcome of DR-worsening. In the training cohort (n = 135), age (odds ratio [OR] = 0.94, 95% confidence interval [CI] 0.90-0.98), baseline best corrected visual acuity (logMAR) (OR = 10.74, 95% CI 1.84-62.52), diabetic nephropathy (OR = 9.32, 95% CI 1.49-58.46), and hyperlipidemia (OR = 3.34, 95% CI 1.05-10.66) were screened out as the independent risk factors, which were incorporated into the predictive model. The area under the receiver operating characteristic curve and calibration slope in the training and validation cohort were 0.79, 0.96 (95% CI 0.60-1.31), and 0.79, 1.00 (95% CI 0.66-1.34), respectively. Two risk groups were developed depending on the best cut-off value of the predicted probability, and the actual probability was 34.90% and 82.79% in the low-risk and high-risk groups, respectively (P < 0.001). CONCLUSIONS: This study developed and internally validated a new model to predict the probability of DR-worsening after PRP treatment within five years. The model can be used as a rapid risk assessment system for clinical prediction of DR-worsening and identify individuals at a high risk of DR-worsening at an early stage and prescribe additional treatment.

Two-dimensional ultrathin Ti3C2 MXene nanosheets coated intraocular lens for synergistic photothermal and NIR-controllable rapamycin releasing therapy against posterior capsule opacification.

Posterior capsule opacification (PCO) is one of the most frequent late-onset complications after cataract surgery. Several kinds of drug-eluting intraocular lenses (IOL) were designed for sustainable drug release to suppress ocular inflammation, the proliferation of lens epithelial cells (LECs) and the development of PCO after cataract surgery. Despite previous advances in this field, the drug-loaded IOLs were limited in ocular toxicity, insufficient drug-loading capacity, and short release time. To prevent PCO and to address these drawbacks, a novel drug-loaded IOL (Rapa@Ti3C2-IOL), prepared from two-dimensional ultrathin Ti3C2 MXene nanosheets and rapamycin (Rapa), was fabricated with a two-step spin coating method in this study. Rapa@Ti3C2 was prepared via electrostatic self-assembly of Ti3C2 and Rapa, with a loading capacity of Rapa at 92%. Ti3C2 was used as a drug delivery reservoir of Rapa. Rapa@Ti3C2-IOL was designed to have the synergistic photothermal and near infrared (NIR)-controllable drug release property. As a result, Rapa@Ti3C2-IOL exhibited the advantages of simple preparation, high light transmittance, excellent photothermal conversion capacity, and NIR-controllable drug release behavior. The Rapa@Ti3C2 coating effectively eliminated the LECs around Rapa@Ti3C2-IOL under a mild 808-nm NIR laser irradiation (1.0 W/cm-2). Moreover, NIR-controllable Rapa release inhibited the migration of LECs and suppressed the inflammatory response after photothermal therapy in vitro. Then, Rapa@Ti3C2-IOL was implanted into chinchilla rabbit eyes, and the effectiveness and biocompatibility to prevent PCO were evaluated for 4 weeks. The Rapa@Ti3C2-IOL implant exhibited excellent PCO prevention ability with the assistance of NIR irradiation and no obvious pathological damage was observed in surrounding healthy tissues. In summary, the present study offers a promising strategy for preventing PCO via ultrathin Ti3C2 MXene nanosheet-based IOLs with synergistic photothermal and NIR-controllable Rapa release properties.

Long-Term Outcomes of Peripheral Pulmonary Cement Embolism in Patients with Polymethylmethacrylate Augmentation: A Case Series with a Minimum Follow-Up of Five Years.

BACKGROUND: Pulmonary cement embolism (PCE) is a rare but lethal complication. However, few long-term follow-up studies have investigated PCE after polymethylmethacrylate augmentation. This study aimed to investigate both the clinical and imaging outcomes of patients with PCE during a follow-up period of at least 5 years. METHODS: A total of 1460 patients were initially included in this retrospective study. After exclusion, the clinical and imaging data were analyzed for selected patients, including the augmented level, location and length of the PCE, symptoms, therapy, migration and disintegration of the embolism, foreign body reaction, and status at follow-up. RESULTS: Twelve female patients (age range, 56-88 years) with PCE and more than 5 years of follow-up (range, 5-13 years) were eventually included. All emboli were found in subsegment pulmonary arteries and were classified as peripheral PCE. Although 2 patients experienced transient symptoms after surgery, the majority of patients (84.6%) were asymptomatic during follow-up. No other reported emboli were observed during the follow-up period. The imaging data showed that the cement embolus could remain in the initial position throughout the long-term follow-up. In terms of the length of the PCE, there was no statistically significant difference between the values post-operation and at the last follow-up time (P > 0.05). CONCLUSIONS: Patients with peripheral PCE do not develop known late complications. Moreover, polymethylmethacrylate can remain stable and inert in the pulmonary vasculature over the long term. Routine prophylactic anticoagulation may not be necessary for patients with peripheral PCE during follow-up.

The Roles of Long Non-coding RNA in Osteoporosis.

The Human Genome Project (HGP) announced in 2001 that it had sequenced the entire human genome, yielding nearly complete human DNA. About 98.5 percent of the human genome has been found to be non-coding sequences. Long non-coding RNA (lncRNA) is a non-coding RNA with a length between 200 and 100,000 nucleotide units. Because of shallow research on lncRNA, it was believed that it had no biological functions, but exists as a by-product of the transcription process. With the development of high-throughput sequencing technology, studies have shown that lncRNA plays important roles in many processes by participating in epigenetics, transcription, translation and protein modification. Current researches have shown that lncRNA also has an important part in the pathogenesis of osteoporosis. Osteoporosis is a common disorder of bone metabolism, also a major medical and socioeconomic challenge worldwide. It is characterized by a systemic reduction in bone mass and microstructure changes, which increases the risk of brittle fractures. It is more common in postmenopausal women and elderly men. However, the roles of lncRNA and relevant mechanisms in osteoporosis remain unclear. Based on this background, we hereby review the roles of lncRNA in osteoporosis, and how it influences the functions of osteoblasts and osteoclasts, providing reference to clinical diagnosis, treatment and prognosis of osteoporosis.