Lipid nanovehicles are currently the most advanced vehicles used for RNA delivery, as demonstrated by the approval of patisiran for amyloidosis therapy in 2018. To illuminate the unique superiority of lipid nanovehicles in RNA delivery, in this review, we first introduce various RNA therapeutics, describe systemic delivery barriers, and explain the lipid components and methods used for lipid nanovehicle preparation. Then, we emphasize crucial advances in lipid nanovehicle design for overcoming barriers to systemic RNA delivery. Finally, the current status and challenges of lipid nanovehicle-based RNA therapeutics in clinical applications are also discussed. Our objective is to provide a comprehensive overview showing how to utilize lipid nanovehicles to overcome multiple barriers to systemic RNA delivery, inspiring the development of more high-performance RNA lipid nanovesicles in the future.

BACKGROUND: Rheumatoid arthritis (RA), a chronic systemic autoimmune disease, is characterized by synovitis and progressive damage to the bone and cartilage of the joints, leading to disability and reduced quality of life. This study was a randomized clinical trial comparing the outcomes between withdrawal and dose reduction of tofacitinib in patients with RA who achieved sustained disease control. METHODS: The study was designed as a multicenter, open-label, randomized controlled trial. Eligible patients who were taking tofacitinib (5 mg twice daily) and had achieved sustained RA remission or low disease activity (disease activity score in 28 joints [DAS28] ≤3.2) for at least 3 months were enrolled at six centers in Shanghai, China. Patients were randomly assigned (1:1:1) to one of three treatment groups: continuation of tofacitinib (5 mg twice daily); reduction in tofacitinib dose (5 mg daily); and withdrawal of tofacitinib. Efficacy and safety were assessed up to 6 months. RESULTS: Overall, 122 eligible patients were enrolled, with 41 in the continuation group, 42 in the dose-reduction group, and 39 in the withdrawal group. After 6 months, the percentage of patients with a DAS28-erythrocyte sedimentation rate (ESR) of <3.2 was significantly lower in the withdrawal group than that in the reduction and continuation groups (20.5%, 64.3%, and 95.1%, respectively; P  < 0.0001 for both comparisons). The average flare-free time was 5.8 months for the continuation group, 4.7 months for the dose reduction group, and 2.4 months for the withdrawal group. CONCLUSION: Withdrawal of tofacitinib in patients with RA with stable disease control resulted in a rapid and significant loss of efficacy, while standard or reduced doses of tofacitinib maintained a favorable state. TRIAL REGISTRATION Chictr.org, ChiCTR2000039799.
Humans ; Quality of Life ; China ; Arthritis, Rheumatoid/drug therapy* ; Piperidines/therapeutic use* ; Treatment Outcome ; Antirheumatic Agents/therapeutic use* ; Pyrroles/therapeutic use*

Tenapanor is a novel phosphorus-lowering drug, which mainly inhibits sodium/hydrogen exchange protein 3 (NHE3), and also reduces intestinal phosphorus absorption by down-regulating the expression of sodium phosphate co-transporter protein (NAPI). Tenapanor is mainly used for the treatment of hyperphosphatemia in patients with end-stage renal disease-hemodialysis (ESRD-HD). Diarrhea is the most common adverse reaction to this product. This article reviews Tenapanor by performing a literature search on its pharmacological effects, pharmacokinetic properties, clinical evaluation, safety, drug interactions and dosage.

Objective:To learn about the incidence of hypertension in residents of arsenic exposure areas of Togtoh County, Inner Mongolia Autonomous Region, and to analyze the influencing factors of hypertension.Methods:In Inner Mongolia Autonomous Region, Ciweigou of Togtoh County, a drinking water-type endemic arsenic poisoning area, and Lanjiayao of Horinger County, a non-arsenic poisoning area with similar living habits and economic conditions, permanent residents who had lived for ≥10 years were selected as the survey subjects. Totally 116 residents of Ciweigou (exposure group) and 68 residents of Lanjiayao (control group) were included in the survey. Blood pressure was measured and the contents of arsenic, selenium, lead and chromium in urine were detected, multivariate logistic regression was used to analyze the influencing factors of hypertension.Results:The detection rates of hypertension in exposure group and control group were 53.45% (62/116) and 70.59% (48/68), respectively, and the difference between the two groups was statistically significant (χ 2 = 5.33, P = 0.022). The contents of arsenic, selenium and chromium in urine of exposure group were higher than those of control group, and the content of lead in urine was lower than that of control group, and the differences were statistically significant ( Z = 13.04, 6.34, 11.28, - 9.91, P < 0.001). The results of multivariate logistic regression analysis showed that female, age ≥60 years old and high urinary arsenic content were the influencing factors of hypertension [odds ratio ( OR) = 2.074, 2.004, 0.424, 95% confidence interval ( CI): 1.113 - 3.866, 1.035 - 3.879, 0.219 - 0.820] in arsenic exposure areas. Conclusion:Female, age ≥60 years old and high urinary arsenic content are the influencing factors of hypertension in arsenic exposure areas of Togtoh County, Inner Mongolia Autonomous Region.

OBJECTIVE: Bufalin is an effective drug for the treatment of liver cancer. But its high toxicity, poor water-solubility, fast metabolism and short elimination half-life limit its use in tumor treatment. How to make the drug accumulate in the tumor and reduce side effects while maintaining its efficacy are urgent problems to be solved. The goal of this study is to solve these problems. METHODS: A copolymer with tunable poly-N-isopropylacrylamide and polylactic acid was designed and synthesized. The corresponding dual targeting immunomicelles (DTIs) loaded with bufalin (DTIs-BF) were synthesized by copolymer self-assembly in an aqueous solution. The size and structure of DTIs-BF were determined by ZetaSizer Nano-ZS and transmission electron microscopy. Then, its temperature sensitivity, serum stability, critical micelle concentration (CMC), entrapment efficiency (EE), drug release and non-cytotoxicity of blank block copolymer micelles (BCMs) were evaluated. Next, the effects of DTIs-BF on cellular uptake, cytotoxicity, and tumor cell inhibition were evaluated. Finally, the accumulation of DTIs-fluorescein isothiocyanate (FITC) and the in vivo anti-tumor effect were observed using an interactive video information system. RESULTS: DTIs-BF had a small size, spherical shape, good temperature sensitivity, high serum stability, low CMC, high EE, and slow drug release. The blank BCMs had very low cytotoxicity. Compared with free bufalin, the in vitro cellular internalization and cytotoxicity of DTIs-BF against SMMC-7721 cells were significantly enhanced, and the effects were obviously better at 40 °C than 37 °C. In addition, the therapeutic effect on SMMC-7721 cells was further enhanced by the programmed cell death specifically caused by bufalin. When DTIs-FITC were injected intravenously in BALB/c nude mice bearing liver cancer, the accumulation of FITC was significantly increased in tumors. CONCLUSION DTIs-BF is a potentially effective nano-formulation and has broad prospects in the clinical treatment of liver cancer.
Animals ; Antineoplastic Agents/pharmacology* ; Bufanolides ; Cell Line, Tumor ; Liver Neoplasms/drug therapy* ; Mice ; Mice, Inbred BALB C ; Mice, Nude

Aged ; Bone Nails ; Hip Fractures/surgery* ; Humans ; Retrospective Studies ; Treatment Outcome

[Abstract] Objective: To investigate the mechanisms of carnitine palmitoyltransferase 1c (CPT1c) expression to affect the proliferation and apoptosis of human thyroid papillary cancer B-CPAP cells through the AMP-dependent/activated protein kinase (AMPK) pathway in the low glucose and hypoxic conditions. Methods: Firstly,humanthyroidpapillarycarcinomaB-CPAP cells were cultured under normal condition or low glucose and hypoxic condition respectively, followed with the treatment of AMPK inhibitor compound C. Western blotting was used to detect the expressions of AMPK, p-AMPK, peroxisome proliferator-activated receptor α (PPARα) and CPT1c; the proliferation and apoptosis were detected by CCK-8 and Flow cytometry, respectively. Then PPARα-siRNA was synthesized and transfected into B-CPAP cells to knock down PPARα, and then the cells were cultured under normal or low glucose and hypoxic condition respectively.Above indicators were also detected to verify the regulation of PPARα on CPT1c. Finally, the human luciferase reporter plasmid containing CPT1c gene promoter was constructed, and the effect of PPARα on the activity of CPT1c promoter luciferase activity was observed by immunofluorescence. Results: The expressions ofAMPK, p-AMPK, PPARα and CPT1c were significantly increased in B-CPAP cells under low glucose and hypoxia condition (P<0.05 or P<0.01), while cell proliferation and apoptosis rate did not change significantly (P>0.05). After the treatment of AMPK inhibitor compound C, the expressions of p-AMPK, PPARα and CPT1c in low glucose and hypoxia group were significantly decreased (P<0.05 or P<0.01), the inhibitory rate on cell proliferation and apoptosis rate were significantly increased (P<0.05). However, the change range was smaller than that in the normal culture + compound C group (P<0.05).After PPARα knockdown, the expressions ofAMPK, p-AMPK, PPARα and CPT1c in cancer cells cultured under normal conditions were significantly decreased (P<0.05 or P<0.01), and the inhibitory rate on cell proliferation and apoptosis rate were significantly increased (P<0.05). While under low glucose and hypoxia condition, the expression of CPT1c in cells after transfection was significantly decreased (P<0.05), and the inhibition rate on cell proliferation and the apoptosis rate were significantly increased (P<0.05); However, the change range was still lower than that of normal condition group after transfection (P<0.05).After PPARα overexpression, the ratio of fluorescence in the empty vector group was not significantly different from that of the blank group (P>0.05), and the ratio of fluorescence was significantly increased in PPARα over-expression group (P<0.05). Conclusions: AMPK can increase the expression of PPARα to promote the expression of CPT1c in thyroid cancer B-CPAP cells under low glucose and hypoxia conditions, thereby inhibiting cell apoptosis and maintaining cell proliferation ability.

Osteoporotic fracture is a clinical problem resulting in significant morbidity and mortality. The main treatment for osteoporosis is bisphosphonate therapy. Bisphosphonates can inhibit the bone resorption by osteoclasts, inhibit bone alteration, and maintain bone mass. In recent years, basic and clinical studies have not found evidence that the use of bisphosphonates for the inhibition of fracture healing. Therefore, for the patients with confirmed osteoporotic fracture, bisphosphonate should be used to reduce the risk of re-fracture. The authors summarize the related studies in the bisphosphonate intervention for osteoporotic fracture and recommend postoperative use of bisphosphonate for osteoporotic fracture.

Objective: To explore the efficacy of open reduction and internal fixation in the treatment of senile osteoporotic ankle fractures. Methods: A retrospective case series study was conducted to analyze the data of 26 elderly patients with osteoporotic ankle fractures which all caused by sprain from June 2012 to June 2018 in Changhai Hospital, including 10 male and 16 female patients aged from 60 to 93 years (mean, 69.72 years). In these 26 patients, three had medial malleolus fractures, four had lateral malleolus fractures, six had double ankle fractures and 13 had cotton's fractures. According to the Lauge-Hansen type, all 26 patients can be classified into four types: 5 with supination external rotation type, 4 supination adduction type, 16 with pronation-external rotation type and 1 with pronation abduction type. All the patients received open reduction and internal fixation. Plate fixation was used for lateral and posterior malleolus fractures, plate fixation and cannulated screws were applied to fix the comminuted posterior malleolus fracture while in the comminuted internal malleolus fracture, the steel plate was used only when needed. Early professional functional rehabilitation training and active anti-osteoporosis treatment were applied. All the operation time and bleeding volume were recorded, and the reduction of fracture plus the healing of wounds were observed. At last follow-up, American Orthopedic Foot & Ankle Society (AOFAS) Ankle Hindfoot Scale was used to evaluate the treatment effect and the Visual Analogue Scale (VAS)to evaluate the therapeutic effect and the subjective satisfaction of the patients. Complications were recorded as well. Results: All patients were followed up for 12-48 months (mean, 23.6 months). Operation time ranged from 30 to 95 minutes (mean, 70 minutes) and bleeding volume ranged from 10 to 150 ml (mean, 70 ml). All patients got satisfied reduction of fracture within 25 patients' incision healing in first intention, although one has fat liquefaction. AOFAS Ankle Hindfoot Scale improved from preoperative (84.4±10.8)points to (31.9±11.4)points at last follow-up (P<0.01), and the results were excellent in five patients, good in 17, fair in three and poor in one, with the excellent and good rate of 85%. VAS improved from preoperative(1.85±0.73)points to (9.23±0.28)points at last follow-up (P<0.01). Among 26 patients, 5 with ankle stiffness of different degree recovered after rehabilitation care, and 2 with internal malleolus fractures had bone displacement when receiving rehabilitation care, with no side effect on basic function. No serious complications such as wound infection or skin necrosis were found. Conclusion For osteoporotic ankle fractures in the elderly, open reduction and internal fixation can promote functional recovery and relieve pain.

Fracture healing is a complex physiological process involving osteoblasts, osteoclasts and other cells and molecules. Typical fracture healing can be divided into four stages: inflammatory response, soft callus formation, hard callus formation, and bone remodeling. Osteoclasts play a leading role in hard callus formation and bone remodeling. Alendronate can inhibit osteoclast activity and bone loss in patients with osteoporosis, but it may also inhibit fracture healing. Therefore, whether alendronate can be used after osteoporotic fracture is controversial. In recent years, it has been found that alendronate can not affect the fracture healing, but also reduce the risk of secondary fracture and improve the prognosis of patients. In this article, the mechanism of alendronate and its effect on osteoporotic fracture healing by systemic and local use are reviewed, which can provide a reference for clinical selection of therapeutic drugs.