Novel one-pot strategy for fabrication of a pH-Responsive bone-targeted drug self-frame delivery system for treatment of osteoporosis.

Osteoporosis (OP) is a systemic metabolic orthopedic disorder prevalent in elderly people, that is characterized by a decrease in bone mass. Although many therapeutics have been adopted for OP treatment, many of them are still not well satisfied clinical requirements and therefore development of novel therapeutics is of great significance. In this work, a novel bone-targeting drug self-frame delivery system (DSFDS) with high drug loading efficiency and pH responsive drug release was fabricated by condensation of curcumin (Cur), amino group terminated polyethylene glycol (NH2-PEG), and alendronate (ALN) using hexachlorocyclotriphosphonitrile (HCCP) as the linker. The final product named as HCCP-Cur-PEG-ALN (HCPA NPs) displayed excellent water dispersity with small size (181.9 â€‹± â€‹25.9 â€‹nm). Furthermore, the drug loading capacity of Cur can reach 25.8%, and Cur can be released from HCPA NPs under acidic environment. Owing to the introduction of ALN, HCPA NPs exhibited strong binding to HAp in vitro and excellent bone-targeting effect in vivo. Results from cellular and biochemical analyses revealed that HCPA NPs could effectively inhibit the formation and differentiation function of osteoclasts. More importantly, we also demonstrated that HCPA NPs could effectively reduce bone loss in OVX mice with low toxicity to major organs. The above results clearly demonstrated that HCPA NPs are promising for OP treatment. Given the simplicity and well designability of fabrication strategy, explicit therapy efficacy and low toxicity of HCPA NPs, we believe that this work should be of great interest for fabrication of various DSFDS to deal with many diseases.

AP39 inhibits ferroptosis by inhibiting mitochondrial autophagy through the PINK1/parkin pathway to improve myocardial fibrosis with myocardial infarction.

BACKGROUND AND PURPOSE: Research has revealed the involvement of mitochondrial autophagy and iron death in the pathogenesis of myocardial fibrosis. The objective of this study is to investigate whether the mitochondrial-targeted H2S donor AP39 inhibits mitochondrial autophagy and antagonizes myocardial cell iron death through the PINK1/Parkin pathway, thereby improving myocardial fibrosis in rats with myocardial infarction. EXPERIMENTAL APPROACH: A rat model of myocardial infarction was created by intraperitoneal injection of a high dose of isoproterenol, and H9c2 myocardial cells were subjected to hypoxic injury induced by CoCl2. Western blot, RT-PCR, transmission electron microscopy, immunohistochemistry, as well as echocardiography, and studies on isolated hearts were employed. KEY RESULTS: In the hearts of rats with myocardial infarction, there was a significant accumulation of interstitial collagen fibers, accompanied by downregulation of CSE protein expression, activation of the PINK1/Parkin signaling pathway, and activation of mitochondrial autophagy. Intervention with AP39 resulted in a significant improvement of the aforementioned changes, which could be reversed by the addition of PAG. Similar results were observed in vitro experiments. Furthermore, the addition of CCCP reversed the antagonistic effect of AP39 on myocardial cell iron death, while the addition of RSL3 reversed the inhibitory effect of AP39 on collagen production in myocardial cells. CONCLUSION AND IMPLICATIONS: The mitochondrial-targeted H2S donor AP39 can inhibit mitochondrial autophagy through the PINK1/Parkin pathway, antagonize myocardial cell iron death, and improve myocardial fibrosis in rats with myocardial infarction.

Facile synthesis of curcumin-containing poly(amidoamine) dendrimers as pH-responsive delivery system for osteoporosis treatment.

Osteoporosis is an age-related metabolic disease of bone, resulting in bone pain and even bone fragility and brittle fracture. Inhibiting overactive osteoclasts while promoting osteoblast activity is an ideal way to treat osteoporosis. Previous studies have demonstrated that natural compounds, such as curcumin (Cur) have dual roles both in promoting bone formation and inhibiting bone resorption, making them promising candidates for osteoporosis treatment. However, their poor water solubility, high dosage of curative effect and significant toxicity to other organs have largely limited their clinical translations. In this study, a novel method was reported to conjugate Cur and poly(amidoamine) dendrimers (PAD) using hexachlorocyclotriphosphazene (HCCP) as the linkage through a one-pot reaction, forming stable and uniform Cur loaded nanospheres (HCCP-Cur-PAD, HCP NPs). Owing to the hydrophilicity of PAD and hydrophobicity of Cur, HCP NPs can self-assemble into nanoparticles with particle size of 138.8 ± 78.7 nm and display excellent water dispersity. The loading capacity of Cur can reach 27.2% and it can be released from HCP NPs with pH-responsiveness. In vitro experimental results demonstrated that the HCP NPs entered lysosomes by endocytosis and proved dual anti-osteoporosis effects of inhibiting osteoclasts and promoting osteoblasts.

Oridonin Inhibits SARS-CoV-2 by Targeting Its 3C-Like Protease.

The current COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an enormous threat to public health. The SARS-CoV-2 3C-like protease (3CLpro), which is critical for viral replication and transcription, has been recognized as an ideal drug target. Herein, it is identified that three herbal compounds, Salvianolic acid A (SAA), (-)-Epigallocatechin gallate (EGCG), and Oridonin, directly inhibit the activity of SARS-CoV-2 3CLpro. Further, blocking SARS-CoV-2 infectivity by Oridonin is confirmed in cell-based experiments. By solving the crystal structure of 3CLpro in complex with Oridonin and comparing it to that of other ligands with 3CLpro, it is identified that Oridonin binds at the 3CLpro catalytic site by forming a C-S covalent bond, which is confirmed by mass spectrometry and kinetic study, blocking substrate binding through a nonpeptidomimetic covalent binding mode. Thus, Oridonin is a novel candidate to develop a new antiviral treatment for COVID-19.

Effects and mechanisms of natural plant active compounds for the treatment of osteoclast-mediated bone destructive diseases.

Bone-destructive diseases, caused by overdifferentiation of osteoclasts, reduce bone mass and quality, and disrupt bone microstructure, thereby causes osteoporosis, Paget's disease, osteolytic bone metastases, and rheumatoid arthritis. Osteoclasts, the only multinucleated cells with bone resorption function, are derived from haematopoietic progenitors of the monocyte/macrophage lineage. The regulation of osteoclast differentiation is considered an effective target for the treatment of bone-destructive diseases. Natural plant-derived products have received increasing attention in recent years due to their good safety profile, the preference of natural compounds over synthetic drugs, and their potential therapeutic and preventive activity against osteoclast-mediated bone-destructive diseases. In this study, we reviewed the research progress of the potential antiosteoclast active compounds extracted from medicinal plants and their molecular mechanisms. Active compounds from natural plants that inhibit osteoclast differentiation and functions include flavonoids, terpenoids, quinones, glucosides, polyphenols, alkaloids, coumarins, lignans, and limonoids. They inhibit bone destruction by downregulating the expression of osteoclast-specific marker genes (CTSK, MMP-9, TRAP, OSCAR, DC-STAMP, V-ATPase d2, and integrin av3) and transcription factors (c-Fos, NFATc1, and c-Src), prevent the effects of local factors (ROS, LPS, and NO), and suppress the activation of various signalling pathways (MAPK, NF-κB, Akt, and Ca2+). Therefore, osteoclast-targeting natural products are of great value in the prevention and treatment of bone destructive diseases.

Cupidesulfovibrio liaohensis gen. nov., sp. nov., a novel sulphate-reducing bacterium isolated from an oil reservoir and reclassification of Desulfovibrio oxamicus and Desulfovibrio termitidis as Cupidesulfovibrio oxamicus comb. nov. and Cupidesulfovibrio termitidis comb. nov.

A novel sulphate-reducing, Gram-stain-negative, anaerobic strain, isolate XJ01T, recovered from production fluid at the LiaoHe oilfield, PR China, was the subject of a polyphasic study. The isolate together with Desulfovibrio oxamicus NCIMB 9442T and Desulfovibrio termitidis DSM 5308T formed a distinct, well-supported clade in the Desulfovibrionaceae 16S rRNA gene tree. The taxonomic status of the clade was underscored by complementary phenotypic data. The three isolates comprising the clade formed distinct phyletic branches and were distinguished using a combination of physiological features and by low average nucleotide identity and digital DNA-DNA hybridization values. Consequently, it is proposed that isolate XJ01T represents a novel genus and species for which the name Cupidesulfovibrio liaohensis gen. nov., sp. nov. is proposed with the type strain XJ01T (=CGMCC 1.5227T=DSM 107637T). It is also proposed that D. oxamicus and D. termitidis be reclassified as Cupidesulfovibrio oxamicus comb. nov. and Cupidesulfovibrio termitidis comb. nov., respectively.

Osteopoikilosis found incidentally in a 17-year-old adolescent with femoral shaft fracture: A case report.

RATIONALE: Osteopoikilosis is a rare and asymptomatic disease of the bone, which is often discovered occasionally on radiography for irrelevant complaints. Characterized by multiple, small, circular, or oval-shaped radiodense lesions, it may be confused with bony metastatic tumors. PATIENT CONCERNS: The present study describes a case of a 17-year-old adolescent who suffered from pain and movement limitation of his left thigh following a fall from standing height. DIAGNOSES: Plain radiographs showed spiral fracture in left femoral shaft; besides, multiple scattered sclerotic lesions of variable size were also observed over the bilateral proximal femurs, left distal femur, proximal tibia, and distal tibia and fibula through X-rays, computed tomography, and magnetic resonance imaging. The patient was finally diagnosed with left femoral shaft fracture and osteopoikilosis. INTERVENTIONS: The patient underwent reduction and internal fixation with intramedullary nail a week after injury. OUTCOMES: The patient was discharged without any complications 12 days after the surgery. At the 3-month follow-up, the patient recovered well and remained symptom-free with no changes to his sclerotic lesions. LESSONS: Although this case is not so complicated, we have to be cautious when differentiating osteopoikilosis and bony metastases in clinical practice in future, which should avoid causing undue distress to both the patients and doctors.

Neurocognitive impairment of mental rotation in major depressive disorder: evidence from event-related brain potentials.

Mental rotation performance may be used as an index of mental slowing or bradyphrenia and may reflect speed of motor preparation. Previous studies suggest that major depressive disorder (MDD) presents correlates of impaired behavioral performance for mental rotation and psychomotor disturbance. Very little is known about the electrophysiological mechanism underlying this deficit. The present study was the first to investigate the event-related brain potential (ERP) correlates of mental rotation and their mental slowing or bradyphrenia in MDD. ERPs were recorded while we tested 25 MDD patients and 26 healthy controls by evaluating the performance of MDD patients on hand and letter rotation tasks at different orientations, and their 400-to-600-msec time window was measured and analyzed for latencies and peak amplitudes over the electrodes. First, individuals with MDD were slower and made more errors in mentally rotating hands and letters than healthy controls did, and individuals with MDD exhibited a greater difference in response times and errors than controls did between hands and letters. Second, the mean peak amplitude was significantly lower and the mean latency was significantly longer in the 400-to-600-msec time window at the parietal site in the hand tasks in MDD patients than in controls, but this was not seen in the letter task, with only lower mean peak amplitude. MDD patients present the absence of a typical mental rotation function for the amplitude of the rotation-related negativity in the hand and letter tasks. Third, the scalp activity maps in MDD patients exhibited the absence of activation in the left parietal site for the mental rotation of hands, as shown in healthy participants. In contrast, their brain activation for the letter task was similar to those of healthy participants. These data suggest that mental imagery of hands and letters relies on different cognitive and neural mechanisms and indicate that the left posterior parietal lobe is a necessary structure for mental transformations of human hands. Importantly, MDD deficits were more seriously present specific to the hands than the letters. Such impairment may also be an important and possibly defining marker of MDD in particular.

The association between the disruption of motor imagery and the number of depressive episodes of major depression.

BACKGROUND: Mental rotation performance may be used as an index of mental slowing or bradyphrenia, and may reflect, in particular, speed of motor preparation. Previous studies suggest depressive patients present the correlates of impaired behavioural performance for mental rotation and psychomotor disturbance. The aim of this study is to compare the mental rotation abilities of patients with a first episode of depression, recurrent depression and healthy control subjects with regard to hand tasks. METHODS: We tested 32 first episode of depression, 38 recurrent depression and 36 healthy control subjects by evaluating the performance of depressed patients with regard to the hand mental rotation tasks. RESULTS: First, the first episode and recurrent depression subjects were significantly slower and made more errors than controls in mentally rotating hands. Second, the first depressive episode but not the recurrent depression displayed the same pattern of response times to stimuli at various orientations relative to control subjects in the hand task. Third, in particular, recurrent depression subjects were significantly slower and made more errors during the mental transformation of hands than first depressive episode relative to control subjects and the differences were significantly larger in female than male subjects in the mental rotation hand task. LIMITATIONS: Patients were on antidepressant medication. CONCLUSIONS: These results suggest that the impaired behavioural performance for mental representation processing are related to the number of previous episodes. Moreover, the recurrent major depressive episodes may contribute to the reinforcement of cognitive impairments and further the development or maintenance of mental representation dysfunctions, especially in female patients. A deficit on mental rotation in the depressive patients may be potential biomarkers for recurrence chronically.