Ultrasensitive PD-L1-Expressing Exosome Immunosensors Based on a Chemiluminescent Nickel-Cobalt Hydroxide Nanoflower for Diagnosis and Classification of Lung Adenocarcinoma.

Programmed death ligand-1 (PD-L1)-expressing exosomes are considered a potential marker for diagnosis and classification of lung adenocarcinoma (LUAD). There is an urgent need to develop highly sensitive and accurate chemiluminescence (CL) immunosensors for the detection of PD-L1-expressing exosomes. Herein, N-(4-aminobutyl)-N-ethylisopropanol-functionalized nickel-cobalt hydroxide (NiCo-DH-AA) with a hollow nanoflower structure as a highly efficient CL nanoprobe was synthesized using gold nanoparticles as a "bridge". The resulting NiCo-DH-AA exhibited a strong and stable CL emission, which was ascribed to the exceptional catalytic capability and large specific surface area of NiCo-DH, along with the capacity of AuNPs to facilitate free radical generation. On this basis, an ultrasensitive sandwich CL immunosensor for the detection of PD-L1-expressing exosomes was constructed by using PD-L1 antibody-modified NiCo-DH-AA as an effective signal probe and rabbit anti-CD63 protein polyclonal antibody-modified carboxylated magnetic bead as a capture platform. The immunosensor demonstrated outstanding analytical performance with a wide detection range of 4.75 × 103-4.75 × 108 particles/mL and a low detection limit of 7.76 × 102 particles/mL, which was over 2 orders of magnitude lower than the reported CL method for detecting PD-L1-expressing exosomes. Importantly, it was able to differentiate well not only between healthy persons and LUAD patients (100% specificity and 87.5% sensitivity) but also between patients with minimally invasive adenocarcinoma and invasive adenocarcinoma (92.3% specificity and 52.6% sensitivity). Therefore, this study not only presents an ultrasensitive and accurate diagnostic method for LUAD but also offers a novel, simple, and noninvasive approach for the classification of LUAD.

MHC1/LILRB1 axis as an innate immune checkpoint for cancer therapy.

Immune checkpoint blockades (ICBs) have revolutionized cancer therapy through unleashing anti-tumor adaptive immunity. Despite that, they are usually effective only in a small subset of patients and relapse can occur in patients who initially respond to the treatment. Recent breakthroughs in this field have identified innate immune checkpoints harnessed by cancer cells to escape immunosurveillance from innate immunity. MHC1 appears to be such a molecule expressed on cancer cells which can transmit a negative signal to innate immune cells through interaction with leukocyte immunoglobulin like receptor B1 (LILRB1). The review aims to summarize the current understanding of MHC1/LILRB1 axis on mediating cancer immune evasion with an emphasis on the therapeutic potential to block this axis for cancer therapy. Nevertheless, one should note that this field is still in its infancy and more studies are warranted to further verify the effectiveness and safety in clinical as well as the potential to combine with existing immune checkpoints.

Function of Steroid Receptor Coactivators in T Cells and Cancers: Implications for Cancer Immunotherapy.

Steroid receptor coactivator (SRC) family members (SRC1, SRC2 and SRC3) are transcriptional co-regulators. SRCs orchestrate gene transcription by inducing transactivation of nuclear receptors and other transcription factors. Overexpression of SRCs is widely implicated in a range of cancers, especially hormone-related cancers. As coactivators, SRCs regulate multiple metabolic pathways involved in tumor growth, invasion, metastasis, and chemo-resistance. Emerging evidence in recent years suggest that SRCs also regulate maturation, differentiation, and cytotoxicity of T cells by controlling metabolic activities. In this review, we summarize the current understanding of the function of SRCs in T cells as well as cancer cells. Importantly, the controversies of targeting SRCs for cancer immunotherapy as well as possible reconciliation strategies are also discussed.

Magnetic Nanoparticles and Methylprednisolone Based Physico-Chemical Bifunctional Neural Stem Cells Delivery System for Spinal Cord Injury Repair.

Neural stem cells (NSCs) transplantation is an attractive and promising treatment strategy for spinal cord injury (SCI). Various pathological processes including the severe inflammatory cascade and difficulty in stable proliferation and differentiation of NSCs limit its application and translation. Here, a novel physico-chemical bifunctional neural stem cells delivery system containing magnetic nanoparticles (MNPs and methylprednisolone (MP) is designed to repair SCI, the former regulates NSCs differentiation through magnetic mechanical stimulation in the chronic phase, while the latter alleviates inflammatory response in the acute phase. The delivery system releases MP to promote microglial M2 polarization, inhibit M1 polarization, and reduce neuronal apoptosis. Meanwhile, NSCs tend to differentiate into functional neurons with magnetic mechanical stimulation generated by MNPs in the static magnetic field, which is related to the activation of the PI3K/AKT/mTOR pathway. SCI mice achieve better functional recovery after receiving NSCs transplantation via physico-chemical bifunctional delivery system, which has milder inflammation, higher number of M2 microglia, more functional neurons, and axonal regeneration. Together, this bifunctional NSCs delivery system combined physical mechanical stimulation and chemical drug therapy is demonstrated to be effective, which provides new treatment insights into clinical transformation of SCI repair.

Comparison of one-hole split endoscopic discectomy and microendoscopic discectomy in the treatment of lumbar disk herniation: a one-year retrospective cohort study.

BACKGROUND: We aim to compare and assess the surgical parameters and follow-up information of one-hole split endoscopic discectomy (OSE) and microendoscopic discectomy (MED) in the treatment of LDH. METHODS: This study included 154 patients with degenerative lumbar disk disease. Sixty-eight patients underwent OSE and 86 patients MED. The VAS score for lower back and lower limb radiation pain, ODI score, modified MacNab score, estimated blood loss (EBL), length of the incision, amount of C-reactive protein, and recurrence and complication rates were examined as indicators for clinical outcomes and adverse events. RESULTS: After surgery, the VAS and ODI scores in the two groups significantly decreased. On the third day after surgery, the VAS and ODI scores of the OSE group were significantly better than those of the MED group. The VAS and ODI scores preoperatively and at 1 month, 3 months, 6 months, and 12 months following the procedure did not substantially vary between the two groups. There was less EBL and a shorter incision with OSE than with MED. There was no significant difference in the rate of complications between the two groups. CONCLUSION: Compared with MED, OSE is a new alternative option for LDH that can achieve similar and satisfactory clinical outcomes. Furthermore, OSE has many advantages, including less EBL and a smaller incision. Further clinical studies are needed to confirm the effectiveness of OSE.

Biomechanical assessment of different transforaminal lumbar interbody fusion constructs in normal and osteoporotic condition: a finite element analysis.

BACKGROUND CONTEXT: With the aging population, osteoporosis, which leads to poor fusion, has become a common challenge for lumbar surgery. In addition, most people with osteoporosis are elderly individuals with poor surgical tolerance, and poor bone quality can also weaken the stability of internal fixation. PURPOSE: This study compared the fixation strength of the bilateral traditional trajectory screw structure (TT-TT), the bilateral cortical bone trajectory screw structure (CBT-CBT), and the hybrid CBT-TT (CBT screws at the cranial level and TT screws at the caudal level) structure under different bone mineral density conditions. STUDY DESIGN: A finite element (FE) analysis study. METHODS: Above all, we established a healthy adult lumbar spine model. Second, under normal and osteoporotic conditions, three transforaminal lumbar interbody fusion (TLIF) models were established: bilateral traditional trajectory (TT-TT) screw fixation, bilateral cortical bone trajectory (CBT-CBT) screw fixation, and hybrid cortical bone trajectory screw and traditional trajectory screw (CBT-TT) fixation. Finally, a 500-N compression load with a torque of 10 N/m was applied to simulate flexion, extension, lateral bending, and axial rotation. We compared the range of motion (ROM), adjacent disc stress, cage stress, and posterior fixation stress of the different fusion models. RESULTS: Under different bone mineral density conditions, the range of motion of the fusion segment was significantly reduced. Compared to normal bone conditions, the ROM of the L4-L5 segment, the stress of the adjacent intervertebral disc, the surface stress of the cage, and the maximum stress of the posterior fixation system were all increased in osteoporosis. Under most loads, the ROM and surface stress of the cage and the maximum stress of the posterior fixation system of the TT-TT structure are the lowest under normal bone mineral density conditions. However, under osteoporotic conditions, the fixation strength of the CBT-CBT and CBT-TT structures are higher than that of the TT-TT structures under certain load conditions. At the same time, the surface stress of the intervertebral fusion cage and the maximum stress of the posterior fixation system for the two structures are lower than those of the TT-TT structure. CONCLUSION: Under normal bone mineral density conditions, transforaminal lumbar interbody fusion combined with TT-TT fixation provides the best biomechanictability. However, under osteoporotic conditions, CBT-CBT and CBT-TT structures have higher fixed strength compared to TT-TT structures. The hybrid CBT-TT structure exhibits advantages in minimal trauma and fixation strength. Therefore, this seems to be an alternative fixation method for patients with osteoporosis and degenerative spinal diseases. CLINICAL SIGNIFICANCE: This study provides biomechanical support for the clinical application of hybrid CBT-TT structure for osteoporotic patients undergoing TLIF surgery.

Schwann Cell-Derived Exosomes and Methylprednisolone Composite Patch for Spinal Cord Injury Repair.

Spinal cord injury (SCI) can cause permanent loss of sensory and motor function, and there is no effective clinical treatment, to date. Due to the complex pathological process involved after injury, synergistic treatments are very urgently needed in clinical practice. We designed a nanofiber scaffold hyaluronic acid hydrogel patch to release both exosomes and methylprednisolone to the injured spinal cord in a non-invasive manner. This composite patch showed good biocompatibility in the stabilization of exosome morphology and toxicity to nerve cells. Meanwhile, the composite patch increased the proportion of M2-type macrophages and reduced neuronal apoptosis in an in vitro study. In vivo, the functional and electrophysiological performance of rats with SCI was significantly improved when the composite patch covered the surface of the hematoma. The composite patch inhibited the inflammatory response through macrophage polarization from M1 type to M2 type and increased the survival of neurons by inhibition neuronal of apoptosis after SCI. The therapeutic effects of this composite patch can be attributed to TLR4/NF-κB, MAPK, and Akt/mTOR pathways. Thus, the composite patch provides a medicine-exosomes dual-release system and may provide a non-invasive method for clinical treatment for individuals with SCI.

Ncoa2 Promotes CD8+ T cell-Mediated Antitumor Immunity by Stimulating T-cell Activation via Upregulation of PGC-1α Critical for Mitochondrial Function.

Nuclear receptor coactivator 2 (Ncoa2) is a member of the Ncoa family of coactivators, and we previously showed that Ncoa2 regulates the differentiation of induced regulatory T cells. However, it remains unknown if Ncoa2 plays a role in CD8+ T-cell function. Here, we show that Ncoa2 promotes CD8+ T cell-mediated immune responses against tumors by stimulating T-cell activation via upregulating PGC-1α expression to enhance mitochondrial function. Mice deficient in Ncoa2 in T cells (Ncoa2fl/fl/CD4Cre) displayed defective immune responses against implanted MC38 tumors, which associated with significantly reduced tumor-infiltrating CD8+ T cells and decreased IFNγ production. Consistently, CD8+ T cells from Ncoa2fl/fl/CD4Cre mice failed to reject tumors after adoptive transfer into Rag1-/- mice. Further, in response to TCR stimulation, Ncoa2fl/fl/CD4Cre CD8+ T cells failed to increase mitochondrial mass, showed impaired oxidative phosphorylation, and had lower expression of PGC-1α, a master regulator of mitochondrial biogenesis and function. Mechanically, T-cell activation-induced phosphorylation of CREB triggered the recruitment of Ncoa2 to bind to enhancers, thus, stimulating PGC-1α expression. Forced expression of PGC-1α in Ncoa2fl/fl/CD4Cre CD8+ T cells restored mitochondrial function, T-cell activation, IFNγ production, and antitumor immunity. This work informs the development of Ncoa2-based therapies that modulate CD8+ T cell-mediated antitumor immune responses.

Overexpression of Pasteurella multocida OmpA induces transcriptional changes and its possible implications for the macrophage polarization.

Pasteurella multocida (P. multocida) is a highly infectious, zoonotic pathogen. Outer membrane protein A (OmpA) is an important virulence component of the outer membrane of P. multocida. OmpA mediates bacterial biofilm formation, eukaryotic cell infection, and immunomodulation. It is unclear how OmpA affects the host immune response. We estimated the role of OmpA in the pathogenesis of P. multocida by investigating the effect of OmpA on the immune cell transcriptome. Changes in the transcriptome of rat alveolar macrophages (NR8383) upon overexpression of P. multocida OmpA were demonstrated. A model cell line for stable transcription of OmpA was constructed by infecting NR8383 cells with OmpA-expressing lentivirus. RNA was extracted from cells and sequenced on an Illumina HiSeq platform. Key gene analysis of genes in the RNA-seq dataset were performed using various bioinformatics methods, such as gene ontology enrichment analysis, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, Gene Set Enrichment Analysis, and Protein-Protein Interaction Analysis. Our findings revealed 1340 differentially expressed genes. Immune-related pathways that were significantly altered in rat alveolar macrophages under the effect of OmpA included focal adhesion, extracellular matrix and vascular endothelial growth factor signaling pathways, antigen processing and presentation, nucleotide oligomerization domain-like receptor and Toll-like receptor signaling pathways, and cytokine-cytokine receptor interaction. The key genes screened were Vegfa, Igf2r, Fabp5, P2rx1, C5ar1, Nedd4l, Gas6, Cxcl1, Pf4, Pdgfb, Thbs1, Col7a1, Vwf, Ccl9, and Arg1. Data of associated pathways and altered gene expression indicated that OmpA might cause the conversion of rat alveolar macrophages to M2-like. The related pathways and key genes can serve as a reference for OmpA of P. multitocida and host interaction mechanism studies.

Schwann cell-derived exosomes containing MFG-E8 modify macrophage/microglial polarization for attenuating inflammation via the SOCS3/STAT3 pathway after spinal cord injury.

Macrophage/microglia polarization acts as an important part in regulating inflammatory responses in spinal cord injury (SCI). However, the regulation of inflammation of Schwann cell-derived exosomes (SCDEs) for SCI repair is still unclear. Therefore, we intend to find out the effect of SCDEs on regulating the inflammation related to macrophage polarization during the recovery of SCI. Firstly, the thesis demonstrated that SCDEs could attenuate the LPS- inflammation in BMDMs by suppressing M1 polarization and stimulating M2 polarization. Similarly, SCDEs improved functional recovery of female Wistar rats of the SCI contusion model according to BBB (Basso, Beattie, and Bresnahan) score, electrophysiological assay, and the gait analysis system of CatWalk XT. Moreover, MFG-E8 was verified as the main component of SCDEs to improve the inflammatory response by proteomic sequencing and lentiviral transfection. Improvement of the inflammatory microenvironment also inhibited neuronal apoptosis. The knockout of MFG-E8 in SCs can reverse the anti-inflammatory effects of SCDEs treatment. The SOCS3/STAT3 signaling pathway was identified to participate in upregulating M2 polarization induced by MFG-E8. In conclusion, our findings will enrich the mechanism of SCDEs in repairing SCI and provide potential applications and new insights for the clinical translation of SCDEs treatment for SCI.

Identification of Key Genes and miRNAs Affecting Osteosarcoma Based on Bioinformatics.

Methods: GSE70367 and GSE69470 were obtained from the GEO database. The differentially expressed genes (DEGs) and miRNAs were analyzed using the GEO2R tool and then visualized with R software. Moreover, the targets of the miRNAs in the DEGs were screened and then used for enrichment analysis. Besides, the STRING database and Cytoscape were applied to illustrate the protein-protein interaction network. RT-qPCR was performed to measure the expression of key genes and miRNAs. Western blot was applied to detect the signaling pathway. Results: 9 upregulated genes and 39 downregulated genes in GSE69470 were identified as the DEGs, and 31 upregulated genes and 56 downregulated genes in GSE70367 were identified as the DEGs. Moreover, 21 common genes were found in the DEGs of GSE70367 and GSE69470. The enrichment analysis showed that the common DEGs of GSE70367 and GSE69470 were related with cell development, covalent chromatin modification, and histone modification and involve in the regulation of MAPK, mTOR, and AMPK pathways. Besides, the miRNAs including miR-543, miR-495-3p, miR-433-3p, miR-381-3p, miR-301a-3p, miR-199b-5p, and miR-125b-5p were identified as the biomarkers of osteosarcoma. In addition, the target genes including HSPA5, PPARG, MAPK14, RAB11A, RAB5A, MAPK8, LEF1, HIF1A, CAV1, GS3KB, FOXO3, IGF1, and NFKBIA were identified as hub nodes. It was found that miR-301a-3p expression was decreased and mRNA expression of RAB5A and NFKBIA was increased in the pathological tissues. The AKT-PI3K-mTOR signaling pathway was activated in pathological tissues. Conclusion: In this study, 7 miRNAs and 13 hub genes were identified, which might be candidate markers. miR-301a-3p, RAB5A, and NFKBIA were abnormally expressed in osteosarcoma tissues.

Effect of Long Noncoding RNA HULC on Proliferation, Migration, and Invasion of Osteosarcoma Cells.

Background: Previous studies had shown that lncRNA HULC exhibited different effects in human cancers. However, the role of HULC was not reported in osteosarcoma. Hence, we designed this research to explore the function of HULC in osteosarcoma. Methods: Firstly, HULC expression was measured in osteosarcoma tissues and cells via the RT-qPCR assay. The protein expression was detected through western blot. Then, CCK-8 and Transwell assays were conducted to measure cell proliferation, migration, and invasion. Results: The expression of HULC was obviously higher in osteosarcoma tissues and cells compared with normal control. Moreover, cell proliferation, migration, and invasion were inhibited by HULC knockdown in osteosarcoma cells. HULC overexpression markedly increased osteosarcoma cell proliferation and tumor size in vivo. Furthermore, HULC increased the activity of AKT-PI3K-mTOR pathway by blocking PTEN in osteosarcoma cells. LY294002 inhibited the phosphorylation of AKT, mTOR, and PI3K. Overexpressing HULC enhanced cell migration and invasion of SAOS-2 cells and MG63 cells, while LY294002 reversed the effects. Conclusion: HULC enhanced the progression of osteosarcoma through targeting PTEN.

Whole-Genome Sequencing Reveals the Genomic Characteristics and Selection Signatures of Hainan Black Goat.

Goats have become one of the most adaptive and important livestock species distributed in developing countries in recent years. The Hainan Black goat is a native goat breed of the Hainan region that is generally well-liked by the local population and is thus raised in large numbers. However, the genomic diversity and selective signals of the Hainan Black goat have not been clearly elucidated yet. Therefore, in this study, we performed whole-genome resequencing of 16 Hainan Black goats and compared the results with those of 71 goats of 6 other breeds from different geographic regions. Principal component analysis (PCA) and phylogenetic analysis identified seven lineages for all goats. Hainan Black goats showed the most similarity with Leizhou goats and the least similarity with Boer goats. Selective sweep analysis identified candidate genes associated with various functions, including immune resistance to disease (TNFAIP2 (TNF alpha induced protein 2) and EXOC3L4 (exocyst complex component 3 like 4)), melanin biosynthetic process (CDH15 (cadherin 15), ASIP (agouti signaling protein), and PARD3 (par-3 family cell polarity regulator)), and light sensitivity (CNGB3 (cyclic nucleotide gated channel subunit beta 3) and CNBD1 (cyclic nucleotide binding domain containing 1)), underlying strong selection signatures in Hainan Black goats. The melanin biosynthetic process, circadian entrainment, regulation of cyclic adenosine 3,5-monophosphate (cAMP)-mediated signaling, and the Rap-1 signaling pathway were significantly enriched in Hainan Black and Alashan Cashmere goats. This result may be important for understanding each trait. Selection signature analysis revealed candidate single nucleotide polymorphisms (SNPs) and genes correlated with the traits of Hainan Black goats. Collectively, our results provide valuable insights into the genetic basis of specific traits correlated with the Hainan island climate, artificial selection in certain local goat breeds, and the importance of protecting breed resources.

Promoting antibody-dependent cellular phagocytosis for effective macrophage-based cancer immunotherapy.

Macrophages are essential in eliciting antibody-dependent cellular phagocytosis (ADCP) of cancer cells. However, a satisfactory anticancer efficacy of ADCP is contingent on early antibody administration, and resistance develops along with cancer progression. Here, we investigate the mechanisms underlying ADCP and demonstrate an effective combinatorial strategy to potentiate its efficacy. We identified paclitaxel as a universal adjuvant that efficiently potentiated ADCP by a variety of anticancer antibodies in multiple cancers. Rather than eliciting cytotoxicity on cancer cells, paclitaxel polarized macrophages toward a state with enhanced phagocytic ability. Paclitaxel-treated macrophages down-regulated cell surface CSF1R whose expression was negatively correlated with patient survival in multiple malignancies. The suppression of CSF1R in macrophages enhanced ADCP of cancer cells, suggesting a role of CSF1R in regulating macrophage phagocytic ability. Together, these findings define a potent strategy for using conventional anticancer drugs to stimulate macrophage phagocytosis and promote the therapeutic efficacy of clinical anticancer antibodies.

Targeting macrophages for enhancing CD47 blockade-elicited lymphoma clearance and overcoming tumor-induced immunosuppression.

Tumor-associated macrophages (TAMs) are often the most abundant immune cells in the tumor microenvironment (TME). Strategies targeting TAMs to enable tumor cell killing through cellular phagocytosis have emerged as promising cancer immunotherapy. Although several phagocytosis checkpoints have been identified, the desired efficacy has not yet been achieved by blocking such checkpoints in preclinical models or clinical trials. Here, we showed that late-stage non-Hodgkin lymphoma (NHL) was resistant to therapy targeting phagocytosis checkpoint CD47 due to the compromised capacity of TAMs to phagocytose lymphoma cells. Via a high-throughput screening of the US Food and Drug Administration-approved anticancer small molecule compounds, we identified paclitaxel as a potentiator that promoted the clearance of lymphoma by directly evoking phagocytic capability of macrophages, independently of paclitaxel's chemotherapeutic cytotoxicity toward NHL cells. A combination with paclitaxel dramatically enhanced the anticancer efficacy of CD47-targeted therapy toward late-stage NHL. Analysis of TME by single-cell RNA sequencing identified paclitaxel-induced TAM populations with an upregulation of genes for tyrosine kinase signaling. The activation of Src family tyrosine kinases signaling in macrophages by paclitaxel promoted phagocytosis against NHL cells. In addition, we identified a role of paclitaxel in modifying the TME by preventing the accumulation of a TAM subpopulation that was only present in late-stage lymphoma resistant to CD47-targeted therapy. Our findings identify a novel and effective strategy for NHL treatment by remodeling TME to enable the tumoricidal roles of TAMs. Furthermore, we characterize TAM subgroups that determine the efficiency of lymphoma phagocytosis in the TME and can be potential therapeutic targets to unleash the antitumor activities of macrophages.

Concurrent Treatment with Vitamin K2 and D3 on Spine Fusion in Patients with Osteoporosis-Associated Lumbar Degenerative Disorders.

STUDY DESIGN: A prospective and nonrandomized concurrent controlled trial. OBJECTIVE: To address the early effects of concurrent treatment with vitamin K2 and vitamin D3 on fusion rates in patients who have undergone spinal surgery. SUMMARY OF BACKGROUND DATA: Intervertebral pseudarthrosis has been reported after transforaminal lumbar interbody fusion (TLIF) or posterior lumbar interbody fusion (PLIF), especially in patients with osteopenia or osteoporosis. No study has assessed the early effects of concurrent treatment with vitamin K2 and vitamin D3 on fusion rates. METHODS: Patients with osteopenia or osteoporosis who underwent TLIF or PLIF in our department were included. Patients in the VK2+VD3 group received vitamin K2, vitamin D3, and calcium treatment, whereas subjects in the control group only received calcium and vitamin D3. Spine fusion was evaluated by computed tomography. The Japanese Orthopedic Association Back Pain Evaluation Questionnaire (JOA-BPEQ) and visual analog scale (VAS) were used to assess the clinical and neurological symptoms. Bone mineral density (BMD) and bone metabolism markers were measured for osteoporotic evaluation. RESULTS: Seventy-eight patients were included, and nine patients subsequently discontinued because of 2019-nCoV. At six months postoperatively, complete fusion rates were significantly higher in the VK2+VD3 group than that in the control group (91.18% vs 71.43%, P = 0.036). At six months postoperatively, BMD was increased in the VK2+VD3 group and was higher than that in the control group, although there was no significant difference. At three months postoperatively, a significant increase in procollagen type I amino terminal propeptide (91.81%) and a slight decrease in C-terminal end peptide (8.06%) were observed in the VK2+VD3 group. In both groups, the JOA-BPEQ and VAS scores were significantly improved after spine surgery. CONCLUSION: Administration of vitamin K2 and vitamin D3 can increase lumbar interbody fusion rates, improve clinical symptoms, promote bone information, and avoid further decline in BMD within six months after TLIF or PLIF.Level of Evidence: 3.

GPR39 agonist TC-G 1008 promotes osteoblast differentiation and mineralization in MC3T3-E1 cells.

Osteoporosis-related bone fracture and falls have a severe impact on patients' daily lives. Osteoblasts are bone-building cells that play a vital role in bone formation and remodeling. Imbalanced osteoblast differentiation could lead to osteoporosis. GPR39 is an orphan G protein-coupled receptor that mediates metabolic pathways. In this study, we show that GPR39 is expressed in MC3T3-E1 cells. Osteoblast differentiation culture media induces GPR39, suggesting that GPR39 is a differentiation-responsive factor. Activation of GPR39 using its selective agonist TC-G 1008 induces alkaline phosphatase (ALP), osteocalcin (OCN), and type I collagen (Col-I) expression, and increases cellular ALP activity and calcium deposition, implying that GPR activation promotes cells toward osteoblast differentiation. Treatment with TC-G 1008 also increases Runx-2 expression and AMPK activation. However, the inhibition of AMPK by Compound C abolished TC-G 1008-mediated ALP, OCN, and Col-I induction, and reduces ALP activity and cellular calcium deposition as well as Runx-2 induction. These data indicate that TC-G 1008-mediated GPR39 activation involves AMPK-mediated Runx-2 induction. In summary, our study uncovers a new role of GPR39 activation in osteoblast differentiation, implying that GPR39 could be a promising therapeutic target for osteoporosis.

Solid-state fermentation of palm kernels by Yarrowia lipolytica modulates the aroma of palm kernel oil.

Solid-state fermentation with Yarrowia lipolytica was applied to palm kernels (PK) with the aim to modulate the aroma of palm kernel oil (PKO) obtained after kernel roasting. The results showed that, the metabolic activities of Y. lipolityca brought about significant changes to the volatile profile of obtained PKO either by providing thermal reaction reactants or by directly contributing aroma compounds. After fermentation, a decreased content in glucose (60%) while an elevated amount (7-fold) in free amino acids was found in PK, which further impacted the formation of volatile compounds by influencing the Maillard reaction and Strecker degradation during roasting. More Strecker aldehydes and N-heterocyclic compounds were formed in PKO derived from fermented PK especially after intensified roasting. In addition, the catabolism of Y. lipolytica imparted some distinct volatile compounds such as 2-phenylethanol to the obtained PKO. However, the lipase excreted by Y. lipolytica hydrolysed PK lipids and released 5-fold more free fatty acids in fermented PKO, relative to the blank and control PKO, which likely contributed to the off-flavor. On the basis of all volatile categories, principal component analysis (PCA) clearly separated the fermented PKO from the blank and control PKO, with light roasted, fermented PKO being correlated with acids, alcohols and aliphatic aldehydes; medium and dark roasted, fermented PKO tending to be dominated by pyrroles, pyrazines and furanones, which is in correspondence with sensory changes of PKO. This study demonstrated that combining fermentation with roasting could provide a novel way to modulate the volatile composition and aroma of PKO.

Protective Smell of Hydrogen Sulfide and Polysulfide in Cisplatin-Induced Nephrotoxicity.

Though historically known as a toxic gas, hydrogen sulfide (H2S) has displayed a new face as the third endogenous gaseous signaling molecule after nitric oxide (NO) and carbon monoxide (CO). Here in this review, we survey the role and therapeutic potential of H2S in cisplatin-induced nephrotoxicity. Specifically, reduction of H2S by cystathionine γ-lyase (CSE) downregulation upon cisplatin treatment may contribute to cisplatin-induced renal cell injury, possibly by augmentation of endogenous reactive oxygen species (ROS) production, while H2S donation may prevent subsequent renal dysfunction by inhibiting NADPH oxidase activation. Intriguingly, H2S slow-releasing compound GYY4137 seems to increase the anticancer activity of cisplatin, at least in several cancer cell lines, and this is probably due to its own anticancer effect. However, the efficacy of H2S donors in tumor-bearing animals remains to be tested in terms of renal protection and cancer inhibition after receiving cisplatin. Furthermore, accumulative evidence regarding usage of polysulfide, a novel H2S derived molecule, in the therapy of cisplatin-induced nephrotoxicity, was also summarized.

Viscozyme L pretreatment on palm kernels improved the aroma of palm kernel oil after kernel roasting.

With an interest to enhance the aroma of palm kernel oil (PKO), Viscozyme L, an enzyme complex containing a wide range of carbohydrases, was applied to alter the carbohydrates in palm kernels (PK) to modulate the formation of volatiles upon kernel roasting. After Viscozyme treatment, the content of simple sugars and free amino acids in PK increased by 4.4-fold and 4.5-fold, respectively. After kernel roasting and oil extraction, significantly more 2,5-dimethylfuran, 2-[(methylthio)methyl]-furan, 1-(2-furanyl)-ethanone, 1-(2-furyl)-2-propanone, 5-methyl-2-furancarboxaldehyde and 2-acetyl-5-methylfuran but less 2-furanmethanol and 2-furanmethanol acetate were found in treated PKO; the correlation between their formation and simple sugar profile was estimated by using partial least square regression (PLS1). Obvious differences in pyrroles and Strecker aldehydes were also found between the control and treated PKOs. Principal component analysis (PCA) clearly discriminated the treated PKOs from that of control PKOs on the basis of all volatile compounds. Such changes in volatiles translated into distinct sensory attributes, whereby treated PKO was more caramelic and burnt after aqueous extraction and more nutty, roasty, caramelic and smoky after solvent extraction.