Intrathecal Fumagillin Alleviates Chronic Neuropathy-Induced Nociceptive Sensitization and Modulates Spinal Astrocyte-Neuronal Glycolytic and Angiogenic Proteins.

Nociceptive sensitization is accompanied by the upregulation of glycolysis in the central nervous system in neuropathic pain. Growing evidence has demonstrated glycolysis and angiogenesis to be related to the inflammatory processes. This study investigated whether fumagillin inhibits neuropathic pain by regulating glycolysis and angiogenesis. Fumagillin was administered through an intrathecal catheter implanted in rats with chronic constriction injury (CCI) of the sciatic nerve. Nociceptive, behavioral, and immunohistochemical analyses were performed to evaluate the effects of the inhibition of spinal glycolysis-related enzymes and angiogenic factors on CCI-induced neuropathic pain. Fumagillin reduced CCI-induced thermal hyperalgesia and mechanical allodynia from postoperative days (POD) 7 to 14. The expression of angiogenic factors, vascular endothelial growth factor (VEGF) and angiopoietin 2 (ANG2), increased in the ipsilateral lumbar spinal cord dorsal horn (SCDH) following CCI. The glycolysis-related enzymes, pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA) significantly increased in the ipsilateral lumbar SCDH following CCI on POD 7 and 14 compared to those in the control rats. Double immunofluorescence staining indicated that VEGF and PKM2 were predominantly expressed in the astrocytes, whereas ANG2 and LDHA were predominantly expressed in the neurons. Intrathecal infusion of fumagillin significantly reduced the expression of angiogenic factors and glycolytic enzymes upregulated by CCI. The expression of hypoxia-inducible factor-1α (HIF-1α), a crucial transcription factor that regulates angiogenesis and glycolysis, was also upregulated after CCI and inhibited by fumagillin. We concluded that intrathecal fumagillin may reduce the expression of ANG2 and LDHA in neurons and VEGF and PKM2 in the astrocytes of the SCDH, further attenuating spinal angiogenesis in neuropathy-induced nociceptive sensitization. Hence, fumagillin may play a role in the inhibition of peripheral neuropathy-induced neuropathic pain by modulating glycolysis and angiogenesis.

STAT3 phosphorylation inhibitor Bt354 exhibits anti-neoplastic activity in glioblastoma multiforme cells.

The high mortality rate of glioblastoma multiforme (GBM), a lethal primary brain tumor, is attributable to postsurgical recurrence. STAT3, an oncogenic protein, is a signal transducer and transcription activator encourages cancer cell migration and proliferation, which results in resistance to therapy. STAT3 inhibition reduces cancer metastasis and improves patient prognosis. Bt354, a small molecule STAT inhibitor, exhibits significant cytotoxic and anti-proliferative activities against certain cancer types. Here, we demonstrated that exposure of GBM cells (U87 MG) to Bt354 had a significant, concentration-dependent growth suppression. Bt354 also induced apoptosis and downregulated the expression of the epithelial-mesenchymal transition genes. Therefore, this study suggests the potential of Bt354 for treating GBM owing to its ability to induce cytotoxicity.

Frailty Prevention Care Management Program (FPCMP) on Frailty and Health Function in Community-Dwelling Older Adults: A Quasi-Experimental Trial Protocol.

BACKGROUND: Frailty often results from deteriorating muscle strength and decreased physical function in older adults. Frailty includes not only physical components, but also psychological and social aspects. Previous research has shown that exercise programs, especially resistance exercises combined with nutritional care, can reduce frailty. OBJECTIVES: This study aimed to develop a Frailty Prevention Care Management Program that prevents frailty and improves physical activity and nutrition compared to usual care for community-dwelling older adults. METHODS: A quasi-experimental and single-blinded trial with a non-equivalent control group using a before-after design will be performed involving Frailty Prevention Care Management Program interventions, taking place both at the communities. Participants will be divided into two different intervention groups and two control groups. All groups will be assessed three times: at baseline, immediately after the intervention, and 3 months post intervention. A total of 72 community-dwelling older adults are recruited. This intervention includes an exercise program (design TRX program) and nutritional education. The control group will not receive any specific exercise training. The primary outcome shall comprise the effect of the Frailty Prevention Care Management Program on frailty using the Taiwanese version of the Tilburg frailty indicator. Secondary outcomes include the effect of physical activity using the Senior Fitness Test and nutrition measures using the Mini Nutritional Assessment-Short Form. A generalized estimating equation is constructed to analyze the effects of the intervention. CONCLUSIONS: This trial will provide vital information to guide interventions to improve outcomes (frailty, physical activity, and nutrition) and inform the integration of nutrition and TRX exercises in community-dwelling older adults.

Oral Administration of Protease-Soluble Chicken Type II Collagen Ameliorates Anterior Cruciate Ligament Transection-Induced Osteoarthritis in Rats.

This study investigated whether oral supplementation with protease-soluble chicken type II collagen (PSCC-II) mitigates the progression of anterior cruciate ligament transection (ACLT)-induced osteoarthritis (OA) in rats. Eight-week-old male Wistar rats were randomly assigned to the following groups: control, sham, ACLT, group A (ACLT + pepsin-soluble collagen type II collagen (C-II) with type I collagen), group B (ACLT + Amano M-soluble C-II with type I collagen), group C (ACLT + high-dose Amano M-soluble C-II with type I collagen), and group D (ACLT + unproteolyzed C-II). Various methods were employed to analyze the knee joint: nociceptive tests, microcomputed tomography, histopathology, and immunohistochemistry. Rats treated with any form of C-II had significant reductions in pain sensitivity and cartilage degradation. Groups that received PSCC-II treatment effectively mitigated the ACLT-induced effects of OA concerning cancellous bone volume, trabecular number, and trabecular separation compared with the ACLT alone group. Furthermore, PSCC-II and unproteolyzed C-II suppressed ACLT-induced effects, such as the downregulation of C-II and upregulation of matrix metalloproteinase-13, tumor necrosis factor-α, and interleukin-1ß. These results indicate that PSCC-II treatment retains the protective effects of traditional undenatured C-II and provide superior benefits for OA management. These benefits encompass pain relief, anti-inflammatory effects, and the protection of cartilage and cancellous bone.

Manoalide Induces Intrinsic Apoptosis by Oxidative Stress and Mitochondrial Dysfunction in Human Osteosarcoma Cells.

Osteosarcoma (OS) is the most common primary malignant bone tumor that produces immature osteoid. Metastatic OS has a poor prognosis with a death rate of >70%. Manoalide is a natural sesterterpenoid isolated from marine sponges. It is a phospholipase A2 inhibitor with anti-inflammatory, analgesic, and anti-cancer properties. This study aimed to investigate the mechanism and effect of manoalide on OS cells. Our experiments showed that manoalide induced cytotoxicity in 143B and MG63 cells (human osteosarcoma). Treatment with manoalide at concentrations of 10, 20, and 40 µM for 24 and 48 h reduced MG63 cell viability to 45.13-4.40% (p < 0.01). Meanwhile, manoalide caused reactive oxygen species (ROS) overproduction and disrupted antioxidant proteins, activating the apoptotic proteins caspase-9/-3 and PARP (Poly (ADP-ribose) polymerase). Excessive levels of ROS in the mitochondria affected oxidative phosphorylation, ATP generation, and membrane potential (ΔΨm). Additionally, manoalide down-regulated mitochondrial fusion protein and up-regulated mitochondrial fission protein, resulting in mitochondrial fragmentation and impaired function. On the contrary, a pre-treatment with n-acetyl-l-cysteine ameliorated manoalide-induced apoptosis, ROS, and antioxidant proteins in OS cells. Overall, our findings show that manoalide induces oxidative stress, mitochondrial dysfunction, and apoptosis, causing the cell death of OS cells, showing potential as an innovative alternative treatment in human OS.

Antinociceptive Effects of Aaptamine, a Sponge Component, on Peripheral Neuropathy in Rats.

Aaptamine, a natural marine compound isolated from the sea sponge, has various biological activities, including delta-opioid agonist properties. However, the effects of aaptamine in neuropathic pain remain unclear. In the present study, we used a chronic constriction injury (CCI)-induced peripheral neuropathic rat model to explore the analgesic effects of intrathecal aaptamine administration. We also investigated cellular angiogenesis and lactate dehydrogenase A (LDHA) expression in the ipsilateral lumbar spinal cord after aaptamine administration in CCI rats by immunohistofluorescence. The results showed that aaptamine alleviates CCI-induced nociceptive sensitization, allodynia, and hyperalgesia. Moreover, aaptamine significantly downregulated CCI-induced vascular endothelial growth factor (VEGF), cluster of differentiation 31 (CD31), and LDHA expression in the spinal cord. Double immunofluorescent staining showed that the spinal VEGF and LDHA majorly expressed on astrocytes and neurons, respectively, in CCI rats and inhibited by aaptamine. Collectively, our results indicate aaptamine's potential as an analgesic agent for neuropathic pain. Furthermore, inhibition of astrocyte-derived angiogenesis and neuronal LDHA expression might be beneficial in neuropathy.

Isoaaptamine increases ROS levels causing autophagy and mitochondria-mediated apoptosis in glioblastoma multiforme cells.

Glioblastoma multiforme (GBM) is a common central nervous system disease with a poor prognosis; its five-year survival rate is <5 %, and its median survival of 15 months. Current treatment includes chemotherapy with temozolomide, which is ineffective against GBM, suggesting an urgent need to develop novel therapies. This study evaluated isoaaptamine and aaptamine in the GBM cell lines for cell viability; GBM 8401, U87 MG, U138 MG, and T98G. Our findings showed that isoaaptamine was more potent than its iso-form aaptamine in these four cell lines, and GBM 8401 was most sensitive to isoaaptamine. The study in GBM 8401 cells showed that apoptosis was induced by isoaaptamine with increased cleaved caspase 3 and poly ADP-ribose polymerase (PARP). Moreover, isoaaptamine enhanced oxidative stress by increasing the levels of reactive oxygen species (ROS), inhibiting mitochondrial and cellular superoxidase dismutases (SOD1&2), peroxidase and an anti-apoptotic protein (Bcl-2), and disrupting mitochondrial membrane potential. In addition, the oxygen consumption rates and activities of mitochondrial complexes I-V were significantly reduced. Mitochondrial dynamics were prone to fission instead of fusion after isoaaptamine treatment, and ATP synthesis was ablated. Also, autophagy-related acidic organelle vesicles were formed, indicating autophagy was triggered. Overall, isoaaptamine-induced ROS overproduction in mitochondria could cause mitochondrial dysfunction, apoptosis, and autophagy in the GBM cells.

Sinularin Induces Oxidative Stress-Mediated Apoptosis and Mitochondrial Dysfunction, and Inhibits Angiogenesis in Glioblastoma Cells.

Glioblastoma multiforme (GBM) is a cancer of largely unknown cause that leads to a 5-year survival rate of approximately 7% in the United States. Current treatment strategies are not effective, indicating a strong need for the development of novel therapies. In this study, the outcomes of sinularin, a marine-derived product, were evaluated against GBM. Our cellular studies using GBM cells revealed that sinularin induces cell death. The measured half maximal inhibitory concentrations (IC50) values ranged from 30 to 6 µM at 24-72 h. Cell death was induced via the generation of ROS leading to mitochondria-mediated apoptosis. This was evidenced by annexin V/propidium iodine staining and an upregulation of cleaved forms of the pro-apoptotic proteins caspase 9, 3, and PARP, and supported by CellROXTM Green, MitoSOXTM Red, and CM-H2DCFDA staining methods. In addition, we observed a downregulation of the antioxidant enzymes SOD1/2 and thioredoxin. Upon treatment with sinularin at the ~IC50 concentration, mitochondrial respiration capacities were significantly reduced, as shown by measuring the oxygen consumption rates and enzymatic complexes of oxidative phosphorylation. Intriguingly, sinularin significantly inhibited indicators of angiogenesis such as vessel tube formation, cell migration, and cell mobility in human umbilical vein endothelial cells or the fusion cell line EA.Hy926. Lastly, in a transgenic zebrafish model, intersegmental vessel formation was also significantly inhibited by sinularin treatment. These findings indicate that sinularin exerts anti-brain cancer properties that include apoptosis induction but also antiangiogenesis.

Investigation of the Characteristics and Antibacterial Activity of Polymer-Modified Copper Oxide Nanoparticles.

The proliferation of drug-resistant pathogens continues to increase, giving rise to serious public health concerns. Many researchers have formulated metal oxide nanoparticles for use as novel antibacterial agents. In the present study, copper oxide (CuO) was synthesized by simple hydrothermal synthesis, and doping was performed to introduce different polymers onto the NP surface for bacteriostasis optimization. The polymer-modified CuO NPs were analyzed further with XRD, FTIR, TEM, DLS and zeta potential to study their morphology, size, and the charge of the substrate. The results indicate that polymer-modified CuO NPs had a significantly higher bacteriostatic rate than unmodified CuO NPs. In particular, polydopamine (PDA)-modified CuO (CuO-PDA) NPs, which carry a weakly negative surface charge, exhibited excellent antibacterial effects, with a bacteriostatic rate of up to 85.8 ± 0.2% within 3 h. When compared to other polymer-modified CuO NPs, CuO-PDA NPs exhibited superior bacteriostatic activity due to their smaller size, surface charge, and favorable van der Waals interactions. This may be attributed to the fact that the CuO-PDA NPs had relatively lipophilic structures at pH 7.4, which increased their affinity for the lipopolysaccharide-containing outer membrane of the Gram-negative bacterium Escherichia coli.

Fumagillin Attenuates Spinal Angiogenesis, Neuroinflammation, and Pain in Neuropathic Rats after Chronic Constriction Injury.

INTRODUCTION: Angiogenesis in the central nervous system is visible in animal models of neuroinflammation and bone cancer pain. However, whether spinal angiogenesis exists and contributes to central sensitization in neuropathic pain remains unclear. This study analyzes the impact of angiogenesis on spinal neuroinflammation in neuropathic pain. METHODS: Rats with chronic constriction injury (CCI) to the sciatic nerve underwent the implantation of an intrathecal catheter. Fumagillin or vascular endothelial growth factor-A antibody (anti-VEGF-A) was administered intrathecally. Nociceptive behaviors, cytokine immunoassay, Western blot, and immunohistochemical analysis assessed the effect of angiogenesis inhibition on CCI-induced neuropathic pain. RESULTS: VEGF, cluster of differentiation 31 (CD31), and von Willebrand factor (vWF) expressions increased after CCI in the ipsilateral lumbar spinal cord compared to that in the contralateral side of CCI and control rats from post-operative day (POD) 7 to 28, with a peak at POD 14. Tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6 concentrations, but not IL-10 levels, also increased in the ipsilateral spinal cord after CCI. Fumagillin and anti-VEGF-A reduced CCI-induced thermal hyperalgesia from POD 5 to 14 and mechanical allodynia from POD 3 to 14. Fumagillin reduced CCI-upregulated expressions of angiogenic factors and astrocytes. Furthermore, fumagillin decreased TNF-α and IL-6 amounts and increased IL-10 levels at POD 7 and 14, but not IL-1ß concentrations. CONCLUSIONS: Fumagillin significantly ameliorates CCI-induced nociceptive sensitization, spinal angiogenesis, and astrocyte activation. Our results suggest that angiogenesis inhibitor treatment suppresses peripheral neuropathy-induced central angiogenesis, neuroinflammation, astrocyte activation, and neuropathic pain.

Glutathione S-Transferase M3 Is Associated with Glycolysis in Intrinsic Temozolomide-Resistant Glioblastoma Multiforme Cells.

Glioblastoma multiforme (GBM) is a malignant primary brain tumor. The 5-year relative survival rate of patients with GBM remains <30% on average despite aggressive treatments, and secondary therapy fails in 90% of patients. In chemotherapeutic failure, detoxification proteins are crucial to the activity of chemotherapy drugs. Usually, glutathione S-transferase (GST) superfamily members act as detoxification enzymes by activating xenobiotic metabolites through conjugation with glutathione in healthy cells. However, some overexpressed GSTs not only increase GST activity but also trigger chemotherapy resistance and tumorigenesis-related signaling transductions. Whether GSTM3 is involved in GBM chemoresistance remains unclear. In the current study, we found that T98G, a GBM cell line with pre-existing temozolomide (TMZ) resistance, has high glycolysis and GSTM3 expression. GSTM3 knockdown in T98G decreased glycolysis ability through lactate dehydrogenase A activity reduction. Moreover, it increased TMZ toxicity and decreased invasion ability. Furthermore, we provide next-generation sequencing-based identification of significantly changed messenger RNAs of T98G cells with GSTM3 knockdown for further research. GSTM3 was downregulated in intrinsic TMZ-resistant T98G with a change in the expression levels of some essential glycolysis-related genes. Thus, GSTM3 was associated with glycolysis in chemotherapeutic resistance in T98G cells. Our findings provide new insight into the GSTM3 mechanism in recurring GBM.

Polydopamine Ultrathin Film Growth on Mica via In-Situ Polymerization of Dopamine with Applications for Silver-Based Antimicrobial Coatings.

The development of polydopamine (PDA) coatings with a nanometer-scale thickness on surfaces is highly desirable for exploiting the novel features arising from the specific structure on the molecular level. Exploring the mechanisms of thin-film growth is helpful for attaining desirable control over the useful properties of materials. We present a systematic study demonstrating the growth of a PDA thin film on the surface of mica in consecutive short deposition time intervals. Film growth at each deposition time was monitored through instrumental techniques such as atomic force microscopy (AFM), water contact angle (WCA) analysis, and X-ray photoelectron spectroscopy (XPS). Film growth was initiated by adsorption of the PDA molecules on mica, with subsequent island-like aggregation, and finally, a complete molecular level PDA film was formed on the surface due to further molecular adsorption. A duration of 60-300 s was sufficient for complete formation of the PDA layer within the thickness range of 0.5-1.1 nm. An outstanding feature of PDA ultrathin films is their ability to act as a molecular adhesive, providing a foundation for constructing functional surfaces. We also explored antimicrobial applications by incorporating Ag nanoparticles into a PDA film. The Ag NPs/PDA film was formed on a surgical blade and then characterized and confirmed by SEM-EDS and XPS. The modified film inhibited bacterial growth by up to 42% on the blade after cutting through a pork meat sample.

Effects of Streptococcus thermophilus on anterior cruciate ligament transection-induced early osteoarthritis in rats.

Osteoarthritis (OA) is the most common joint disorder and is classically defined as a progressively degenerative disease of articular cartilage. It manifests as joint pain and disability and currently has no comprehensive treatments. The primary purpose of the present study was to test the effects of probiotics, Streptococcus thermophilus (TCI633), on anterior cruciate ligament transection (ACLT)-induced experimental osteoarthritis (OA) in rats. In the current study, the experimental groups were given TCI633 (5x109, 5x1010 and 5x1011 CFU/kg/day) and glucosamine sulfate (250 mg/kg) between week 8 and 20 following ACLT. The results showed that oral administration of TCI633 and glucosamine had significant therapeutic effects on pain behaviors and knee swelling. Dose-dependent effects of TCI633 were also observed in ACLT-treated rats. Histopathological analysis demonstrated that ACLT+TCI633 (5x109, 5x1010 and 5x1011 CFU/kg/day) improved the synovial inflammation and cartilage damage of ACLT rats. Histology evaluation using the Osteoarthritis Research Society International system and synovial inflammatory score analysis showed the dose-dependent inhibition of TCI633 on synovial inflammation and cartilage damage. Immunohistochemical staining and TUNEL apoptosis staining showed that TCI633 could effectively increase the expression of type II collagen and reduce the amount of chondrocyte apoptosis in cartilage. Therefore, the present study demonstrated that oral intake of TCI633 could significantly suppressing pain behavior, reduce joint swelling and synovial tissue inflammation and increase type II collagen expression in cartilage. There was also a reduction in chondrocyte apoptosis and decreased progression of OA in ACLT-treated rats.

Association of early vertebroplasty with risk of hip replacement: A nationwide population-based cohort study in Taiwan.

Studies show that vertebral fractures could predict the risk of hip fractures. We aimed to evaluate the potential benefits of whether the timing of vertebroplasty (VP) for vertebral fracture associated with the risk of hip fracture for hip replacement.We identified 142,782 patients from the Taiwan National Health Insurance Database with thoracolumbar vertebral fracture (International Classification of Diseases, Ninth Revision, Clinical Modification:805.2-805.9) who were followed up from 2000 to 2013. These patients were divided into those who underwent VP (VP group) (International Classification of Diseases, Ninth Revision, Clinical Modification : 78.49) within 3 months and those who did not (non-VP group). After adjusting for the confounding factors, the Cox proportional hazards analysis was used to estimate the effect of early VP on reducing the risk of hip fracture. The difference in the risk of hip replacement, between the VP group and non-VP group was estimated using the Kaplan-Meier method with the log-rank test.In the 14-year follow-up, the cumulative incidence rate of hip replacement in the VP group was lower than that in the non-VP group (0.362% and 0.533%, respectively, long-rank P < .001). There was a significant difference between the 2 groups since the first-year follow-up.Our study showed that early VP performed to avoid progression of the kyphotic changes following thoracolumbar vertebral fracture may reduce the risk of hip fracture. These results, obtained from retrospective data, indicate that a prospective study is warranted.

TP3, an antimicrobial peptide, inhibits infiltration and motility of glioblastoma cells via modulating the tumor microenvironment.

Glioblastoma multiforme (GBM) is a cancer of the central nervous system with limited therapeutic outcomes. Infiltrating cancer cells are the contributing factor to high GBM malignancy. The intracranial brain cancer cell infiltration is a complex cascade involving adhesion, migration, and invasion. An arsenal of natural products has been under exploration to overcome GBM malignancy. This study applied the antimicrobial peptide tilapia piscidin 3 (TP3) to GBM8401, U87MG, and T98G cells. The cellular assays and microscopic observations showed that TP3 significantly attenuated cell adhesion, migration, and invasion. A live-cell video clip showed the inhibition of filopodia protrusions and cell attachment. Probing at the molecular levels showed that the proteolytic activities (from secretion), the mRNA and protein expression levels of matrix metalloproteinases-2 and -9 were attenuated. This result strongly evidenced that both invasion and metastasis were inhibited, although metastatic GBM is rare. Furthermore, the protein expression levels of cell-mobilization regulators focal adhesion kinase and paxillin were decreased. Similar effects were observed in small GTPase (RAS), phosphorylated protein kinase B (AKT) and MAP kinases such as extracellular signal-regulated kinases (ERK), JNK, and p38. Overall, TP3 showed promising activities to prevent cell infiltration and metastasis through modulating the tumor microenvironment balance, suggesting that TP3 merits further development for use in GBM treatments.

Etoricoxib prevents progression of osteolysis in repeated intra-articular monosodium urate-induced gouty arthritis in rats.

Deposition of monosodium urate (MSU) crystals in the joint or synovium is the major factor in Gouty arthritis (GA). The clinical features of chronic and recurrent GA include pain and the subsequent development of chronic tophaceous GA with multiple tophi deposits accompanied by osteolysis. The majority of previous animal studies have focused on MSU-induced acute GA without making observations regarding osteolysis. In the study, intra-articular injections of MSU into the knee (2 times/week for 10 weeks) was used to induce chronic and recurrent attacks of GA that in turn induced progressive osteolysis. Moreover, we also evaluated whether the clinical, nonsteroidal anti-inflammatory drug (NSAID) etoricoxib attenuated the osteoclastogenesis of progressive osteolysis. The knee morphometry and the expression of osteoclastogenesis-related proteins (cathepsin K and matrix metalloproteinase-9 and -13) in the knee were examined by micro-CT and immunohistochemistry, respectively. Results showed that oral etoricoxib not only significantly attenuated the nociceptive behaviors of the rats but that it also inhibited the expression of osteoclastogenesis-related proteins in their knee joints in chronic and recurrent attacks of GA. Our findings thus suggest that NSAIDs not only inhibit nociception but also prevent the progression of osteolysis in chronic and repeated attacks of GA.

Piscidin-1 Induces Apoptosis via Mitochondrial Reactive Oxygen Species-Regulated Mitochondrial Dysfunction in Human Osteosarcoma Cells.

Osteosarcoma (OSA) is the most common type of cancer that originates in the bone and usually occurs in young children. OSA patients were treated with neoadjuvant chemotherapy and surgery, and the results were disappointing. Marine antimicrobial peptides (AMPs) have been the focus of antibiotic research because they are resistant to pathogen infection. Piscidin-1 is an AMP from the hybrid striped bass (Morone saxatilis × M. chrysops) and has approximately 22 amino acids. Research has shown that piscidin-1 can inhibit bacterial infections and has antinociception and anti-cancer properties; however, the regulatory effects of piscidin-1 on mitochondrial dysfunction in cancer cells are still unknown. We aimed to identify the effects of piscidin-1 on mitochondrial reactive oxygen species (mtROS) and apoptosis in OSA cells. Our analyses indicated that piscidin-1 has more cytotoxic effects against OSA cells than against lung and ovarian cancer cells; however, it has no effect on non-cancer cells. Piscidin-1 induces apoptosis in OSA cells, regulates mtROS, reduces mitochondrial antioxidant manganese superoxide dismutase and mitochondrial transmembrane potential, and decreases adenosine 5'-triphosphate production, thus leading to mitochondrial dysfunction and apoptosis. The mitochondrial antioxidant, mitoTempo, reduces the apoptosis induced by piscidin-1. Results suggest that piscidin-1 has potential for use in OSA treatment.

Therapeutic Role of Protein Tyrosine Phosphatase 1B in Parkinson's Disease via Antineuroinflammation and Neuroprotection In Vitro and In Vivo.

Parkinson's disease (PD) is one of the most widespread neurodegenerative diseases. However, the currently available treatments could only relieve symptoms. Novel therapeutic targets are urgently needed. Several previous studies mentioned that protein tyrosine phosphatase 1B (PTP1B) acted as a negative regulator of the insulin signal pathway and played a significant role in the inflammation process. However, few studies have investigated the role of PTP1B in the central nervous system. Our study showed that suramin, an inhibitor of PTP1B, could improve neuronal damage. It could significantly attenuate the interferon-gamma-induced upregulation of proinflammatory cytokines, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). It enhanced M2 type microglia markers, such as arginase-1 and Ym-1 in BV2 murine microglial cells. PTP1B inhibition also reversed 6-hydroxydopamine- (6-OHDA-) induced downregulation of phospho-cAMP response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) in SH-SY5Y cells. Besides, we knocked down and overexpressed PTP1B in the SH-SY5Y cells to confirm its role in neuroprotection. We also verified the effect of suramin in the zebrafish PD model. Treatment with suramin could significantly reverse 6-OHDA-induced locomotor deficits and improved tyrosine hydroxylase (TH) via attenuating endoplasmic reticulum (ER) stress biomarkers. These results support that PTP1B could potentially regulate PD via antineuroinflammation and antiapoptotic pathways.

Therapeutic Effect of Modulating TREM-1 via Anti-inflammation and Autophagy in Parkinson's Disease.

Parkinson's disease (PD) is one of the most common age-related neurodegenerative diseases, and neuroinflammation has been identified as one of its key pathological characteristics. Triggering receptors expressed on myeloid cells-1 (TREM-1) amplify the inflammatory response and play a role in sepsis and cancer. Recent studies have demonstrated that the attenuation of TREM-1 activity produces cytoprotective and anti-inflammatory effects in macrophages. However, no study has examined the role of TREM-1 in neurodegeneration. We showed that LP17, a synthetic peptide blocker of TREM-1, significantly inhibited the lipopolysaccharide (LPS)-induced upregulation of proinflammatory cascades of inducible nitric oxide synthase (iNOS), cyclooxygenase-2, and nuclear factor-kappa B. Moreover, LP17 enhanced the LPS-induced upregulation of autophagy-related proteins such as light chain-3 and histone deacetylase-6. We also knocked down TREM-1 expression in a BV2 cell model to further confirm the role of TREM-1. LP17 inhibited 6-hydroxydopamine-induced locomotor deficit and iNOS messenger RNA expression in zebrafish. We also observed therapeutic effects of LP17 administration in 6-hydroxydopamine-induced PD syndrome using a rat model. These data suggest that the attenuation of TREM-1 could ameliorate neuroinflammatory responses in PD and that this neuroprotective effect might occur via the activation of autophagy and anti-inflammatory pathways.

BA6 Induces Apoptosis via Stimulation of Reactive Oxygen Species and Inhibition of Oxidative Phosphorylation in Human Lung Cancer Cells.

Lung cancer is the leading cause of cancer deaths in the world, with a five-year survival rate of less than 30%. Clinically effective chemotherapeutic treatments at the initial stage may eventually face the dilemma of no drug being effective due to drug resistance; therefore, finding new effective drugs for lung cancer treatment is a necessary and important issue. Compounds capable of further increasing the oxidative stress of cancer cells are considered to have anticancer potential because they possessed the ability to induce apoptosis. This study mainly investigated the effects of BA6 (heteronemin), the marine sponge sesterterpene, on lung cancer cell apoptosis, via modulation of mitochondrial reactive oxygen species (mtROS) and oxidative phosphorylation (OXPHOS). BA6 has cellular cytotoxic activities against a variety of cancer cell lines, but it has no effect on nontumor cells. The BA6-treated lung cancer cells show a significant increase in both cellular ROS and mtROS, which in turn caused the loss of mitochondrial membrane potential (MMP). The increase of oxidative stress in lung cancer cells treated with BA6 was accompanied by a decrease in the expression of antioxidant enzymes Cu/Zn SOD, MnSOD, and catalase. In addition, OXPHOS performed in the mitochondria and glycolysis in the cytoplasm were inhibited, which subsequently reduced downstream ATP production. Pretreatment with mitochondria-targeted antioxidant MitoTEMPO reduced BA6-induced apoptosis through the mitochondria-dependent apoptotic pathway, which was accompanied by increased cell viability, decreased mtROS, enhanced MMP, and suppressed expression of cleaved caspase-3 and caspase-9 proteins. In conclusion, the results of this study clarify the mechanism of BA6-induced apoptosis in lung cancer cells via the mitochondrial apoptotic pathway, suggesting that it is a potentially innovative alternative to the treatment of human lung cancer.