Effects of Etanercept on Experimental Osteoarthritis in Rats: Role of Histone Deacetylases.

OBJECTIVE: Mounting evidence suggests that histone deacetylases (HDAC) inhibitors reduce cartilage destruction in animal models of osteoarthritis (OA). Tumor necrosis factor (TNF)-α-blocking treatment for OA may provide effective joint protection by slowing joint damage. To investigate the effects of intraperitoneal administration of etanercept (a TNF-α inhibitor) on OA development in rats and changes in the nociceptive behavior of rats and expression of HDACs, RUNX2, and MMP13 in cartilage. METHODS: Induction of OA in Wistar rats was accomplished through anterior cruciate ligament transection (ACLT). One or five milligrams (mg) of etanercept was administered intraperitoneally for 5 consecutive weeks after ACLT to the ACLT + etanercept (1 and 5 mg/kg) groups. Nociceptive behavior and changes in knee joint width were analyzed. Cartilage was evaluated histologically and immunohistochemically. RESULTS: ACLT + etanercept significantly improved mechanical allodynia and weight-bearing distribution compared to ACLT alone. In OA rats treated with etanercept, cartilage degeneration and synovitis were significantly less pronounced than those in ACLT rats. OA-affected cartilage also showed reduced expression of HDAC 6, 7, RUNX-2, and MMP-13 in response to etanercept but increased expression of HDAC4. CONCLUSION: Our study demonstrated that etanercept therapy (1) attenuated the development of OA and synovitis in rats, (2) reduced nociception, and (3) regulated chondrocyte metabolism, possibly by inhibiting cell HDAC6 and HDAC7, RUNX2, and MMP13 and increasing HDAC4 expression. Based on new evidence, etanercept may have therapeutic potential in OA.

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.

Intra-Articular Lactate Dehydrogenase A Inhibitor Oxamate Reduces Experimental Osteoarthritis and Nociception in Rats via Possible Alteration of Glycolysis-Related Protein Expression in Cartilage Tissue.

Osteoarthritis (OA) is the most common form of arthritis and joint disorder worldwide. Metabolic reprogramming of osteoarthritic chondrocytes from oxidative phosphorylation to glycolysis results in the accumulation of lactate from glycolytic metabolite pyruvate by lactate dehydrogenase A (LDHA), leading to cartilage degeneration. In the present study, we investigated the protective effects of the intra-articular administration of oxamate (LDHA inhibitor) against OA development and glycolysis-related protein expression in experimental OA rats. The animals were randomly allocated into four groups: Sham, anterior cruciate ligament transection (ACLT), ACLT + oxamate (0.25 and 2.5 mg/kg). Oxamate-treated groups received an intra-articular injection of oxamate once a week for 5 weeks. Intra-articular oxamate significantly reduced the weight-bearing defects and knee width in ACLT rats. Histopathological analyses showed that oxamate caused significantly less cartilage degeneration in the ACLT rats. Oxamate exerts hypertrophic effects in articular cartilage chondrocytes by inhibiting glucose transporter 1, glucose transporter 3, hexokinase II, pyruvate kinase M2, pyruvate dehydrogenase kinases 1 and 2, pyruvate dehydrogenase kinase 2, and LHDA. Further analysis revealed that oxamate significantly reduced chondrocyte apoptosis in articular cartilage. Oxamate attenuates nociception, inflammation, cartilage degradation, and chondrocyte apoptosis and possibly attenuates glycolysis-related protein expression in ACLT-induced OA rats. The present findings will facilitate future research on LDHA inhibitors in prevention strategies for OA progression.

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.

Briastecholide M, a New Polyoxygenated Briarane from Briareum stechei.

A formerly unpublicized briarane diterpenoid, briastecholide M (1), and its established analogue, brianodin B (2), were purified from Briareum stechei, an octocoral collected from Okinawan waters. Using spectroscopic methods, the structure of 1 was established. Functional study showed that 1 can reducing the release of inducible nitric oxide synthase (iNOS) but enhancing cyclooxygenase-2 (COX-2) protein expression.

Complications of Unilateral Biportal Endoscopic Lumbar Discectomy: A Systematic Review.

OBJECTIVE: In recent years, biportal endoscopic surgery has gained popularity, and the number of publications on it has also increased. We herein aimed to investigate the complications of biportal endoscopic surgery. In this study, the available literature was reviewed systematically and the published complications of discectomy in biportal endoscopic spinal surgery were summarized. METHODS: A systematic search of the literature published until December 31, 2021, was performed using the PubMed, Cochrane Library, Embase, and Web of Science databases. Studies on spinal discectomy using the biportal method were included. RESULTS: Twenty-two articles were finally included for review. The reported complication rate of this procedure was 0%-23.6% (radiological hematoma). In most studies, the complication rate was less than 11%. The mean complication rate was 5.37% when 596 patients (from 16 studies) underwent unilateral biportal endoscopic discectomy for the treatment of lumbar disk herniation. The reported complications of this procedure included dural tear, hematoma, incomplete decompression, recurrence, instability, neurological complications (post-op paresthesia, dysthesia or numbness, or root injury), pseudomeningocele, ascites, infection, retinal hemorrhage, and burn injury. The complication rate was higher in the early learning curve. CONCLUSIONS: Unilateral biportal endoscopic discectomy has an acceptable complication rate. Knowing the possible complications and risks of this procedure could help surgeons in taking measures to avoid common complications.

A meta-analysis of clinical effects of microscopic unilateral laminectomy bilateral decompression (ULBD) versus biportal endoscopic ULBD for lumbar canal stenosis.

Osbjective: Several studies have shown that both microscopic unilateral laminotomy bilateral decompression (ULBD) and unilateral biportal endoscopic (UBE) ULBD are effective for treating lumbar canal stenosis (LCS). However, there are different viewpoints as to which surgical technique is superior. Therefore, this meta-analysis investigated the clinical efficacy and side effects of microscopic ULBD and UBE ULBD for treating LCS. Methods: To identify relevant studies describing the clinical outcomes and complication rates of microscopic ULBD and UBE ULBD for LCS, several databases were systematically searched in the Internet. The visual analog scale score for back and leg pain and the Oswestry Disability Index were used to assess clinical outcomes. Furthermore, data about perioperative outcomes and complications were documented. Results: In total, six studies with 450 participants were included in this meta-analysis. The UBE ULBD was found to be superior to microscopic ULBD in terms of efficacy against early postoperative back and leg pain. However, there was no significant difference between the two procedures in terms of final clinical outcomes and complications. In addition, compared with microscopic ULBD, UBE ULBD was associated with a significant reduction in the length of hospital stay and C-reactive protein levels 2 days after surgery. Conclusion: UBE ULBD and microscopic ULBD for the treatment of LCS were similar in terms of final clinical outcomes and complications. However, UBE ULBD has several advantages over microscopic ULBE, including a shorter hospital stay and faster alleviation of postoperative back and leg pain.

The anti-inflammatory properties of ethyl acetate fraction in ethanol extract from Sarcodia suiae sp. alleviates atopic dermatitis-like lesion in mice.

Atopic dermatitis (AD) is a chronic inflammatory and pruritic disease; it can be treated by inhibiting inflammation. Sarcodia suiae sp. is an edible, artificially cultivable red algae with multiple bioactivities. We assessed the anti-inflammatory activity of the ethyl acetate fraction of S. suiae sp. ethanol extract (PD1) on 1-chloro-2,4-dinitrochlorobenzene (DNCB)-induced AD-like lesions. Results show that PD1 alleviated symptoms and significantly decreased clinical dermatitis score. PD1 inhibited serum immunoglobulin E expression and alleviated swelling in the spleen and subiliac lymph nodes. In skin tissues, PD1 alleviated aberrant hyperplasia, decreased epidermal thickness, and decreased the accumulation of mast cells. PD1 mediated the recovery of skin barrier-related proteins, such as claudin-1 and filaggrin. Our study demonstrated that PD1 has anti-inflammatory effects, alleviates AD symptoms, inhibits inflammatory responses in skin tissues, and restores barrier function in DNCB-induced AD mice. These findings reveal that S. suiae sp. extract provides an alternative protective option against AD.

Evaluation of the Outcomes of Biportal Endoscopic Lumbar Interbody Fusion Compared with Conventional Fusion Operations: A Systematic Review and Meta-Analysis.

OBJECTIVE: In recent years, biportal endoscopic lumbar interbody fusion (BE-LIF) has been increasingly used in the treatment of lumbar degenerative diseases. BE-LIF combines the benefits of minimally invasive fusion with endoscopic spine surgery. However, there is little evidence on whether BE-LIF is superior to posterolateral lumbar interbody fusion (PLIF). The purpose of this meta-analysis is to compare the clinical outcomes, complications, and fusion rates of BE-LIF and minimally invasive transforaminal lumbar interbody fusion (MI-TLIF)/PLIF in treating lumbar degenerative diseases. METHODS: A comprehensive assessment of the literature was conducted, and the quality of the retrieved studies was evaluated using the Newcastle-Ottawa Scale. Clinical parameters were investigated using a visual analog scale (VAS) for pain levels and the Oswestry Disability Index for disability levels. The operative times, estimated blood loss, fusion rates, and complications were also analyzed. RESULTS: This meta-analysis comprised 5 studies with a total of 444 participants. No significant differences between the techniques were seen in VAS scores for legs, Oswestry Disability Index, complications, or fusion rates. There were significantly lower VAS scores for back pain in the BE-LIF group than the MI-TLIF/PLIF group, postoperatively. In addition, BE-LIF resulted in significantly less blood loss but required a longer operative time than did MI-TLIF/PLIF. CONCLUSIONS: The benefits of BE-LIF and MI-TLIF/PLIF were approximately equivalent in terms of clinical outcomes and achievement of fusion, and complication rates were similar in both groups. However, BE-LIF reduced postoperative back pain and blood loss, despite longer operative times.

Briarane-Related Diterpenoids from Octocoral Briareum stechei.

A known polyoxygenated briarane, briaexcavatolide P (1), was isolated from a Formosan octocoral Briareum stechei. Moreover, the same species B. stechei, collected from Okinawan waters, yielded three chlorine-containing briaranes, including two new compounds, briastecholides B (2) and C (3) as well as a known analogue, briarenol R (4). The structures of 1-4 were established using spectroscopic methods. In addition, briarane 1 demonstrated anti-inflammatory activity in lipo-polysaccharide-induced RAW 264.7 mouse macrophage cells by suppressing the expression of inducible nitric oxide synthase (iNOS) protein.

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.

Chondroprotective Effects of a Histone Deacetylase Inhibitor, Panobinostat, on Pain Behavior and Cartilage Degradation in Anterior Cruciate Ligament Transection-Induced Experimental Osteoarthritic Rats.

Osteoarthritis (OA) is the most common articular degenerative disease characterized by chronic pain, joint inflammation, and movement limitations, which are significantly influenced by aberrant epigenetic modifications of numerous OA-susceptible genes. Recent studies revealed that both the abnormal activation and differential expression of histone deacetylases (HDACs) might contribute to OA pathogenesis. In this study, we investigated the chondroprotective effects of a marine-derived HDAC inhibitor, panobinostat, on anterior cruciate ligament transection (ACLT)-induced experimental OA rats. The intra-articular administration of 2 or 10 µg of panobinostat (each group, n = 7) per week from the 6th to 17th week attenuates ACLT-induced nociceptive behaviors, including secondary mechanical allodynia and weight-bearing distribution. Histopathological and microcomputed tomography analysis showed that panobinostat significantly prevents cartilage degeneration after ACLT. Moreover, intra-articular panobinostat exerts hypertrophic effects in the chondrocytes of articular cartilage by regulating the protein expressions of HDAC4, HDAC6, HDAC7, runt-domain transcription factor-2, and matrix metalloproteinase-13. The study indicated that HDACs might have different modulations on the chondrocyte phenotype in the early stages of OA development. These results provide new evidence that panobinostat may be a potential therapeutic drug for OA.

Rhabdomyolysis as a postoperative complication of multilevel soft-tissue surgery in a child with cerebral palsy.

Rhabdomyolysis is a potentially life-threatening syndrome if unrecognized. The most common causes are trauma, excessive muscle activity, alcohol abuse, and toxic substances. Rhabdomyolysis as a postoperative complication in children with cerebral palsy who have received multilevel soft-tissue surgery has not been reported in the literature. The purposes of this study are to present the case of a 12-year-old boy with spastic quadriplegic cerebral palsy who developed rhabdomyolysis after soft-tissue release and to review the literature. The patient was treated with adequate sedation and hydration, and discharged in a stable condition 11 days after surgery. His serum creatine kinase level had returned to within the normal range by the 17th postoperative day. At the 6-month follow-up, there were no systemic sequelae. The prompt recognition of rhabdomyolysis depends on a high level of suspicion. Routine checks of urine color after surgery is mandatory. For patients with high muscle tone, monitoring of muscle enzymes is recommended. Adequate sedation, pain control and hydration may prevent the progression of this life-threatening condition.