Shenjinhuoxue Mixture Attenuates Inflammation, Pain, and Cartilage Degeneration by Inhibiting TLR-4 and NF-κB Activation in Rats with Osteoarthritis: A Synergistic Combination of Multitarget Active Phytochemicals.

Osteoarthritis (OA), a highly prevalent chronic joint disease, involves a complex network of inflammatory mediators that not only triggers pain and cartilage degeneration but also accelerates disease progression. Traditional Chinese medicinal shenjinhuoxue mixture (SHM) shows anti-inflammatory and analgesic effects against OA with remarkable clinical efficacy. This study explored the mechanism underlying anti-OA properties of SHM and evaluated its efficacy and safety via in vivo experiments. Through network pharmacology and published literature, we identified the key active phytochemicals in SHM, including ß-sitosterol, oleanolic acid, licochalcone A, quercetin, isorhamnetin, kaempferol, morusin, lupeol, and pinocembrin; the pivotal targets of which are TLR-4 and NF-κB, eliciting anti-OA activity. These phytochemicals can enter the active pockets of TLR-4 and NF-κB with docking score ≤ -3.86 kcal/mol, as shown in molecular docking models. By using surface plasmon resonance assay, licochalcone A and oleanolic acid were found to have good TLR-4-binding affinity. In OA rats, oral SHM at mid and high doses (8.72 g/kg and 26.2 g/kg) over 6 weeks significantly alleviated mechanical and thermal hyperalgesia (P < 0.0001). Accordingly, the expression of inflammatory mediators (TLR-4, interleukin (IL-) 1 receptor-associated kinase 1 (IRAK1), NF-κB-p65, tumor necrosis factor (TNF-) α, IL-6, and IL-1ß), receptor activator of the NF-κB ligand (RANKL), and transient receptor potential vanilloid 1 (TRPV1) in the synovial and cartilage tissue of OA rats was significantly decreased (P < 0.05). Moreover, pathological observation illustrated amelioration of cartilage degeneration and joint injury. In chronic toxicity experiment of rats, SHM at 60 mg/kg demonstrated the safety. SHM had an anti-inflammatory effect through a synergistic combination of active phytochemicals to attenuate pain and cartilage degeneration by inhibiting TLR-4 and NF-κB activation. This study provided the experimental foundation for the development of SHM into a more effective dosage form or new drugs for OA treatment.

Danshen prevents articular cartilage degeneration via antioxidation in rabbits with osteoarthritis.

OBJECTIVE: To evaluate the efficacy of Danshen on histological parameters and antioxidative activity in the articular cartilage of rabbits with osteoarthritis (OA). DESIGN: Twenty-four rabbits were randomly divided into three groups (control, OA, and Danshen OA; eight rabbits per group). Anterior cruciate ligament transection (ACLT) of the left hind knees was performed in all rabbits in the OA and Danshen OA group for induction of OA. The rabbits in the control group underwent a sham operation. After surgery, 3 g/kg body weight of Danshen granules dissolved in 5 mL distilled water was administered by gastric intubation once per day and over a 6-week period to the Danshen OA group. The same volume of distilled water was administered to the OA and control groups. After 6 weeks, the medial femoral condyles and synoviums of the left hind knees in all three groups were harvested and used for histological and biochemical analyses. RESULTS: Severe articular cartilage degeneration as well as lower proteoglycan (PG) content were noted in the OA group compared to the Danshen OA group (P < 0.05). The glutathione (GSH) levels in the synovium and articular cartilage of the rabbits in the Danshen OA group were significantly higher compared to the OA group (P < 0.001). The malondialdehyde (MDA) levels of the synovium and articular cartilage in the Danshen OA group was markedly depleted compared to the OA group (P < 0.001). CONCLUSION: Danshen can prevent articular cartilage degeneration in OA through the defense against oxidative stress.

Dietary 2-oxoglutarate mitigates gastrectomy-evoked structural changes in cartilage of female rats.

Gastrectomy (Gx) leads to osteopenia/osteoporosis in humans and animals. However, little is known about the influence of Gx on the cartilage in this regard. Recent studies have demonstrated a protective effect of 2-oxoglutaric acid (2-Ox) on bone and cartilage. Hence, the purpose of this study was to investigate whether 2-Ox can mitigate eventual Gx-induced cartilage impairment. Twenty female Sprague-Dawley rats were subjected to Gx and randomly divided into two groups: Gx + 2-Ox and Gx. Another 20 rats were sham-operated (ShO) and randomly divided into two groups: ShO + 2-Ox and ShO. The daily dose of 2-Ox administered to the rats in the drinking water was 0.43 g per 100 g rat. After eight weeks, rats were euthanized and femora and tibiae were collected. Histology and histomorphometry analyses of the articular cartilage and the growth plate were done. Gx resulted in a 32% (±44.5 femur, ±35.8 tibia) decrease in overall thickness of articular cartilage in both bones (femur: ShO 279.1 ± 48.5 vs. Gx 190.2 ± 38.4 µm, tibia: ShO 222.9 ± 50.3 µm vs. Gx 151.3 ± 52.6 µm) (in some zones up to 58 ± 28.0%), and in the growth plate up to 20% (±22.4) (femur: ShO 243.0 ± 34.0 vs. Gx 207.0 ± 33.7 µm, tibia: ShO 220.0 ± 24.6 µm vs. Gx 171.1 ± 16.1 µm). Gx altered the spatial distribution of thick and thin collagen fibers, and chondrocyte shape and size. 2-Ox administration prevented the reduction in both cartilages thickness (Gx + 2-Ox: articular cartilage 265.2 ± 53.8 µm, 235.6 ± 42.7 µm, growth plate 236.7 ± 39.2 µm, 191.3 ± 16.5 µm in femur and tibia, respectively), and abolished the spatial changes in collagen distribution and structure induced by Gx. Gx affects cartilage structure and thickness, however, 2-Ox administration mitigates these effects and showed protective and stimulatory properties. Our observations suggest that dietary 2-Ox can be used to offset some of the changes in hyaline cartilage, in particular articular cartilage, following bariatric surgeries.

Fucoidan Prevents the Progression of Osteoarthritis in Rats.

This study investigated the effects of fucoidan (extract from Hizikia fusiforme) on symptoms and inflammatory cytokine activation in rats with monosodium iodoacetate (MIA)-induced osteoarthritis (OA). Forty male SD rats were divided into five groups, including normal, negative control (MIA), positive control (Lyprinol), and two experimental groups treated with 50 or 100 mg/kg fucoidan. Weight-bearing assessments were done after MIA injection into the right knee to induce OA. After 14 days of treatment, microcomputed tomographic (micro-CT) images were made of rat knee joints, and then animals were sacrificed for joint histology and inflammatory cytokine level assessments. MIA injection successfully induced OA by causing 40% weight-bearing imbalance, severe bone loss and cartilage degeneration, and markedly increased cytokine levels. However, fucoidan groups showed over 45% of imbalance and no articular cartilage surface lesions or change in subchondral trabecular bones in Micro-CT images. Histological analysis revealed that cartilage morphology and cell counts were also normal in the 100 mg/kg fucoidan group. In addition, the 100 mg/kg fucoidan groups exhibited lower serum tumor necrosis factor alpha (TNF-α) (30%), interleukin 1 beta (IL-1ß) (48%), and matrix metalloproteinase-1 (MMP-1) (65%) compared to the MIA groups. These results suggest that administration of fucoidan prevents the progression of OA in a MIA-induced OA rat model.

Sclerostin inhibition reverses systemic, periarticular and local bone loss in arthritis.

OBJECTIVE: To test whether inhibition of sclerostin by a targeted monoclonal antibody (Scl-Ab) protects from bone and cartilage damage in inflammatory arthritis. Sclerostin is a potent inhibitor of bone formation and may be responsible for the low level of bone repair in patients with rheumatoid arthritis. METHODS: Human tumour necrosis factor transgenic mice (hTNFtg mice) developing inflammatory arthritis and local and bone loss were administered either vehicle, anti-TNF antibody, Scl-Ab, or a combination of both agents. Inflammation, systemic and periarticular bone loss, bone erosion and cartilage damage were evaluated at baseline (week 8) and after 3 weeks of treatment by clinical assessment, micro-CT and histology. RESULTS: Scl-Ab did not affect joint swelling or synovitis. Systemic bone loss in the spine and periarticular bone loss in the proximal tibia were completely blocked and partially reversed by inhibition of sclerostin but not by inhibition of TNF. Moreover, Scl-Ab completely arrested the progression of bone erosion in hTNFtg mice and in combination with TNF inhibition even led to significant regression of cortical bone erosions. Protective effects of Scl-Ab were also observed for the articular cartilage. CONCLUSIONS: These data suggest that sclerostin inhibition is a powerful tool to enhance bone repair in inflammatory arthritis.

The role of physical medicine and rehabilitation in haemophiliac patients.

Physical medicine and rehabilitation aim to evaluate, diagnose and treat disability in haemophiliac patients, while preventing injury or deterioration. They also aim to maintain the greatest degree of functional capacity and independence in patients with haemophilia, or to return them to that state. Rehabilitation, together with clotting factor replacement therapy, has revolutionized the management of these patients in developed countries and reduced their morbidity/mortality rates. A knowledge of the musculoskeletal signs and symptoms of haemophilia is essential for providing a treatment which is suitable and customized. Physical medicine and rehabilitation techniques, which are based on physical means, are intended to reduce the impact which these injuries and their consequences or sequelae can have on the quality of life of patients with haemophilia. Under ideal haemostatic control conditions (primary prophylaxis), people with haemophilia could achieve good physical condition which will allow them to enjoy both physical activity and a daily life without limitations. Currently, children undergoing primary prophylaxis are quite close to this ideal situation. For these physical activities to be carried out, the safest possible situations must be sought.

Activity study of a hydroxynaphthoquinone fraction from Arnebia euchroma in experimental arthritis.

Although various drugs for the treatment of rheumatoid arthritis (RA) have been used in clinics, RA is not completely curable to date. Thus, to seek new drugs for the treatment of RA has been a hotspot. Hydroxynaphthoquinones are the major anti-inflammatory active constituents in Arnebia euchroma (Royle) Johnst. The present study aims to evaluate the anti-arthritic activity of a hydroxynaphthoquinone mixture (HM) of A. euchroma (Royle) Johnst, including its anti-inflammatory and analgesic effects. The anti-arthritic efficacy of HM was examined using complete Freund's adjuvant- and bovine type II collagen-induced arthritic models. The paw edema, polyarthritis index and histopathological change were evaluated. The analgesic effect was assessed using the chemical and thermal models of nociception. Results found that HM administered prophylactically and curatively showed marked anti-arthritic activity by suppressing the paw swelling and development of inflammation, lowering the levels of TNF-α and IL-1ß and protecting cartilage and bone from damage. The protection of HM was superior to that of reference drugs such as prednisone acetate or etanercept, and showed no direct deleterious effect. Similarly, HM showed significant analgesic effects. In summary, HM possessed potent anti-arthritic activity. It could relieve inflammatory symptoms and protect against joint destruction. These findings indicate that HM would be a potential therapeutic agent for arthritic disease, which provide pharmacological evidence for its clinical application.

Selenium for preventing Kashin-Beck osteoarthropathy in children: a meta-analysis.

OBJECTIVE: To assess the efficacy of selenium supplementation for prevention of Kashin-Beck Osteoarthropathy in children. METHODS: We searched eight electronic databases and seven journals (upto July 2007) to identify randomized controlled trials (RCTs) and prospective non-RCTs comparing selenium supplementations with placebo or no intervention for preventing Kashin-Beck disease (KBD). The methodological qualities of included studies were assessed according to the guidelines of Cochrane Handbook for Systematic Reviews of Interventions for RCTs and the method described by Deeks et al. for non-RCTs. Outcomes were presented as Peto-odds ratios (Peto-ORs) with 95% confidence intervals (95% CIs) based on fixed effect model. The number needed to treat (NNT) was calculated. Meta-regression was also conducted to explore the possible impacts of potential confounding variables (place of study, age, selenium form, etc.) of included trials on the incidence of KBD. RESULTS: Five RCTs and 10 non-RCTs were included in this review. The methodological quality of included studies was low. The pooled Peto-OR and NNT favoring selenium supplement was 0.13 (95% CI: 0.04-0.47) and 21 in RCTs, and 0.16 (95% CI: 0.09-0.30) and 26 in non-RCTs. Meta-regression indicated that the effect of potential confounding variables on KBD incidence was not statistically significant. One trial reported the side effects of nausea and vomiting in the process of selenium supplementation. CONCLUSIONS: Current evidence supports the benefits of selenium supplementation for prevention of KBD in children. However, the evidence was limited by potential biases and confounders. Large, well-designed trials are still needed.

Diminished ciprofloxacin-induced chondrotoxicity by supplementation with magnesium and vitamin E in immature rats.

Quinolone-induced chondrotoxicity in juvenile rats and multiple other species has been demonstrated previously. Identical damages can be induced in immature rats by feeding them a magnesium-deficient diet. The objective of the present study was to investigate whether, in reverse, oral supplementation with magnesium, vitamin E, or both can diminish the typical quinolone-induced arthropathy in juvenile Wistar rats. Four groups of 12 (6 male, 6 female) 24-day-old Wistar rats were each fed either normal feed (group A), a vitamin E-enriched diet (group B), a magnesium-enriched diet (group C), or a diet enriched with both vitamin E and magnesium (group D) for 10 days. All rats received two subcutaneous ciprofloxacin doses of 600 mg/kg of body weight on postnatal day 32. Two days later, the rats were sacrificed and cartilage samples from knee joints were examined under a light microscope for the presence of typical quinolone-induced joint cartilage lesions. In addition, magnesium, calcium, and vitamin E concentrations in cartilage and plasma were determined. In the samples from rats fed a normal diet (group A), 17 quinolone-induced joint cartilage lesions were observed. In groups fed an enriched diet, the incidence of specific lesions (n) was significantly lower: group B, n = 10 (41% reduction compared to the incidence for group A; P < 0.05); group C, n = 6 (65% reduction; P < 0.01); and group D, n = 3 (82% reduction; P < 0.01). In comparison to the standard diet, diets with magnesium and vitamin E supplementation resulted in significantly higher magnesium and vitamin E concentrations in plasma and articular cartilage. Supplementation with magnesium and vitamin E alone or in combination may relevantly diminish joint cartilage lesions induced by quinolones in immature rats, with an additive effect of combined supplementation. The data further support the proposed pathomechanism of quinolone-induced arthropathy and the crucial role of magnesium in immature joint cartilage.

Effect of copper supplementation on the evidence of developmental orthopaedic disease in pasture-fed New Zealand Thoroughbreds.

The effect of copper status on the evidence of bone and cartilage lesions was investigated in 21 Thoroughbred foals. The foals and their dams were grazed on pasture containing 4.4-8.6 mg Cu/kg dry matter (DM). Four treatment groups were created by randomly allocating mares and their foals to either copper supplemented (0.5 mg Cu/kg liveweight (LW)/day), or control (pasture only) groups. This experimental design allowed the effect of copper supplementation of mare and foal to be examined independently. Parameters of bone and cartilage development were assessed in the foals both in vivo, and at post mortem at approximately age 150 days. Mare copper supplementation significantly (P<0.01) decreased radiographic indices of physitis in the distal third metatarsal bone of the foals at 150 days, and the prevalence of articular cartilage lesions (P<0.05). Articular cartilage lesions were minor in all foals, with no evidence of clinical developmental orthopaedic disease (DOD) in vivo, with the exception of minor radiographic changes assessed at post mortem. Copper supplementation of the foal had no effect on any of the bone and cartilage parameters. Copper supplementation of the mares did not abolish DOD in the growing foals, emphasising the probable multifactorial nature of this condition. However, mare supplementation may be a useful treatment regime on a farm where the incidence and severity of DOD are of concern.

Effect of a benzylidene derivative, a novel antirheumatic agent, on IL-1 production.

3,4-Diacetoxy benzylidene diacetate (ACP) is a prodrug of protocatechualdehyde (PAL). PAL significantly inhibited interleukin-1 (IL-1) production and release in human monocytes in a dose dependent fashion under lipopolysaccharide (LPS) stimulation. ACP showed inhibitory effects on cartilage destruction of the femoral condyles induced by adjuvant arthritis in vivo in a significant and dose dependent fashion. To clarify the mechanism of action of ACP on rat adjuvant arthritis, we investigated the effects of PAL, a metabolite of ACP, on IL-1 production using synovial cell cultures derived from patients with rheumatoid arthritis. PAL significantly inhibited the IL-1 beta production induced by IL-1 alpha or PMA without inhibition of total protein synthesis and cytotoxicity. A protein kinase C (PKC) inhibitor, staurosporine, also suppressed the IL-1 beta production induced by IL-1 alpha or PMA, suggesting that the PKC pathway plays an important role in IL-1 alpha-induced IL-1 beta production. The calcium ionophore A23187 (A23187) potentiated the IL-1 beta production induced by IL-1 alpha. Whereas PAL slightly inhibited under these conditions, it was not statistically significant. These results suggest that PAL has a favourable action on cartilage destruction through the inhibition of IL-1 production induced by the modification of the PKC pathway.

Otologic aspects of ear burns.

Otologic experiences in a large burn center are discussed and the following areas are emphasized. First, the otologic effects of hyperbaric oxygen therapy and the prevention and treatment of barotrauma that is occasionally secondary to this therapy. Second, the diagnosis and treatment as well as the prevention of perichondritis in severely burned ears will be discussed. A total of thirty-five cases of perichondritis will be reviewed. An encouraging aspect of the method of treatment has evolved over the past five years: there has been a minimum of deformity in the healed ear, with no subsequent reconstruction necessary. My experience stresses the importance of otologic supervision and ready consultation in all ear burns, and cooperation with the surgeons in charge of the overall care of the burn patient.