Challenges and opportunities of medicines for treating tendon inflammation and fibrosis: A comprehensive and mechanistic review.

BACKGROUND: Tendinopathy refers to conditions characterized by collagen degeneration within tendon tissue, accompanied by the proliferation of capillaries and arteries, resulting in reduced mechanical function, pain, and swelling. While inflammation in tendinopathy can play a role in preventing infection, uncontrolled inflammation can hinder tissue regeneration and lead to fibrosis and impaired movement. OBJECTIVES: The inability to regulate inflammation poses a significant limitation in tendinopathy treatment. Therefore, an ideal treatment strategy should involve modulation of the inflammatory process while promoting tissue regeneration. METHODS: The current review article was prepared by searching PubMed, Scopus, Web of Science, and Google Scholar databases. Several treatment approaches based on biomaterials have been developed. RESULTS: This review examines various treatment methods utilizing small molecules, biological compounds, herbal medicine-inspired approaches, immunotherapy, gene therapy, cell-based therapy, tissue engineering, nanotechnology, and phototherapy. CONCLUSION: These treatments work through mechanisms of action involving signaling pathways such as transforming growth factor-beta (TGF-ß), mitogen-activated protein kinases (MAPKs), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), all of which contribute to the repair of injured tendons.

Evaluation of Anti-Nociceptive, Anti-Inflammatory, and Anti-Fibrotic effects of noscapine against a rat model of Achilles tendinopathy.

During tendinopathy, prolonged inflammation results in fibrosis and the adherence of tendons to the adjacent tissues, causing discomfort and movement disorders. As a natural compound, noscapine has several anti-inflammatory and anti-fibrotic properties. Therefore, we aimed to investigate the effects of noscapine against a rat model of tendinopathy. We created a surgical rat model of Achilles tendon damage to emulate tendinopathy. Briefly, an incision was made on the Achilles tendon, and it was then sutured using an absorbable surgical thread. Immediately, the injured area was topically treated with the vehicle, noscapine (0.2, 0.6, and 1.8 mg/kg), or dexamethasone (0.1 mg/kg) as a positive control. During the 19-day follow-up period, animals were assessed for weight, behavior, pain, and motor coordination testing. On day 20th, the rats were sacrificed, and the tendon tissue was isolated for macroscopic scoring, microscopic (H&E, Masson's trichrome, Ki67, p53) analyses, and cytokine secretion levels. The levels of macroscopic parameters, including thermal hyperalgesia, mechanical and cold allodynia, deterioration of motor coordination, tendon adhesion score, and microscopic indices, namely histological adhesion, vascular prominence and angiogenesis, and Ki67 and p53 levels, as well as fibrotic and inflammatory biomarkers (IL-6, TNF-α, TGF-ß, VEGF) were significantly increased in the vehicle group compared to the sham group (P < 0.05-0.001 for all cases). In contrast, the administration of noscapine (0.2, 0.6, and 1.8 mg/kg) attenuated the pain, fibrosis, and inflammatory indices in a dose-dependent manner compared to the vehicle group (P < 0.05-0.001). Histological research indicated that noscapine 0.6 and 1.8 mg/kg had the most remarkable healing effects. Interestingly, two higher doses of noscapine had impacts similar to those of the positive control group in both clinical and paraclinical assessments. Taken together, our findings suggested that noscapine could be a promising medicine for treating tendinopathies.

Edible Herbal Medicines as an Alternative to Common Medication for Sleep Disorders: A Review Article.

Insomnia is repeated difficulty in falling asleep, maintaining sleep, or experiencing low-quality sleep, resulting in some form of daytime disturbance. Sleeping disorders cause daytime fatigue, mental confusion, and over-sensitivity due to insufficient recovery from a sound sleep. There are some drugs, such as benzodiazepines and anti-histaminic agents, which help to sleep induction and insomnia cure. However, the prolonged administration is unsuitable because of tolerance and dependence. Therefore, the researchers attempt to find new medicines with lesser adverse effects. Natural products have always been good sources for developing new therapeutics for managing diseases such as cancer,cardiovascular disease, diabetes, insomnia, and liver and renal problems. Ample research has justified the acceptable reason and relevance of the use of these herbs in the treatment of insomnia. It is worth noting that in this study, we looked into various Persian herbs in a clinical trial and in vivo to treat insomnia, such as Artemisia annua, Salvia reuterana, Viola tricolor, Passiflora incarnata, lettuce, and Capparis spinose. According to research, herb extracts and fractions, particularly n-butanol fractions with non-polar agents, impact the benzodiazepine receptors and have hypnotic properties. Also, alkaloids, glycosides, flavonoids, saponins, and tannins in practically every plant are mentioned making them the popular natural compounds to help with sleep disorders and promote calmness.

Comparative study on the impacts of visnagin and its methoxy derivative khellin on human lymphocyte proliferation and Th1/Th2 balance.

BACKGROUND: Visnagin is a phenolic and natural compound in turmeric and fenugreek, and its anti-inflammatory effect has been indicated. Therefore, this study aimed to investigate and compare the anti-inflammatory properties of visnagin and its methoxy derivative khellin on human lymphocytes. METHODS: Human lymphocytes were treated with khellin, visnagin (10, 30, and 100 µM), and dexamethasone (0.1 mM) in the presence of phytohemagglutinin (PHA). The levels of cell proliferation, nitric oxide (NO), glutathione (GSH), malondialdehyde (MDA), and MDA/GSH ratio were measured using biochemistry methods. Furthermore, the mRNA levels of interferon-γ (IFN-γ), interleukin (IL)-4, and IL-10 were assessed using real-time PCR, while IFN-γ/IL-4(Th1/Th2), IFN-γ/IL-10(Th1/Treg), and IL-4/IL-10(Th2/Treg) ratios were made by dividing their exact values. RESULTS: In the PHA-stimulated group, GSH and IFN-γ/IL-4 levels were markedly diminished, but other variables were significantly elevated compared to the control group. Khellin and visnagin significantly declined the levels of cell proliferation, MDA, MDA/GSH ratio, and NO production. Khellin and visnagin concentration-dependently diminished IFN-γ and IL-4 levels and increased IL-10 levels compared to the PHA-stimulated group. Two higher concentrations of khellin and visnagin (30 and 100 µM) considerably diminished the IFN-γ, IFN-γ/IL-10, and IL-4/IL-10 values compared to the PHA-stimulated group. However, 100 µM of khellin and visnagin significantly increased GSH level compared to the PHA-stimulated group. CONCLUSIONS: In PHA-stimulated lymphocytes, representing Th2 dominant allergic diseases, khellin and visnagin provides more specific anti-oxidant, anti-inflammatory, and immunomodulatory functions than dexamethasone. In addition, the effects of khellin were more prominent than visnagin.

The molecular evaluation of thioredoxin (TXN1 & TXN2), thioredoxin reductase 1 (TXNRd1), and oxidative stress markers in a binary rat model of hypo- and hyperthyroidism after treatment with gallic acid.

Oxidative stress plays an important role in the pathology of thyroid disorders. This study examined the effect of gallic acid (GA) on the oxidative status and expression of liver antioxidant genes including thioredoxin (TXN1 & TXN2) and thioredoxin reductase1 (TXNRd1) in hypo- and hyperthyroid rat models. Forty-nine male Wistar rats were randomly assigned into seven groups as follows: control group, hypothyroid and hyperthyroid groups respectively induced by propylthiouracil and levothyroxine, hypo- and hyper thyroid-treated groups (where the groups were separately treated with 50 and 100 mg/kg of GA daily, orally). The levels of thyroid hormones and serum oxidative stress markers were evaluated after 5 weeks. The relative expression of TXN1,2 and TXNRd1 genes was measured via real-time qRT-PCR. The mean level of total antioxidant capacity (TAC), malondialdehyde, and uric acid index diminished in the hypothyroid group. Increased TAC reached almost the level of control in hypothyroid groups treated with GA. Elevation of thiol index in the hypothyroid group was observed (p < 0.01), which diminished to the control level after GA treatment. The relative expression of TXN1, TXNRd1, and TXN2 genes in the hypothyroid and hyperthyroid groups significantly increased compared to the control group (p ≥ 0.05), but in the groups treated with GA, the expression of these genes declined significantly (p ≥ 0.05). Our results indicated GA can affect the expression of TXN system genes in the rat liver. Also, the results suggest GA has a more positive effect on modulating serum oxidative parameters in hypothyroid rat models than in hyperthyroid.

Persistent effects of the orexin-1 receptor antagonist SB-334867 on naloxone precipitated morphine withdrawal symptoms and nociceptive behaviors in morphine dependent rats.

AIM OF THE STUDY: In this study, we investigated the effect of long-term administration of orexin receptor 1 (OXR1) antagonist on naloxone-precipitated morphine withdrawal symptoms and nociceptive behaviors in morphine-dependent rats. MATERIALS AND METHODS: Wistar rats received subcutaneous (s.c.) injections of morphine (6, 16, 26, 36, 46, 56, and 66 mg/kg, 2 ml/kg) at an interval of 24 h for 7 days. In chronic groups, the OXR1 antagonist, SB-334867 (20 mg/kg, i.p.), or its vehicle, was injected repetitively from postnatal day 1 (PND1)-PND23 and then for the following seven days before each morphine injection. Meanwhile, in acute groups, SB-334867, or its vehicle, was administered before each morphine injection. In groups of rats that were designated for withdrawal experiments, naloxone (2.5 mg/kg, i.p.) was administered after the last injection of morphine. In the formalin-induced pain, the effect of OXR1 inhibition on the antinociceptive effects of morphine was measured by injecting formalin after the final morphine injection. RESULTS: Animals that received long-term SB-334867 administration before morphine injection demonstrated a significant reduction in chewing, defecation, diarrhea, grooming, teeth chattering, wet-dog shake, and writhing. Inhibiting OXR1 for a long time increased formalin-induced nociceptive behaviors in interphase and phase II of the formalin-induced pain. CONCLUSIONS: Our results indicated that the inhibition of OXR1 significantly reduces the development of morphine dependence and behavioral signs elicited by the administration of naloxone in morphine-dependent rats. Furthermore, the prolonged blockade of OXR1 might be involved in formalin-induced nociceptive behaviors.