TDP-43-immunity-microbiota axis in amyotrophic lateral sclerosis: A potential pathogenic mechanism.

Osteoarthritis (OA) is a leading cause of pain and disability worldwide, with the hip and knee being the most commonly affected major joints. These forms of OA lead to individual suffering, reduced quality of life, and increased healthcare costs. According to a very recent study, the pooled prevalence of hip OA in Europe is estimated at 6%, while knee OA prevalence is higher, at 10% []. Joint replacement surgery is a common treatment used to address severe arthritis and is widely recognized as the most effective treatment for this pathology, significantly improving outcomes for arthritis patients []. However, even after successful surgery, the immediate postoperative phase is often characterized by pain, inflammatory swelling, and temporary functional limitations; these factors can influence the progress of rehabilitation. Despite substantial technical advances in surgical procedures and developments in prosthetic design in recent years, the postoperative phase remains a critical period in which pain, inflammation, and functional impairment may negatively affect rehabilitation outcomes []. During the postoperative period, the inflammatory response to surgical procedures plays an essential role in tissue repair but may also become disproportionate, leading to excessive edema, uncontrolled pain, and functional limitations that delay recovery []. Untreated chronic swelling could exacerbate discomfort and lead to difficulties in mobility and flexibility []. Moreover, edema potentially increases the risk of infection in the impacted region, reduces the flow of blood, and impacts the elasticity of the arteries []. Individuals are greatly affected by these complaints, causing both physical and psychological harm. Usually, nonsteroidal anti-inflammatory drugs (NSAIDs) are administered in order to control post-surgical inflammation and this represents a fundamental component of care, integrated within rehabilitation programs. However, the prolonged use of NSAIDs and other analgesic agents is often restricted by their potential adverse effects, particularly gastrointestinal, renal, and cardiovascular complications, which are of greater concern in older adults and in individuals with multimorbidity [,]. This scenario has stimulated growing interest in ‘natural’ anti-inflammatory molecules capable of modulating the inflammatory process with minimal or absent side effects. Some studies have been conducted about the efficacy of these agents in various settings [,,]. A product containing Diosmine, Cumarin and Arbutin (Linfadren, Omega Pharma srl) has been commercially available for several years, with the indication for the treatment of lymphatic and venous edema. Some studies have demonstrated its efficacy in the management of patients with a breast cancer-related lymphedema [], in reducing post-trauma/surgery persistent hand edema [], and in reducing persistent posttraumatic/postsurgery ankle edema []. Diosmin belongs to a group of glycosylated flavonoids and was first isolated from the plants of the Rutaceae family. It is composed of diosmetin (aglycone) and a sugar part, which is the disaccharide 6-O-L-rhamnosyl-D-glucose. This flavonoid, as a phlebotonic drug, is able to improve the condition of the veins with its anti-inflammatory and antioxidant properties. Diosmin is also able to increase venous tone, reduce the inflammatory response and capillary leakage, and improve microcirculation []. A recent placebo-controlled study has proven single-agent Diosmin as effective in reducing lower-extremity swelling and pain during motion in patients who underwent total knee arthroplasty [].