Lymphatic filariasis, caused by Brugia malayi, leads to chronic lymphatic dysfunction and lymphedema. The molecular mechanisms underlying interactions between filarial worms and their hosts remain poorly understood. Using untargeted metabolomics, we identify previously unknown acetylcholine analogs synthesized from leucine and isoleucine that are secreted by Brugia adult males. In the mammalian host, these metabolites selectively activate host M2 muscarinic acetylcholine receptors, alter lymphatic endothelial cell integrity, and trigger constriction of lymphatic vessels. These metabolites added to cultures also reduce microfilarial production in B. malayi and egg-laying in Caenorhabditis elegans, implying a role in regulating nematode reproduction. Their production is potently inhibited by ethacrynic acid, an existing FDA-approved drug. Our findings reveal a previously unexplored role for filarial-derived cholinergic signaling in parasite reproduction that impacts host lymphatic homeostasis. This work offers insights into the biochemical adaptations that function in the worm life cycle and reveals potential metabolic vulnerabilities in filarial worms.

Lymphatic filariasis (LF) encompasses grotesque and irreversible chronic conditions such as lymphedema, hydrocele, and elephantiasis. Asymptomatic or subclinical infections remain largely unnoticed as microscopy, serological tests, and antigen detection typically lack sufficient sensitivity to detect circulating microfilariae. Herein, we utilised high-resolution accurate mass spectrometry (HRAMS)-based metabolomics to thoroughly examine host metabolic responses in 25 patients with active microfilaremic infections compared with 30 healthy controls. Metabolites were annotated using the Compound Discoverer platform and analysed with MetaboAnalyst, confirming significant differential levels of 161 metabolites. The PCA scoring plot showed clear segregation between the two groups (R2X = 0.892 for the positive ESI mode and R2X = 0.904 for the negative ESI mode). The VIP score plots confirmed the top 15 defining metabolites (scores > 1.3), with arachidoyl ethanolamide, retinal, 17-OH pregnenolone sulfate, and N-acetyl-l-cysteine contributing most to the discrimination between the mf and healthy groups in both ionisation modes. The metabolite-gene function network revealed that several metabolites, such as retinal and progesterone, had the maximum number of interacting genes. Retinoids regulate cell differentiation and proliferation, especially in immune cells, like T cell subsets and regulatory T cells. Prostaglandins regulate the type 2 immune response to parasitic helminths. We identified that in individuals with bancroftian microfilaremia, lipid metabolic dysregulation is most crucially affected, with arachidonic acid metabolism being the most affected pathway. The metabolic pathways of alpha-linolenic acid, linoleic acid, and arachidonic acid were considerably enriched (p < 0.05). Overall, the levels of retinal and prostaglandin E2 changed significantly during asymptomatic infection, and therefore, these molecules have emerged as promising biomarkers in this study. Thus, our findings on bancroftian filarial metabolomics will pave the way for the development of an early diagnosis tool and provide a more insightful understanding of the affected metabolic processes in LF infections.

Filariases are neglected tropical diseases caused by Clade III parasitic nematodes transmitted by biting insects as microfilaria which mature into female and male adults in the host. One example of filariasis is lymphatic filariasis or elephantiasis, caused by three species of filaria: Brugia malayi, Wuchereria bancrofti, and/or Brugia timori. Elephantiasis results from the occlusion of lymphatic vessels by adult parasites and subsequent swelling of the limbs. It is a disfiguring disease that occurs in 120 million people worldwide. Another filarial disease is onchocerciasis caused by Onchocerca volvulus. Microfilaria of this parasite invade the eye producing corneal scarring and blindness. The infected female blackflies that transmit these microfilaria belong to the Simulium genus, and breed in fast flowing rivers. Onchocerciasis occurs near these rivers and gives rise to the common name of the disease, i.e., "river blindness." Diethylcarbamazine (Hetrazan[R]) was described as effective for treating filariases over 75 years ago by Yellapragada Subbarow and collaborators and is currently still in use. Diethylcarbamazine is characterized by a simple but flexible structure that provides it with the ability to combine with several target proteins, and a complex mode of action with effects on both filarial parasites and hosts. This Chapter reviews new observations on the activation of Transient Receptor Potential (TRP) ion-channels of B. malayi and older observations on the mechanisms of action of diethylcarbamazine. Diethylcarbamazine has three major effects: 1) A direct activating effect on filaria TRP channels producing transient inhibition of motility; 2) Reduction of host and parasite PGI2 and PGE2 production, thereby reducing host immune suppression; and 3) Activation and adhesion of host granulocytes which attack the filaria. We emphasize recent observations that include activation of TRP channels by diethylcarbamazine, an underappreciated mode of action of this classic anthelmintic.

Calotropis procera (Aiton) W.T. Aiton, a perennial shrub of the Apocynaceae family, is widely valued in Ayurveda, Unani, Siddha, and homeopathy for its broad therapeutic potential, attributed to a diverse phytochemical repertoire that includes alkaloids, triterpenoids, flavonoids, saponins, steroids, fatty acids, glycosides, and proteases. Traditionally, it is used to treat bronchitis, asthma, leprosy, eczema, elephantiasis, joint disorders, various skin ailments, and is also employed as a laxative, anthelmintic, and antiulcer agent. Phytochemical investigations of its latex, leaves, flowers, and stem bark reveal abundant terpenoids, cardenolides, steroids, and proteolytic enzymes, which underpin its antimicrobial, anti-inflammatory, analgesic, hypoglycemic, hepatoprotective, and wound-healing activities; notably, the stem bark demonstrates strong anti-inflammatory and gastroprotective effects. This review compiles and evaluates literature from PubMed, Google Scholar, and Web of Science up to November 2025, providing an integrated account of the plant's traditional uses, botanical characteristics, phytochemistry, pharmacology, and safety, while also incorporating comparative insights on the closely related species Calotropis gigantea. Given its rich bioactive profile and multifaceted pharmacological value, C. procera emerges as a promising candidate for future drug development, warranting detailed mechanistic studies, extract standardization, and evidence-based integration into modern healthcare systems.

Lymphedema is a chronic, progressive condition characterized by the accumulation of lymphatic fluid, followed by fat deposition and tissue fibrosis. It can also lead to local immune compromise and, in some cases, cutaneous malignancies. Here, we report a case of a patient with stage III combined perineal and lower limb lymphedema secondary to trauma. The patient was treated with lymphaticovenous anastomoses in the suprapubic region and both lower limbs, along with excision of excess skin and tissue in the perineal area. Optimal clinical improvement was achieved through this staged approach. This case emphasizes that although lymphaticovenous anastomosis effectively addresses extremity edema, radical excision remains essential for fibrotic genital elephantiasis. Comprehensive postoperative management is crucial for maintaining long-term results and minimizing recurrence.

Elephantiasis nostras verrucosa (ENV) is a rare, end-stage complication of chronic nonfilarial lymphedema, marked by progressive dermal fibrosis, hyperkeratosis, and verrucous skin changes, which increase susceptibility to recurrent infections and chronic wounds. We present a 77-year-old man with longstanding bilateral lower-extremity lymphedema, severe hyperkeratosis, malodorous drainage, and polymicrobial wound infection. Examination revealed extensive verrucous lesions with worsening edema and drainage from chronic venous stasis wounds, along with hyperkeratotic changes consistent with ENV. Management included intravenous cefepime and a multidisciplinary approach using the TIME framework, with involvement of infectious disease, wound care, and vascular surgery. He was discharged with a structured wound care plan, ongoing antimicrobials, and coordinated outpatient follow-up. This case underscores the dermatologic and infectious complications of advanced lymphedema and the microbiologic complexity of chronic wounds. Effective management requires early recognition, culture-guided therapy, edema control, structured wound management, and optimization of comorbidities to improve healing, reduce recurrence, and minimize healthcare burden.

A 65-years-old woman underwent right mastectomy in 2010 for invasive ductal carcinoma of the breast (HR=95% PgR=18% ki67= 25% HER2= 0). Stage pT2(30mm)pN1(2/10)M0. She started adjuvant chemotherapy then endocrine therapy. In March 2021 a CT scan showed suspected right breast and axillary lymph node recurrence; a biopsy confirmed the luminal B, HER2- phenotype. Surgery was excluded, so she started CDK4/6 inhibitor and letrozole. One year later she started palliative radiotherapy. Because of further skin and lymph node progression, the patient began everolimus and exemestane in July 2023. The patient continued this treatment for only three months, because a new CT scan showed skin, subcutaneous and axillary lymph nodes progression. The patient started capecitabine and vinorelbine. Subsequent CT scans showed further disease progressions especially in the right axilla, leading to obstructed lymphatic drainage and consequently to upper right limb elephantiasis. Several skin nodules involving the right hemithorax were associated. The patient wore a cuff to limit oedema and started further chemotherapies, without any clinical improvement. Subsequent CT scans otherwise revealed radiological liver and bones lesions. In March 2025 she began sacituzumab govitecan (SG): after the first month, clinical examination revealed partial remission of subcutaneous nodules and pathological lymph nodes in the right axilla, gradually leading to cuff removal. The possibility to use SG in luminal breast cancer patients gave this woman a chance, in a scenario poor in exciting options.

This case report describes a rare and clinically highly complex constellation of massive scrotal elephantiasis, generalized lymphedema, and septic deterioration, which initially raised the suspicion of a malignant soft tissue tumor. The report highlights the diagnostic pitfalls associated with extreme scrotal enlargement, the nuanced decision-making regarding timing and extent of surgical intervention in a persistent septic setting, and the urological, pathological, and reconstructive implications of radical resection under extraordinary anatomical conditions. Reports of scrotal elephantiasis presenting as a primary septic focus in non-endemic regions remain rare and are largely limited to isolated case descriptions. This case illustrates clinically relevant diagnostic and therapeutic decision-making in the management of this unusual constellation.

The anthelmintics ivermectin, albendazole, and diethylcarbamazine are the backbone of mass drug administration (MDA) campaigns targeting human filariasis, yet their direct effects on parasites are still not fully defined or understood. The clinical effects of these drugs are stage dependent, resulting in effective clearance of circulating microfilariae but only limited activity against adult worms, a pattern that complicates disease surveillance and elimination efforts. Although molecular targets have been identified or proposed for some antifilarial drugs, their precise modes of action remain opaque, and conventional in vitro assays of motility or viability have generally failed to reflect pharmacologically relevant effects. There is growing evidence that cryptic phenotypes involving altered host-parasite interactions, including changes in parasite secretions, may help reconcile these discrepancies. Focusing on the causative species of lymphatic filariasis, we used high content imaging and quantitative mass spectrometry to enable deeper phenotypic profiling of drug responses in microfilariae and adult worms exposed to antifilarial compounds. In microfilariae, altered environmental conditions (temperature and salinity) lead to modest ivermectin effects on motility at therapeutic concentrations. In adult parasites, we show that drug responses vary with worm age and that different anthelmintics induce distinct changes in the secretory proteome. This improved phenotypic resolution advances our understanding of drug action in intra-host stages and highlights how antifilarial drugs can alter secretory cargo relevant to the detection of adult parasites that persist after drug treatment.

Lymphatic filariasis is a vector-borne infectious disease, most commonly caused by Wuchereria bancrofti, that affects 120 million people. It invades the lymphatic system of humans, who are the definitive hosts. We compared the administration of doxycycline with intensified hygiene measures alone in patients diagnosed with bancroftian filariasis. We searched PubMed, Scopus, and Embase and included 12 randomized controlled trials. A random-effects model was used to calculate the mean difference (MD)/risk ratio (RR) and I2 for heterogeneity. The risk of bias and GRADE evaluated the certainty of evidence. Pooled analysis showed a significant reduction in the number of Wolbachia per microfilaria (MD = -3.09; 95% CI: -3.94 to -2.25; P <0.00001, I2 = 42%). Although initial analysis suggested a reduction in microfilarial count, this finding was highly heterogeneous (I2 = 99%) and became nonsignificant upon sensitivity analysis, indicating unstable results. Regarding adverse events, vomiting was significantly more common in the doxycycline group (RR = 6.25; 95% CI: 2.14-18.24; P = 0.0008, I2 = 0%). In conclusion, doxycycline combined with intensified hygiene protocols reduces the Wolbachia burden but shows a limited role in clinically significant lymphedema reduction, and the evidence for microfilarial reduction is not robust. Large-scale trials are required to better combat this neglected tropical disease in endemic populations worldwide.