https://discovery.dundee.ac.uk/ws/files/42216872/1_s2.0_S1074761318304813_main.pdf

Modulation of Host Immunity by Helminths: The Expanding Repertoire of Parasite Effector Molecules.

The roles of macrophage polarization in the host immune response to sepsis.

Parasitic helminths have coevolved with humans over millennia, intricately refining and developing an array of mechanisms to suppress or skew the host’s immune system, thereby promoting their long-term survival. Some helminths, such as hookworms, cause little to no overt pathology when present in modest numbers and may even confer benefits to their human host. To exploit this evolutionary phenomenon, clinical trials of human helminth infection have been established and assessed for safety and efficacy for a range of immune dysfunction diseases and have yielded mixed outcomes. Studies of live helminth therapy in mice and larger animals have convincingly shown that helminths and their excretory/secretory products possess anti-inflammatory drug-like properties and represent an untapped pharmacopeia. These anti-inflammatory moieties include extracellular vesicles, proteins, glycans, post-translational modifications, and various metabolites. Although the concept of helminth-inspired therapies holds promise, it also presents a challenge to the drug development community, which is generally unfamiliar with foreign biologics that do not behave like antibodies. Identification and characterization of helminth molecules and vesicles and the molecular pathways they target in the host present a unique opportunity to develop tailored drugs inspired by nature that are efficacious, safe, and have minimal immunogenicity. Even so, much work remains to mine and assess this out-of-the-box therapeutic modality. Industry-based organizations need to consider long-haul investments aimed at unraveling and exploiting unique and differentiated mechanisms of action as opposed to toe-dipping entries with an eye on rapid and profitable turnarounds.

/pdf/harnessing-helminth-driven-immunoregulation-in-the-search-agtr2plu0r.pdf

Harnessing helminth-driven immunoregulation in the search for novel therapeutic modalities

Cystatin SN (CST1) belongs to the type 2 cystatin (CST) superfamily, which restricts the proteolytic activities of cysteine proteases CST1 has been recently considered to be involved in the development of several human cancers However, the prognostic significance and function of CST1 in breast cancer remains unknown In the current study, we found that CST1 was generally upregulated in breast cancer at both mRNA and protein level Furthermore, overall survival (OS) and disease-free survival (DFS) in the low CST1 expression subgroup were significantly superior to the high CST1 expression subgroup (OS, p < 0001; DFS, p < 0001), which indicated that CST1 expression level was closely correlated to the survival risk of these patients Univariate and multivariate analyses demonstrated that CST1 expression was an independent prognostic factor, the same as ER status and nodal status Next, CST1 overexpression promoted breast cancer cell proliferation, clonogenicity, migration, and invasion abilities By contrast, knockdown of CST1 attenuated these malignant characteristics in breast cancer cells Collectively, our study indicates that CST1 cannot only serve as a significant prognostic indicator but also as a potential therapeutic target for breast cancer

/pdf/elevated-expression-of-cst1-promotes-breast-cancer-2jl0pbqhf8.pdf

Elevated expression of CST1 promotes breast cancer progression and predicts a poor prognosis

Helminth parasites are highly prevalent in many low- and middle-income countries, in which inflammatory bowel disease and other immunopathologies are less frequent than in the developed world. Many of the most common helminths establish themselves in the gastrointestinal tract and can exert counter-inflammatory influences on the host immune system. For these reasons, interest has arisen as to how parasites may ameliorate intestinal inflammation and whether these organisms, or products they release, could offer future therapies for immune disorders. In this review, we discuss interactions between helminth parasites and the mucosal immune system, as well as the progress being made toward identifying mechanisms and molecular mediators through which it may be possible to attenuate pathology in the intestinal tract.

https://www.physiology.org/doi/pdf/10.1152/ajpgi.00024.2017

Helminths in the gastrointestinal tract as modulators of immunity and pathology

Ubiquitin C-terminal hydrolase-L1 (UCH-L1), a member of the lesser-known deubiquitinating enzyme family, has deubiquitinase and ubiquitin (Ub) ligase activity and the role of stabilizing Ub. UCH-L1 was first discovered in the brain and is associated with regulating cell differentiation, proliferation, transcriptional regulation and numerous other biological processes. UCH-L1 is predominantly expressed in the brain and serves a role in tumor promotion or inhibition. There is still controversy about the effect of UCH-L1 dysregulation in cancer and its mechanisms are unknown. Extensive research to investigate the mechanism of UCH-L1 in different types of cancer is key for the future treatment of UCH-L1-associated cancer. The present review details the molecular structure and function of UCH-L1. The role of UCH-L1 in different types of cancer is also summarized and how novel treatment targets provide a theoretical foundation in cancer research is discussed.

/pdf/ubiquitin-c-terminal-hydrolase-l1-a-new-cancer-marker-and-3ssu4fhj.pdf

Ubiquitin C‑terminal hydrolase‑L1: A new cancer marker and therapeutic target with dual effects (Review)

The purpose of this study was to analyze the prognosis of patients tested positive for Stenotrophomonas maltophilia (SMA) from different sources.A retrospective study was conducted among 651 patients tested positive for SMA from January 2020 to October 2022 in the First Affiliated Hospital of Anhui Medical University. The patients were divided into seven groups by the source of SMA. Univariate and multivariate analyses were used to identify risk factors for mortality in patients tested positive for SMA from different sources.A total of 651 SMA isolates were collected from various sources, including sputum (348 isolates, 53%), bronchoalveolar lavage fluid (52, 8%), abdominal drainage fluid (76, 12%), wound secretion (66, 10%), blood (62, 10%), urine (41, 6%) and cerebrospinal fluid (6, 1%). Compared with other groups, the mortality of the patients in the bronchoalveolar lavage fluid culture group, blood culture group, and abdominal drainage fluid culture group was higher, at 40.38%, 32.26%, and 26.32%, respectively. Multivariate analysis showed that continuous renal replacement therapy was an independent risk factor for mortality in patients with SMA bloodstream infection (P=0.020, OR=6.86), and effective antimicrobial therapy after being positive for S. maltophilia isolates (P=0.002, OR=0.10) was negatively correlated with the death of patients with SMA bloodstream infection. Age ≥65 years (P= 0.043, OR=4.96), kidney disease (P=0.045, OR=4.62) and antifungal agent exposure (P=0.036, OR=5.13) were independent risk factors for mortality in patients with SMA intra-abdominal infection. Antifungal agent exposure (P=0.024, OR=0.51) and glycopeptide exposure (P=0.045, OR=0.53) were independent risk factors for mortality in patients in the sputum culture group.SMA has a high rate of antimicrobial resistance and can cause multisite infection. Pulmonary infections, bloodstream infections and abdominal infections caused by SMA have high mortality, and timely standardized treatment can reduce mortality. 

The Prognosis of Patients Tested Positive for Stenotrophomonas maltophilia from Different Sources

A high glucose diet (HGD) is associated with many metabolic diseases including type 2 diabetes, and cardiovascular diseases. Additionally, a HGD increases the oxidative stress resistance of young animals but shortens their lifespan. To investigate the role of HGD feeding on the aging of aged animals, we tested for oxidative stress resistance and changes in lifespan using C. elegans. We showed that a HGD extends the lifespan of aged worms that are dependent on oxidative stress resistance. Furthermore, we measured the lifespan of oxidative stress responding genes of HGD-fed worms. We found that gpdh-1 and col-92 are highly expressed in HGD and paraquat (PQ) treated worms. Further experiments indicated that intestinal gpdh-1 is essential for the HGD induced lifespan extension of aged worms. Our studies provide new insights into understanding the correlation between glucose metabolism, oxidative stress resistance, and aging.

Intestinal GPDH-1 regulates high glucose diet induced lifespan extension in aged worms.

Helminth infections and their components have been shown to have a protective effect on autoimmune diseases. The isolated purified protein from Schisotosoma japonicum and its potential therapeutic effect on trinitrobenzene sulfonic acid (TNBS)-induced colitis could provide an alternative way to treat inflammatory bowel disease (IBDs). Colitis was induced in Balb/c mice by rectal administration of 2.5 % TNBS, followed by intraperitoneal injection of rSjcystatin 50 μg at 6 h and 24 h afterwards. The inflammation was monitored by recording weight change, stool character and bleeding, colon length, macroscopic score (MAO), microscopic score (MIO), myeloperoxidase activity (MPO) and disease activity index (DAI). The potential underlying mechanism was investigated by examining cytokine profiles including Th1 (IFNγ), Th2 (IL-4), Th17 (IL-17A) and Treg subsets from lymphocytes of spleen, mesenteric lymph nodes (MLN) and intestinal lamina propria mononuclear cells (LPMCs) by flow cytometry. The mRNA relative expressions of the cytokines in splenocytes and MLN were analysed by quantitative real time reverse-transcriptase polymerase chain reaction (qRT-PCR). Simultaneously, the concentrations of the cytokines in the colon homogenate supernatants were tested by enzyme-linked immunosorbent assay (ELISA) and key transcription factors were detected by Western blotting. Administration of rSjcystatin significantly reduced inflammatory parameters and ameliorated the severity of the TNBS-induced colitis through decreasing IFNγ in three organs and lifting the level of IL-4, IL-13, IL-10, and TGF-β in the colon tissues, with uptrending Tregs in the MLN and LPMC. The findings provide evidence that rSjcystatin has a therapeutic potential for diminishing colitis inflammation in Balb/c mice. The immunological mechanism may involve the down-regulation of Th1 response and up-regulation of Th2 and Tregs in the MLN and colon.

/pdf/therapeutic-potential-of-recombinant-cystatin-from-3zjutu93s2.pdf

Therapeutic potential of recombinant cystatin from Schistosoma japonicum in TNBS-induced experimental colitis of mice

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Ubiquitin C‑terminal hydrolase‑L1: A new cancer marker and therapeutic target with dual effects (Review)

The Prognosis of Patients Tested Positive for Stenotrophomonas maltophilia from Different Sources

Intestinal GPDH-1 regulates high glucose diet induced lifespan extension in aged worms.

Therapeutic potential of recombinant cystatin from Schistosoma japonicum in TNBS-induced experimental colitis of mice