Thymopentin

Thymopentin enhances adenoviral oncolytic therapy by regulating macrophages and CD8+ T cells.

Lingkai Kong, Kua Liu, Yan Liu +11 more

Oncolytic viruses are cancer therapies that selectively replicate in tumors, deliver therapeutic genes, and stimulate immune responses. Combining these viruses with immune-boosting agents could enhance their effectiveness. Thymopentin (TP5), an immune-modulating peptide, may enhance the antitumour efficacy of ADV.

Efficacy and Safety of PRaG Therapy in Elderly Patients with Advanced Malignant Tumors: A Prospective, Multicenter Clinical Study Protocol (PRaG 9.0 Study).

Xiangrong Zhao, MengMeng Yang, Junjun Zhang +8 more

Background: Current evidence from evidence-based medicine is limited regarding the efficacy and safety of immunotherapy in elderly patients aged 75 years and older with malignant solid tumors. PRaG therapy, which combines PD-1/PD-L1 inhibitors, radiotherapy, and granulocyte-macrophage colony-stimulating factor (GM-CSF), aims to treat patients with advanced, refractory tumors. Preliminary findings indicate that patients aged 75 years and older can benefit from this treatment and can tolerate it well. Objective: This study aims to evaluate the efficacy and safety of the PRaG regimen in elderly patients with advanced malignant solid tumors to provide evidence-based support for immunotherapy in this population. Methods and Analysis: This study involves a multicenter, prospective, single-arm phase II clinical trial designed to enroll 29 patients aged 75 years and older with either newly diagnosed or recurrent metastatic advanced solid tumors that are histologically confirmed. All of the eligible patients will have had to receive at least two cycles of PRaG therapy until disease progression or intolerable adverse effects occurred. The study protocol was approved on September 12, 2023, by the Ethics Committee of the Second Affiliated Hospital of Soochow University (JD-LK-2023-082-I01) and by the ethics committees of all of the participating centers (Trial Registration Number: NCT06112041).

Thymopentin Enhances Antitumor Immunity Through Thymic Rejuvenation and T Cell Functional Reprogramming.

Md Amir Hossain, Ye Zhang, Li Ji +7 more

Background/Objectives: T cell dysfunction represents a fundamental barrier to effective cancer immunotherapy. Although immune checkpoint blockades and adoptive cell transfer have achieved clinical success, therapeutic resistance remains prevalent across cancer types. Thymopentin (TP5), a synthetic immunomodulatory pentapeptide (Arg-Lys-Asp-Val-Tyr), has demonstrated immunostimulatory properties, yet its anticancer potential remains unexplored. The aim of this study was to investigate TP5's antitumor efficacy and underlying immunological mechanisms. Methods: We evaluated TP5's therapeutic effects in multiple murine tumor models, including B16-F10 melanoma, MC38 colorectal carcinoma, Hepa 1-6, and LM3 hepatocellular carcinoma. Immune cell populations and functional states were characterized using flow cytometry, ELISAs, and immunofluorescence analyses. The potential of TP5 as an adjuvant for T cell-based therapies was also systematically assessed. Results: The TP5 treatment markedly suppressed tumor growth across caner models through strictly T cell-dependent mechanisms. Critically, TP5 promoted thymic rejuvenation under immunocompromised conditions, restoring the thymus-tumor immunological balance and revitalizing peripheral T cell immunity. TP5 functionally reprogrammed T cell states, preserving effector function while ameliorating exhaustion. Furthermore, TP5 demonstrated synergistic efficacy when combined with adoptive T cell therapies, enhancing both proliferation and effector functions. Conclusions: TP5 represents a promising immunomodulator that addresses fundamental limitations of current T cell therapies by simultaneously enhancing T cell function and reversing thymic involution under immunocompromised conditions. Our findings provide compelling evidence for TP5's clinical translation in cancer treatment.

Effectiveness and safety of thymopentin for infection prophylaxis in peritoneal dialysis patients: a retrospective study.

Xueying Chen, Yilin Ruan, Jingyuan Xie +5 more

Patients undergoing peritoneal dialysis are at high risk of infection, which significantly impacts morbidity and mortality. This retrospective study aimed to evaluate the association of thymopentin use with infection risk, immune function, and inflammatory markers in peritoneal dialysis patients.

Self-assembly driven nano-salinomycin for high-efficiency cancer immunotherapy by reticulum stress mediated stemness suppression.

Longqin Wang, Wenting Cheng, Siyuan Qin +6 more

Cancer cells with stemness characteristics effectively escape the recognition and killing of immune-active cells, such as T cells, which has been considered as the root cause of cancer recurrence and metastasis. To sensitize cancer immunotherapy, we have developed salinomycin-repurposed endoplasmic reticulum (ER) stress nanoinducers (DTSS NPs) to synergistically suppress cancer cell stemness. Salinomycin, as a polyether antibiotic demonstrating robust cytotoxicity against tumor stem cell, is co-assembled with thymopentin (TP5) and ER-targeted phototherapeutic agent s-780, and tailored with DSPE-PEG-biotin to obtain DTSS NPs. This nanoplatform not only improves the bioavailability of TP5 and salinomycin, but also ensures controlled drug release and reduces the side effects of therapeutic agents. Moreover, the hyperpyrexia and ROS produced by s-780 further induced ER stress, which downregulates PD-L1 expression and activates the cGAS-STING pathway, while TP5 significantly promotes the proliferation and differentiation of T lymphocytes, resulting in the augment of the anti-tumor immunity. Importantly, salomycin synergistically boosted s-780-mediated ER stress to effectively inhibit the stemness of cancer cells, thereby enhancing the responsiveness of cancer cells to T cells. As expected, DTSS NPs activate systemic immunity and suppress cancer metastasis and recurrence, providing promising solutions for sensitizing cancer immunotherapy by inhibiting cancer cell stemness.

Thymopentin-integrated self-assembling nanoplatform for enhanced photo-immunotherapy in diabetic wound healing.

Runze Wang, Wenting Cheng, Hailong Tian +4 more

Diabetic wounds represent a significant clinical challenge owing to infection, oxidative stress, and immune dysregulation. In this study, a multifunctional photoimmunotherapy nanoplatform (I-P-T NPs) was developed through the self-assembly of the near-infrared photosensitizer IR820, the immunomodulatory agent thymopentin (TP5), and the antioxidant phloretin (Phl) via intermolecular hydrogen bonding and hydrophobic interactions. This nanoplatform integrates photothermal therapy (PTT), immune modulation, and reactive oxygen species scavenging to address the infection-oxidation-immunosuppression triad in diabetic wounds. The I-P-T NPs exhibited robust photothermal conversion under 808 nm irradiation, generating localized hyperthermia with antibacterial effects. In vitro experiments demonstrated that I-P-T NPs promoted M2 macrophage polarization, reduced oxidative stress, enhanced endothelial and keratinocyte migration, and suppressed pro-inflammatory cytokine release. Additionally, the nanoplatform displayed potent antibacterial activity against both Gram-positive and Gram-negative bacteria. In a streptozotocin-induced diabetic mouse model with infected wounds, topical application of I-P-T NPs combined with photothermal treatment accelerated wound closure, enhanced re-epithelialization and collagen deposition, and mitigated inflammation. The self-assembled design improved the solubility of Phl and enabled spatiotemporally controlled delivery of multiple therapeutic components. No significant systemic toxicity was observed, confirming the biocompatibility of I-P-T NPs. This study presents a novel nanoplatform that synergistically combines photothermal sterilization, TP5-mediated immune regulation, and Phl-driven antioxidant effects, offering a promising strategy for managing complex diabetic wounds. This modular design highlights the potential for translating multifunctional nanotherapies into clinical applications for the treatment of chronic wounds.

Evidence-Based Recommendations for Managing Atopic Dermatitis in Pediatric Patients: A Systematic Review and Meta-Analysis From the Pediatric Dermatology Special Interest Group of IADVL.

Rahul Mahajan, Rashmi Sarkar, Maitreyee Panda +10 more

Atopic dermatitis (AD) is the most common inflammatory skin disease in the pediatric age group, affecting 15%-20% of children globally. Initial treatment modes include hydration, occlusive topical medicines, antimicrobial treatment, phototherapy, and systemic immune suppressants in the case of severe to moderate refractory AD. However, there is a lack of head-to-head studies on the choice of topical and systemic therapies for moderate to severe AD in the pediatric age group.

Self-assembled Palmitic Acid-modified Thymopentin Functions as a Delivery System of Nanovaccine for Cancer Immunotherapy.

Danhong Chen, Xiaoyun Ye, Ran Xu +9 more

In clinical practice, thymopentin (TP-5) is a commonly utilized immunomodulatory peptide drug. The relatively short half-life of TP-5, however, significantly limits its applicability in immunotherapy. Inspired by the structure of the TLR2 ligand lipopeptide Pam3CSK4, fatty acid-modified TP-5 peptides were designed and synthesized in this study. Utilizing its amphiphilicity, they were sonicated to assemble into nanoparticles with the diameters of approximately 100 nm. Compared with TP-5, TP-5 monopalmitate-modified nanoparticle has immune-activating properties both in vivo and in vitro. It markedly increased TNF-α secretion from RAW264.7 cells and aided in the maturation of DCs. The immunogenicity of OVA model antigen was increased in vivo when capsulated by TP-5 lipopeptide nanoparticle, which considerably slowed the growth of B16-OVA melanoma. This fatty acid-modified TP-5 assembled nanoparticle offers a straightforward and useful delivery system for the design of innovative nanovaccine for cancer immunotherapy.

Copper-coordination driven brain-targeting nanoassembly for efficient glioblastoma multiforme immunotherapy by cuproptosis-mediated tumor immune microenvironment reprogramming.

Yang Chen, Hailong Tian, Xiaodian Zhang +4 more

Limited drug accumulation and an immunosuppressive microenvironment are the major bottlenecks in the treatment of glioblastoma multiforme (GBM). Herein, we report a copper-coordination driven brain-targeting nanoassembly (TCe6@Cu/TP5 NPs) for site-specific delivery of therapeutic agents and efficient immunotherapy by activating the cGAS-STING pathway and downregulating the expression of PD-L1. To achieve this, the mitochondria-targeting triphenylphosphorus (TPP) was linked to photosensitizer Chlorin e6 (Ce6) to form TPP-Ce6 (TCe6), which was then self-assembled with copper ions and thymopentin (TP5) to obtain TCe6@Cu/TP5 NPs. This nanoassembly effectively accumulated in tumor sites through the copper transport mechanism. Meanwhile, TCe6@Cu/TP5 could induce mitochondrial impairment by photodynamic therapy (PDT) mediated reactive oxygen species (ROS) accumulation and Cu2+ triggered cuproptosis, resulting in evoking the AMP-activated protein kinase (AMPK) pathway to degrade PD-L1, and activating the cGAS-STING pathway to enhance anti-tumor immunity. Moreover, TP5 significantly promoted the proliferation and differentiation of dendritic cells (DCs) and T lymphocytes to further amplify the cancer immunity cycle. Collectively, our TCe6@Cu/TP5 NPs effectively facilitate drug accumulation and activate systemic antitumor immunity in vitro and in vivo, providing an innovative solution across the BBB that potentiates GBM immunotherapy.

Carrier-free delivery of thymopentin-regulated injectable nanogels via an enhanced cancer immunity cycle against melanoma metastasis.

Ning Ding, Kai He, Hailong Tian +10 more

Thymopentin (TP5), a clinically used immunomodulatory pentapeptide, can efficiently promote thymocyte differentiation and influence mature T-cell function, thus playing an essential role in the cancer immunotherapy. However, the excellent water solubility and high IC50 of TP5 result in an uncontrolled release behavior, requiring a high loading efficiency to achieve high dosage. Here in, we reported that TP5, combined with specific chemotherapeutic agents, can co-assemble into nanogels due to multiple hydrogen bonding sites. The co-assembly of TP5 with chemotherapeutic agent doxorubicin (DOX) into a carrier-free and injectable chemo-immunotherapy nanogel can enhance the cancer immunity cycle against melanoma metastasis. In this study, the designed nanogel guarantees high drug loading of TP5 and DOX and ensures a site-specific and controlled release of TP5 and DOX with minimal side effects, thus addressing the bottlenecks encountered by current chemo-immunotherapy. Moreover, the released DOX can effectively induce tumor cell apoptosis and immunogenic cell death (ICD) to activate immune initiation. Meanwhile, TP5 can significantly promote the proliferation and differentiation of dendritic cells (DCs) and T lymphocytes to amplify the cancer immunity cycle. As a result, this nanogel shows excellent immunotherapeutic efficacy against melanoma metastasis, as well as an effective strategy for TP5 and DOX application.

Structural analysis of Salvia miltiorrhiza polysaccharide and its regulatory functions on T cells subsets in tumor-bearing mice combined with thymopentin.

Haiyu Ji, Yuting Fan, Yan Long +5 more

Salvia miltiorrhiza ethanol-extracted polysaccharide (SMEP) and thymopentin (TP5) have been proved with strong immunomodulatory activity, and T cells subsets play pivotal roles in the inhibition of solid tumors growth. In the present study, the structure of SMEP was further identified via methylation and nuclear magnetic resonance spectra, and the immunomodulatory activity in combination with TP5 was investigated via evaluating T cell subsets spatial distributions in tumor-bearing mice, finally the cellular status of solid tumor cells was analyzed. The results revealed that SMEP was a neutral heteropolysaccharide using (1 → 4)-α-D-Glcp and (2 → 1)-β-D-Fruf as the main chain, along with branched chains of (1 → 6)-α-D-Galp. The SMEP+TP5 treatments could effectively promote the differentiation and improve the specific recognition capacity of CD4+ T cells in tumor-bearing mice, thereby activate tumor-infiltrating CD8+ T cells to exert cytotoxic effects, finally promoting the tumor cells apoptosis via blocking cell cycle at G0/G1 phase, which might be relevant with suppression of Wnt/β-catenin signaling pathway. These findings highlighted the potential of SMEP as an immunoadjuvant for patients bearing immune-deficiency related diseases, and provided data support for the functional researches of T cell subsets in tumor immunity.

Supramolecular Nanofibrils Formed by Coassembly of Clinically Approved Drugs for Tumor Photothermal Immunotherapy.

Shukun Li, Wenjia Zhang, Ruirui Xing +3 more

Pancreatic cancer, one of the most lethal malignancies, compromises the performance of traditional therapeutic regimens in the clinic because of stromal resistance to systemic drug delivery and poor prognosis caused by tumor metastasis. Therefore, a biocompatible therapeutic paradigm that can effectively inhibit pancreatic tumor growth while simultaneously eliminating tumor metastasis is urgently needed. Herein, supramolecular nanofibrils are fabricated through coassembly of clinically approved immunomodulatory thymopentin and near-infrared indocyanine green for localized photothermal immunotherapy of pancreatic tumors. The resulting long-range ordered fibrous nanodrugs show improved photophysical capabilities for fluorescence imaging and photothermal conversion and significantly promote the proliferation and differentiation of antitumor immune cells. Hence, the integration of rapid photothermal therapy and moderate immunomodulation for inhibiting tumor growth and eliminating tumor metastasis is promising. The utilization of clinically approved molecules to construct nanodrugs administered via localized injection amplifies the complementary photothermal immunotherapeutic effects of the components, creating opportunities for clinical translation as a treatment for pancreatic cancer.

Thymopentapeptide Affects T-Cell Subsets by Modulating the Flora of the Skin Surface to Alleviate Psoriasis.

Xin Liu, Ruofan Xi, Xinran Du +6 more

Psoriasis is a common chronic inflammatory skin condition. The emergence of psoriasis has been linked to dysbiosis of the microbiota on the skin surface and an imbalance in the immunological microenvironment. In this study, we investigated the therapeutic impact of topical thymopentin (TP5) on imiquimod (IMQ)-induced psoriasis in mice, as well as the modulatory influence of TP5 on the skin immune milieu and the skin surface microbiota.

Repurposing FDA-approved phytomedicines, natural products, antivirals and cell protectives against SARS-CoV-2 (COVID-19) RNA-dependent RNA polymerase.

Mahmoud Kandeel, Yukio Kitade, Abdullah Almubarak

Following the recent emergence of SARS-CoV-2 or coronavirus disease 2019 (COVID-19), drug discovery and vaccine design to combat this fatal infection are critical. In this study, an essential enzyme in the SARS-CoV-2 replication machinery, RNA-dependent RNA polymerase (RDRP), is targeted in a virtual screening assay using a set of 1,664 FDA-approved drugs, including sets of botanical and synthetic derivatives. A set of 22 drugs showed a high docking score of >-7. Notably, approximately one-third of the top hits were either from natural products or biological molecules. The FDA-approved phytochemicals were sennosides, digoxin, asiaticoside, glycyrrhizin, neohesperidin, taxifolin, quercetin and aloin. These approved natural products and phytochemicals are used as general tonics, antioxidants, cell protectives, and immune stimulants (nadid, thymopentin, asiaticoside, glycyrrhizin) and in other miscellaneous systemic or topical applications. A comprehensive analysis was conducted on standard precision and extra precision docking, two-step molecular dynamics simulations, binding energy calculations and a post dynamics analysis. The results reveal that two drugs, docetaxel and neohesperidin, showed strong binding profiles with SARS CoV-2 RdRP. These results can be used as a primer for further drug discovery studies in the treatment of COVID-19. This initiative repurposes safe FDA-approved drugs against COVID-19 RdRP, providing a rapid channel for the discovery and application of new anti-CoV therapeutics.

Thymopentin plays a key role in restoring the function of macrophages to alleviate the sepsis process.

Zhenliang Wen, Hui Li, Chenghua Zhou +11 more

Immune dysfunction is one of the leading causes of death of sepsis. How to regulate host immune functions to improve prognoses of septic patients has always been a clinical focus. Here we elaborate on the efficacy and potential mechanism of a classical drug, thymopentin (TP5). TP5 could decrease peritoneal bacterial load, and reduce inflammatory cytokine levels both in the peritoneal lavage fluid (PLF) and serum, alleviate pathological injuries in tissue and organ, coaxed by cecal ligation and perforation (CLP) in mice, ultimately improve the prognosis of septic mice. Regarding the mechanism, using RNA-seq and flow cytometry, we found that TP5 induced peptidoglycan recognition protein 1 (PGLYRP1) expression, increased phagocytosis and restored TNF-α expression of small peritoneal macrophage (SPM) in the septic mice. This may be increased SPM's ability to clear peritoneal bacteria, thereby attenuates the inflammatory response both in the peritoneal cavity and the serum. It was shown that TP5 plays a key role in restoring the function of peritoneal macrophages to alleviate the sepsis process. We reckon that this is closely relevant to SPM phagocytosis, which might involve increased PGLYRP1 expression and restored TNF-α secretion.

The Protective Effects of Water-Soluble Alginic Acid on the N-Terminal of Thymopentin.

Haiyu Ji, Yuting Fan, Xiaoji Gao +5 more

Thymopentin (TP5) has exhibited strong antitumor and immunomodulatory effects in vivo. However, the polypeptide is rapidly degraded by protease and aminopeptidase within a minute at the N-terminal of TP5, resulting in severe limitations for further practical applications. In this study, the protective effects of water-soluble alginic acid (WSAA) on the N-terminal of TP5 were investigated by establishing an H22 tumor-bearing mice model and determining thymus, spleen, and liver indices, immune cells activities, TNF-α, IFN-γ, IL-2, and IL-4 levels, and cell cycle distributions. The results demonstrated that WSAA+TP5 groups exhibited the obvious advantages of the individual treatments and showed superior antitumor effects on H22 tumor-bearing mice by effectively protecting the immune organs, activating CD4+ T cells and CD19+ B cells, and promoting immune-related cytokines secretions, finally resulting in the high apoptotic rates of H22 cells through arresting them in S phase. These data suggest that WSAA could effectively protect the N-terminal of TP5, thereby improving its antitumor and immunoregulatory activities, which indicates that WSAA has the potential to be applied in patients bearing cancer or immune deficiency diseases as a novel immunologic adjuvant.

Thymopentin (TP-5) prevents lipopolysaccharide-induced neuroinflammation and dopaminergic neuron injury by inhibiting the NF-κB/NLRP3 signaling pathway.

Si-Jia Peng, Ya Feng, Xuan Li +6 more

Neuroinflammation plays a pivotal role in neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and stroke, and is accompanied by excessive release of inflammatory cytokines and mediators by activated microglia. Microglial inflammatory response inhibition may be an effective strategy for preventing inflammatory disorders. However, the reciprocal connections between the central nervous system (CNS) and immune system have not been elucidated. Thus far, these links have been proven to mainly involve immuno- and neuropeptides. The pentapeptide thymopentin (TP-5) exerts a significant immunomodulatory effect; however, its antineuroinflammatory effects and underlying mechanism are still unclear. In this study, lipopolysaccharide (LPS) was used to establish an inflammation model, and the therapeutic effect of TP-5 was evaluated. Behavioral tests showed that TP-5 treatment could improve the performance of LPS-treated mice in the open field and pole test, but not hanging wire test. TP-5 also attenuated neuronal lesions in the brains of LPS-treated mice. TP-5 reduced cytotoxicity and morphological changes in activated microglia. Label-free quantitative analysis indicated that the expression of multiple proteins and the activation of associated signaling pathways were altered by TP-5. Moreover, TP-5 could inhibit LPS-induced neuroinflammation in the brain and BV2 microglia and the expression of major genes in the NF-κB/NLRP3 signaling pathway. Additionally, tyrosine hydroxylase (TH) expression downregulation was rescued in the LPS + TP-5 group compared with the LPS group. We conclude that TP-5 exerts neuroprotection by alleviating LPS-induced inflammatory damage and dopaminergic neurodegeneration. The protective effect of TP-5 may involve the NF-κB/NLRP3 signaling pathway.

Altered Membrane Expression and Function of CD11b Play a Role in the Immunosuppressive Effects of Morphine on Macrophages at the Nanomolar Level.

Peng-Cheng Yu, Cui-Yun Hao, Ying-Zhe Fan +5 more

Morphine, one of the most efficacious analgesics, is effective in severe pain, especially in patients with concomitant painful cancers. The clinical use of morphine may be accompanied by increased immunosuppression, susceptibility to infection and postoperative tumor metastatic recurrence, and the specific mechanisms and clinical strategies to alleviate this suppression remain to be investigated. Expression of CD11b is closely associated with the macrophage phagocytosis of xenobiotic particles, bacteria or tumor cells. Here, we find that morphine at 0.1-10 nM levels inhibited CD11b expression and function on macrophages via a μ-opioid receptor (MOR)-dependent mechanism, thereby reducing macrophage phagocytosis of tumor cells, a process that can be reversed by thymopentin (TP5), a commonly used immune-enhancing adjuvant in clinical practice. By knocking down or overexpressing MOR on macrophages and using naloxone, an antagonist of the MOR receptor, and LA1, a molecule that promotes macrophage CD11b activation, we suggest that morphine may regulate macrophage phagocytosis by inhibiting the surface expression and function of macrophage CD11b through the membrane expression and activation of MOR. The CD47/SIRPα axis, which is engaged in macrophage-tumor immune escape, was not significantly affected by morphine. Notably, TP5, when combined with morphine, reversed the inhibition of macrophage phagocytosis by morphine through mechanisms that promote membrane expression of CD11b and modulate its downstream signaling (e.g., NOS2, IFNG, IL1B and TNFA, as well as AGR1, PDGFB, IL6, STAT3, and MYC). Thus, altered membrane expression and function of CD11b may mediate the inhibition of macrophage phagocytosis by therapeutic doses of morphine, and the reversal of this process by TP5 may provide an effective palliative option for clinical immunosuppression by morphine.

Structure-based inhibitor screening of natural products against NSP15 of SARS-CoV-2 revealed thymopentin and oleuropein as potent inhibitors.

Ramachandran Vijayan, Samudrala Gourinath

Coronaviruses are enveloped, non-segmented positive-sense RNA viruses with the largest genome among RNA viruses. Their genome contains a large replicase ORF which encodes nonstructural proteins (NSPs), structural, and accessory genes. NSP15 is a nidoviral RNA uridylate-specific endoribonuclease (NendoU) with C-terminal catalytic domain. The endoribonuclease activity of NSP15 interferes with the innate immune response of the host. Here, we screened Selleckchem Natural product database of the compounds against NSP15, and we found that thymopentin and oleuropein displayed highest binding energies. The binding of these molecules was further validated by molecular dynamic simulations that revealed them as very stable complexes. These drugs might serve as effective counter molecules in the reduction of virulence of this virus; may be more effective if treated in combination with replicase inhibitors. Future validation of both these inhibitors is worth the consideration for patients being treated for COVID-19.

Clinical Efficacy of a Combination of Thymopentin and Antituberculosis Drugs in Treating Drug-Resistant Pulmonary Tuberculosis: Meta Analysis.

Yi-Ran Han, Tian-Hao Wang, Wen-Ping Gong +2 more

To make a systematic evaluation of the clinical efficacy of thymopentin combined with antituberculous drugs in treating drug-resistant pulmonary TB (PTB).

Thymopentin treatment of murine premature ovarian failure via attenuation of immune cell activity and promotion of the BMP4/Smad9 signalling pathway.

Xueqin Zhu, Jianjun Liu, Hao Pan +4 more

Premature ovarian failure (POF) is a typical form of pathological aging with complex pathogenesis and no effective treatment. Meanwhile, recent studies have reported that a high-fat and high-sugar (HFHS) diet adversely affects ovarian function and ovum quality. Here, we investigated the therapeutic effect of thymopentin (TP-5) as a treatment for murine POF derived from HFHS and its target. Pathological examination and hormone assays confirmed that TP-5 significantly improved murine POF symptoms. And, TP-5 could reduce oxidative stress injury and blood lipids in the murine POF derived from HFHS. Flow cytometry and qPCR results suggested that TP-5 attenuated activation of CD3+ T cells and type I macrophages. RNA-Seq results indicated somedifferences in gene transcription between the TP-5 intervention group and the control group. KEGG analysis indicated that the expression of genes involved in the mTOR signaling pathway was the most significantly different between the two groups. Additionally, compared with the control groups, the expression levels of interleukin, NFκB, and TNF families of genes were significantly downregulated in the POF+TP-5 group, whereas expression of the TGFβ/Smad9 genes was significantly upregulated. Finally, immunofluorescence staining and qPCR confirmed that TP-5 promoted the polarization of Mø2 cells in the ovary by activating the expression of the BMP4/Smad9 signalling pathway. Thus, our study confirmed that TP-5 has a significant therapeutic effect on POF by upregulating BMP4/Smad9 signalling pathway so as to promote the balance and polarization of immune cell and reducing the release of inflammatory factors and reduce lipid oxidative stress injury.

The effect of thymopentin on immune function and inflammatory levels in end-stage renal disease patients with maintenance hemodialysis.

Qian Zou, Ling Zhang, Funyun Sun

This study investigated and analyzed the effect of Thymopentin on immune function and inflammatory levels in end-stage renal disease (ESRD) patients who were undergoing maintenance hemodialysis.

The immunosuppressive effects of low molecular weight chitosan on thymopentin-activated mice bearing H22 solid tumors.

Hai-Yu Ji, Chao Liu, Ke-Yao Dai +3 more

In the present study, the low molecular weight of chitosan (CS) was prepared and its activity on thymopentin-activated mice bearing H22 solid tumors was further researched. The purity and molecular weight of CS were determined by UV and HPGPC spectra, and its immunosuppressive effects on H22 tumor-bearing mice were evaluated through determination on immune organs, cells and cytokines. Results showed that CS contained little impurities with the average molecular weight of 1.20 × 104 Da. The in vivo antitumor experiments demonstrated that CS facilitated to destroy immune organs (thymuses and spleens), suppress immune cells (lymphocytes, macrophages and NK cells) activities and reduce immune-related cytokines (TNF-α, IFN-γ, IL-2 and IL-4) expressions of H22 tumor-bearing mice even with simultaneous TP5 stimulation. Our data suggested that CS could not be applied to improve immune response in cancer-bearing patients, but might be employed for treatments on autoimmune diseases or organ transplant patients.

Targeting the TLR2 Receptor With a Novel Thymopentin-Derived Peptide Modulates Immune Responses.

Xubiao Wei, Lulu Zhang, Rijun Zhang +9 more

The innate and adaptive immune systems act in concert to protect us from infectious agents and other harmful substances. As a state of temporary or permanent immune dysfunction, immunosuppression can make an organism more susceptible to infection, organ injury, and cancer due to damage to the immune system. It takes a long time to develop new immunomodulatory agents to prevent and treat immunosuppressive diseases, with slow progress. Toll-like receptor 2 (TLR2) agonists have been reported as potential immunomodulatory candidates due to their effective activation of immune responses. It has been demonstrated that thymopentin (TP5) could modulate immunity by binding to the TLR2 receptor. However, the fairly short half-life of TP5 greatly reduces its pharmacological potential for immunosuppression therapy. Although peptide cathelicidin 2 (CATH2) has a long half-life, it shows poor immunomodulatory activity and severe cytotoxicity, which seriously hampers its clinical development. Peptide hybridization is an effective approach for the design and engineering of novel functional peptides because hybrid peptides combine the advantages and benefits of various native peptides. In this study, to overcome all these challenges faced by the parental peptides, six hybrid peptides (CaTP, CbTP, CcTP, TPCa, TPCb, and TPCc) were designed by combining the full-length TP5 with different active fragments of CATH2. CbTP, the most potent TLR2 agonist among the six hybrid peptides, was effectively screened through in silico analysis and in vitro experiments. The CbTP peptide exhibited lower cytotoxicity than either CATH2 or TP5. Furthermore, the immunomodulatory effects of CbTP were confirmed in a CTX-immunosuppressed mouse model, which showed that CbTP has increased immunopotentiating activity and physiological stability compared to the parental peptides. CbTP successfully inhibited immunosuppression and weight loss, increased immune organ indices, and improved CD4+/CD8+ T lymphocyte subsets. In addition, CbTP significantly increased the production of the cytokine TNF-α and IL-6, and the immunoglobulins IgA, IgM, and IgG. The immunoenhancing effects of CbTP were attributed to its TLR2-binding activity, promoting the formation of the TLR2 cluster, the activation of the TLR2 receptor, and thus activation of the downstream MyD88-NF-кB signaling pathway.

Evaluation of the treatment efficacy of systemic care combined with thymopentin and 2HRZE/4HR for primary tuberculosis.

Ying He, Wandi Zheng

To investigate the efficacy of systemic care combined with thymopentin and 2HRZE/4HR in the treatment of primary tuberculosis.

Effects of immunopotentiators on biochemical parameters, proinflammatory cytokine, and nonspecific immune responses in Shaoxing ducklings.

Tiantian Gu, Guoqin Li, Xinsheng Wu +6 more

Antibiotics are one of the most important medical discoveries of the 20th century and will remain an essential tool for treating animal and human diseases in the 21st century. However, misuse of antibiotics imperils the development of animal husbandry and human health all over the world, and it is important to find reliable alternatives to antibiotics to reduce the use of antibiotics. In this study, 22 potential immunopotentiators were screened on the levels of apoptosis and inflammatory factor in duck embryo fibroblast cells (DEFs). The results indicated that interferon (IFN)-β and tumor necrosis factor-α gene transcriptions were significantly upregulated, while interleukin (IL)-2 and Bcl2 mRNA levels were significantly decreased during 22 immunopotentiators treatment. Besides, the expression level of IL-1β mRNA showed significant increase during dihydromyricetin, chlorogenic acid, naringin, imiquimod, thymopentin, β-D-Glucan, astragalus polysacharin, astragalus saponin I, astragalus flavone, curcumin, CpG-DNA-2, and LPS treatment. And the level of caspase 3 protein was significantly upregulated with treating chlorogenic acid, β-D-Glucan, astragalus polysacharin, astragalus flavone, curcumin, CpG-DNA-2, chicken IgG, LPS, and poly(I:C). These results indicated that chlorogenic acid, β-D-Glucan, astragalus flavone, CpG-DNA-2, and chicken IgG have the positive immune regulation effects on duck DEFs. Thus, the 5 immunopotentiators were chosen to further verify their immunomodulatory function in vivo. The results showed that the activity of serum AST was significantly downregulated during all immunopotentiators treatments excepting for β-D-Glucan, and the activities of serum IL12p40, IL-1β, IFN-α, and IFN-β were significantly increased compared with the control group. Five immunopotentiators also induced the duck's pattern recognition receptors and inflammatory factor gene expression. In addition, 5 immunopotentiators could facilitate the contents of serum caspase 3, iNOSm and COX2 and reduce the Bcl2. These results suggested that these 5 immunopotentiators could enhance duck innate immune responses. Taken together, our study not only screened out 5 kinds of duck innate immune immunopotentiators but also initially clarified their underlying mechanism of action, which provide a new insight for the development of efficient approaches to prevent the duck disease from pathogen infections.

Thymopentin improves the survival of septic mice by promoting the production of 15-deoxy-prostaglandin J2 and activating the PPARγ signaling pathway.

Ye Zhang, Xue Yang, Wenchao Yan +13 more

Sepsis, a systemic inflammatory response syndrome (SIRS) caused by infection, is a major public health concern with limited therapeutic options. Infection disturbs the homeostasis of host, resulting in excessive inflammation and immune suppression. This has prompted the clinical use of immunomodulators to balance host response as an alternative therapeutic strategy. Here, we report that Thymopentin (TP5), a synthetic immunomodulator pentapeptide (Arg-Lys-Asp-Val-Tyr) with an excellent safety profile in the clinic, protects mice against cecal ligation and puncture (CLP)-induced sepsis, as shown by improved survival rate, decreased level of pro-inflammatory cytokines and reduced ratios of macrophages and neutrophils in spleen and peritoneum. Regarding mechanism, TP5 changed the characteristics of LPS-stimulated macrophages by increasing the production of 15-deoxy-Δ12,14 -prostaglandin J2 (15-d-PGJ2). In addition, the improved effect of TP5 on survival rates was abolished by the peroxisome proliferator-activated receptor γ (PPARγ) antagonist GW9662. Our results uncover the mechanism of the TP5 protective effects on CLP-induced sepsis and shed light on the development of TP5 as a therapeutic strategy for lethal systemic inflammatory disorders.

Thymopentin ameliorates dextran sulfate sodium-induced colitis by triggering the production of IL-22 in both innate and adaptive lymphocytes.

Qiuhua Cao, Xinghua Gao, Yanting Lin +13 more

Background: Ulcerative colitis (UC) is a chronic inflammatory gastrointestinal disease, notoriously challenging to treat. Previous studies have found a positive correlation between thymic atrophy and colitis severity. It was, therefore, worthwhile to investigate the effect of thymopentin (TP5), a synthetic pentapeptide corresponding to the active domain of the thymopoietin, on colitis. Methods: Dextran sulfate sodium (DSS)-induced colitis mice were treated with TP5 by subcutaneous injection. Body weight, colon length, colon weight, immune organ index, disease activity index (DAI) score, and the peripheral blood profile were examined. The immune cells of the spleen and colon were analyzed by flow cytometry. Histology was performed on isolated colon tissues for cytokine analysis. Bacterial DNA was extracted from mouse colonic feces to assess the intestinal microbiota. Intestinal lamina propria mononuclear cells (LPMCs), HCT116, CT26, and splenocytes were cultured and treated with TP5. Results: TP5 treatment increased the body weight and colon length, decreased the DAI score, and restored colon architecture of colitic mice. TP5 also decreased the infiltration of immune cells and expression levels of pro-inflammatory cytokines such as IL-6. Importantly, the damaged thymus and compromised lymphocytes in peripheral blood were significantly restored by TP5. Also, the production of IL-22, both in innate and adaptive lymphoid cells, was triggered by TP5. Given the critical role of IL-22 in mucosal host defense, we tested the effect of TP5 on mucus barrier and gut microbiota and found that the number of goblet cells and the level of Mucin-2 expression were restored, and the composition of the gut microbiome was normalized after TP5 treatment. The critical role of IL-22 in the protective effect of TP5 on colitis was further confirmed by administering the anti-IL-22 antibody (αIL-22), which completely abolished the effect of TP5. Furthermore, TP5 significantly increased the expression level of retinoic acid receptor-related orphan receptor γ (RORγt), a transcription factor for IL-22. Consistent with this, RORγt inhibitor abrogated the upregulation of IL-22 induced by TP5. Conclusion: TP5 exerts a protective effect on DSS-induced colitis by triggering the production of IL-22 in both innate and adaptive lymphocytes. This study delineates TP5 as an immunomodulator that may be a potential drug for the treatment of UC.

Immunomodulatory effect of thymopentin on lymphocytes from supramammary lymph nodes of dairy cows.

Ran Guan, Wei Xu, Lijia Yuan +3 more

Previous study showed that injection of thymopentin (TP 5) in the area of supramammary lymph nodes (SMLN) had therapeutic effect on the intramammary infection (IMI) in cows. This study was to explore the underlying mechanisms by investigating the immunomodulatory effect of TP 5 on SMLN lymphocytes. Lymphocyte proliferation, cell cycle distribution and cytokine mRNA expression were determined by MTT, FCM and RT-qPCR, respectively. Laser scanning confocal microscope (LSCM) was used to observe the binding between TP 5 and SMLN lymphocytes. Moreover, RNA-sequencing (RNA-seq) was performed to observe the difference between the lymphocytes with and without TP 5 treatment. The results showed that TP 5 significantly promoted lymphocyte proliferation, accelerated cell cycle progression, and enhanced mRNA expression of IL-17A and IL-17F. Laser scanning confocal microscopic analysis revealed the binding of TP 5 to the surface of SMLN lymphocytes. A total of 1094 genes were identified as differentially expressed genes (DEGs) using RNA-seq with 692 up- and 402 down-regulated genes. 48 significantly enriched GO terms were identified by RNA-seq. In KEGG analysis, 1/3 of DEGs were enriched in the immune system pathway, including IL-17 signaling pathway, cytokine-cytokine receptor interaction, Th1 and Th2 cell differentiation, T cell receptor signaling pathway, Th17 cell differentiation. Among them, IL-17 signaling pathway was the most prominent. This study suggested that the therapeutic benefit of TP 5 in the treatment of bovine mastitis might be attributed to its immunomodulatory activity in SMLN lymphocytes.

Clinical efficacy and safety of synthetic thymic peptides with chemotherapy for non-small cell lung cancer in China: A systematic review and meta-analysis of 27 randomized controlled trials following the PRISMA guidelines.

Fen-Lian Zeng, Zheng Xiao, Cheng-Qiong Wang +10 more

Synthetic thymic peptides (sTPs) are used with chemotherapy to treat non-small cell lung cancer (NSCLC). In this study, we have performed a systematic review and meta-analysis of published trials to confirm the clinical efficacy and safety of sTPs, and determine the optimal types, usages, and sTP/chemotherapy combinations to produce the desired responses.