Hirudin, an acidic polypeptide secreted by the salivary glands of Hirudo medicinalis (also known as “Shuizhi” in traditional Chinese medicine), is the strongest natural specific inhibitor of thrombin found so far. Hirudin have been demonstrated to possess potent anti-thrombotic effect in previous studies. Recently, increasing researches have focused on the anti-thrombotic activity of the derivatives of hirudin, mainly because these derivatives have stronger antithrombotic activity and lower bleeding risk. Additionally, various bioactivities of hirudin have been reported as well, including wound repair effect, anti-fibrosis effect, effect on diabetic complications, anti-tumor effect, anti-hyperuricemia effect, effect on cerebral hemorrhage, and others. Therefore, by collecting and summarizing publications from the recent two decades, the pharmacological activities, pharmacokinetics, novel preparations and derivatives, as well as toxicity of hirudin were systematically reviewed in this paper. In addition, the clinical application, the underlying mechanisms of pharmacological effects, the dose-effect relationship, and the development potential in new drug research of hirudin were discussed on the purpose of providing new ideas for application of hirudin in treating related diseases.

/pdf/pharmacological-activities-and-mechanisms-of-hirudin-and-its-3uyicw28vg.pdf

Pharmacological Activities and Mechanisms of Hirudin and Its Derivatives - A Review.

Exploring the spatio-temporal dynamics of poverty is important for research on sustainable poverty reduction in China. Based on the perspective of development geography, this paper proposes a panel vector autoregressive (PVAR) model that combines the human development approach with the global indicator framework for Sustainable Development Goals (SDGs) to identify the poverty-causing and the poverty-reducing factors in China. The aim is to measure the multidimensional poverty index (MPI) of China’s provinces from 2007 to 2017, and use the exploratory spatio-temporal data analysis (ESTDA) method to reveal the characteristics of the spatio-temporal dynamics of multidimensional poverty. The results show the following: (1) The poverty-causing factors in China include the high social gross dependency ratio and crop-to-disaster ratio, and the poverty-reducing factors include the high per capita GDP, per capita social security expenditure, per capita public health expenditure, number of hospitals per 10,000 people, rate of participation in the new rural cooperative medical scheme, vegetation coverage, per capita education expenditure, number of universities, per capita research and development (R&D) expenditure, and funding per capita for cultural undertakings. (2) From 2007 to 2017, provincial income poverty (IP), health poverty (HP), cultural poverty (CP), and multidimensional poverty have been significantly reduced in China, and the overall national poverty has dropped by 5.67% annually. there is a differentiation in poverty along different dimensions in certain provinces. (3) During the study period, the local spatial pattern of multidimensional poverty between provinces showed strong spatial dynamics, and a trend of increase from the eastern to the central and western regions was noted. The MPI among provinces exhibited a strong spatial dependence over time to form a pattern of decrease from northwestern and northeastern China to the surrounding areas. (4) The spatio-temporal networks of multidimensional poverty in adjacent provinces were mainly negatively correlated, with only Shaanxi and Henan, Shaanxi and Ningxia, Qinghai and Gansu, Hubei and Anhui, Sichuan and Guizhou, and Hainan and Guangdong forming spatially strong cooperative poverty reduction relationships. These results have important reference value for the implementation of China’s poverty alleviation strategy.

Multidimensional measurement of poverty and its spatio-temporal dynamics in China from the perspective of development geography

Coagulation proteases and the generation of thrombin are increased in tumors. In addition, chemotherapeutic agents commonly used to treat malignant cancers can exacerbate cancer‐associated thromboses. Thrombin can modify tumor cell behavior directly through the activation of protease‐activated receptors (PAR) or indirectly by generating fibrin matrices. In addition to its role in generating fibrin to promote hemostasis, thrombin acts directly on multiple effector cells of the immune system impacting both acute and chronic inflammatory processes. Thrombin‐mediated release of interleukin‐6, tumor necrosis factor‐α, and monocyte chemoattractant protein‐1 leads to the accumulation of multiple tumor‐infiltrating immunosuppressive cell populations including myeloid derived suppresser cells, M2‐like macrophages, and T regulatory cells. Ablation of PAR‐1 from the tumor microenvironment, but not the tumor, has been shown to dramatically reduce tumor growth and metastasis in multiple tumor models. Thrombin‐activated platelets release immunosuppressive cytokines including transforming growth factor‐β that can inhibit natural killer cell activity, helping tumor cells to evade host immunosurveillance. Taken together, there is strong evidence that thrombin influences cancer progression via multiple mechanisms, including the tumor immune response, with thrombin emerging as a target for novel therapeutic strategies for cancer.

Immunomodulatory role of thrombin in cancer progression

Medicinal leeches have been used in health care since before written history, with widely varying popularity over the centuries. Nowadays, medicinal leech therapy is mainly used in plastic and reconstructive microsurgery, with new interesting potential therapeutic applications in many other diseases. The leech's best-known salivary product, hirudin - one of the most powerful natural anticoagulants - was the only remedy to prevent blood clotting until the discovery of heparin. Starting from hirudin, pharmacological research succeeded in developing new anticoagulants, which represent a cornerstone of prevention and treatment of thromboembolic disease. While we are perhaps on the threshold of a new era of anticoagulation, with the development of FXI and XII inhibitors and direct reversible covalent thrombin inhibitors, which promise to achieve effective anticoagulation without bleeding risk. This review retraces the intriguing journey of these drugs in cardiovascular disease, highlighting the fil rouge that links the ancient leech to the current and oncoming antithrombotic therapy. We think that knowledge of the past is key to understanding and appreciating the present and to seize future opportunities. 

From ancient leech to direct thrombin inhibitors and beyond: New from old.

https://doi.org/10.1016/j.ajps.2022.02.005

Design and fabrication of r-hirudin loaded dissolving microneedle patch for minimally invasive and long-term treatment of thromboembolic disease

Background and purpose Cancer cachexia and cancer-associated thrombosis are potentially fatal outcomes of advanced cancer. Nevertheless, thrombin expression in non-small cell lung cancer (NSCLC) primary tumour tissues and the association between prognosis of NSCLC patients remain largely unknown. Experimental approach Clinical pathological analysis was performed to determine the relationship between thrombin and tumour progression. Effects of r-hirudin and direct thrombin inhibitor peptide (DTIP) on cancer progression were evaluated. Western blotting, immunohistochemistry, and immunofluorescence were used to explore the inhibition mechanism of r-hirudin and DTIP. The therapeutic effect of the combination of DTIP and chemotherapy was determined. Key results Thrombin expression in NSCLC tissues was closely related to clinicopathological features and the prognosis of patients. Thrombin deficiency inhibited tumour progression. The novel thrombin inhibitors, r-hirudin and DTIP, inhibited cell invasion and metastasis in vitro. They inhibited tumour growth and metastasis in orthotopic lung cancer model, inhibited cell invasion, and prolonged survival after injection of tumour cells via the tail vein. They also inhibited angiogenesis and spontaneous metastases from subcutaneously inoculated tumours. The promotion by thrombin of invasion and metastasis was abolished in PAR-1-deficient NSCLC cells. r-hirudin and DTIP inhibited tumour progression through the thrombin-PAR-1-mediated RhoA and NF-κB signalling cascades via inhibiting MMP9 and IL6 expression. DTIP potentiated chemotherapy-induced growth and metastatic inhibition and inhibited chemotherapy-induced resistance in mice. Conclusions and implications Thrombin makes a substantial contribution, together with PAR-1, to NSCLC malignancy. The anti-coagulants, r-hirudin and DTIP, could be used in anti-tumour therapy and a combination of DTIP and chemotherapy might improve therapeutic effects.

A novel oncotherapy strategy: Direct thrombin inhibitors suppress progression, dissemination and spontaneous metastasis in non-small cell lung cancer.

Thromboembolic disease is a common cardio-cerebral vascular disease that threatens human life and health. Thrombin not only affects the exogenous coagulation pathway, but also the endogenous pathway. Thus, it becomes one of the most important targets of anticoagulant drugs. RGD-hirudin is an anticoagulant drug targeting thrombin, but it can only be administered intravenously. We designed a low molecular weight peptide based on RGD-hirudin that could prevent blood clots. We first used NMR to identify the key amino acid residues of RGD-hirudin that interacted with thrombin. Then, we designed a novel direct thrombin inhibitor peptide (DTIP) based on the structure and function of RGD-hirudin using homology modeling. Molecular docking showed that the targeting and binding of DTIP with thrombin were similar to those of RGD-hirudin, suggesting DTIP interacted directly with thrombin. The active amino acids of DTIP were identified by alanine scanning, and mutants were successfully constructed. In blood clotting time tests in vitro, we found that aPTT, PT, and TT in the rat plasma added with DTIP were greatly prolonged than in that added with the mutants. Subcutaneous injection of DTIP in rats also could significantly prolong the clotting time. Thrombelastography analysis revealed that DTIP significantly delayed blood coagulation. Bio-layer interferometry study showed that there were no significant differences between DTIP and the mutants in thrombin affinity constants, suggesting that it might bind to other sites of thrombin rather than to its active center. Our results demonstrate that DTIP with low molecular weight can prevent thrombosis via subcutaneous injection.

/pdf/rgd-hirudin-based-low-molecular-weight-peptide-prevents-45i2rpzk8w.pdf

RGD-hirudin-based low molecular weight peptide prevents blood coagulation via subcutaneous injection

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A novel oncotherapy strategy: Direct thrombin inhibitors suppress progression, dissemination and spontaneous metastasis in non-small cell lung cancer.

RGD-hirudin-based low molecular weight peptide prevents blood coagulation via subcutaneous injection