Establishment of human cerebral organoid systems to model early neural development and assess the central neurotoxicity of environmental toxins

Human brain development is a complex process,and animal models often have significant limitations.To address this,researchers have developed pluripotent stem cell-derived three-dimensional structures,known as brain-like organoids,to more accurately model early human brain development and disease.To enable more consistent and intuitive reproduction of early brain development,in this study,we incorporated forebrain organoid culture technology into the traditional unguided method of brain organoid culture.This involved embedding organoids in matrigel for only 7 days during the rapid expansion phase of the neural epithelium and then removing them from the matrigel for further cultivation,resulting in a new type of human brain organoid system.This cerebral organoid system replicated the temporospatial characteristics of early human brain development,including neuroepithelium derivation,neural progenitor cell production and maintenance,neuron differentiation and migration,and cortical layer patterning and formation,providing more consistent and reproducible organoids for developmental modeling and toxicology testing.As a proof of concept,we applied the heavy metal cadmium to this newly improved organoid system to test whether it could be used to evaluate the neurotoxicity of environmental toxins.Brain organoids exposed to cadmium for 7 or 14 days manifested severe damage and abnormalities in their neurodevelopmental patterns,including bursts of cortical cell death and premature differentiation.Cadmium exposure caused progressive depletion of neural progenitor cells and loss of organoid integrity,accompanied by compensatory cell proliferation at ectopic locations.The convenience,flexibility,and controllability of this newly developed organoid platform make it a powerful and affordable alternative to animal models for use in neurodevelopmental,neurological,and neurotoxicological studies.

Botulinum toxin type A in treating early-stage patients with small-angle acute acquired comitant esotropia

AIM:To investigate botulinum toxin A(BTXA)efficacy on small-angle(≤25Δ)acute acquired concomitant esotropia(AACE)in early-stage patients.METHODS:The electronic medical record data of AACE patients during March 2019 and June 2023 were collected in this retrospective and hospital-based cohort study.A total of 72 small-angle AACE patients received BTXA extraocular muscle injection.Patients were grouped by onset-to-treatment time(Group A:≤6mo,Group B:>6mo).Deviation of esotropia,eye alignment and stereopsis were analyzed at the period of pre/post-injection(1wk,1,3,and 6mo).Orthophoria rate at 6mo(horizontal deviation<10Δand binocular single vision)were considered as outcome index.RESULTS:There were no significant baseline differences(P>0.05)between two groups except onset-to-treatment time(2mo vs 11mo,P<0.001).Higher orthophoria rates were in Group A at last follow-up(94.74%vs 73.53%,P=0.013).Post-BTXA deviations of two groups at 1mo showed no difference(P>0.05);while in 3 and 6mo Group A was significantly smaller than group B(all P<0.001).No statistically significant differences were observed among all post-BTXA deviations of near and distance in Group A.In Group B,deviation at 3mo(near:2Δvs 0,P<0.001;distance:4Δvs 0,P<0.001)and 6mo(near:6Δvs 0,P<0.001;distance:6Δvs 0,P<0.001)was significant increased compared to deviation at 1wk after treatment.Group A showed better stereopsis recovery in last follow-up compared to Group B(80″vs 200″,P=0.002).Both groups obtained improved stereopsis after treatment(Group A:80″vs 300″,P<0.001;Group B:200″vs 300″,P=0.037).CONCLUSION:BTXA is effective for AACE with small deviation(≤25Δ)in early stage.Delayed treatment(>6mo)may reduce BTXA efficacy.Early BTXA intervention benefits long-term eye alignment and stereopsis recovery.

Botulinum toxin type A-targeted SPP1 contributes to neuropathic pain by the activation of microglia pyroptosis

BACKGROUND Neuropathic pain(NP)is the primary symptom of various neurological condi-tions.Patients with NP often experience mood disorders,particularly depression and anxiety,that can severely affect their normal lives.Microglial cells are as-sociated with NP.Excessive inflammatory responses,especially the secretion of large amounts of pro-inflammatory cytokines,ultimately lead to neuroinflam-mation.Microglial pyroptosis is a newly discovered form of inflammatory cell death associated with immune responses and inflammation-related diseases of the central nervous system.METHODS Two models,an in vitro lipopolysaccharide(LPS)-stimulated microglial cell model and a selective nerve injury model using BTX-A and SPP1 knockdown treatments,were used.Key proteins in the pyroptosis signaling pathway,NLRP3-GSDMD,were assessed using western blotting,real-time quantitative polymerase chain reaction,and immunofluorescence.Inflammatory factors[interleukin(IL)-6,IL-1β,and tumor necrosis factor(TNF)-α]were assessed using enzyme-linked immuno-sorbent assay.We also evaluated microglial cell proliferation and apoptosis.Furthermore,we measured pain sensation by assessing the delayed hind paw withdrawal latency using thermal stimulation.RESULTS The expression levels of ACS and GSDMD-N and the mRNA expression of TNF-α,IL-6,and IL-1βwere enhanced in LPS-treated microglia.Furthermore,SPP1 expression was also induced in LPS-treated microglia.Notably,BTX-A inhibited SPP1 mRNA and protein expression in the LPS-treated microglia.Additionally,depletion of SPP1 or BTX-A inhibited cell viability and induced apoptosis in LPS-treated microglia,whereas co-treatment with BTX-A enhanced the effect of SPP1 short hairpin(sh)RNA in LPS-treated microglia.Finally,SPP1 depletion or BTX-A treatment reduced the levels of GSDMD-N,NLPRP3,and ASC and suppressed the production of inflammatory factors.CONCLUSION Notably,BTX-A therapy and SPP1 shRNA enhance microglial proliferation and apoptosis and inhibit microglial death.It improves pain perception and inhibits microglial activation in rats with selective nerve pain.

Dermal thickness,rather than drug concentration and injection speed,influences the effective area of botulinum toxin type A in the dermis

Background:Recently,microbotulinum,a new technique that involves injecting botulinum toxin type A(BoNTA)microdroplets into superficial cutaneous tissue,has gained popularity.The precise distribution of BoNTA in the targeted area profoundly affects outcomes.Many factors may influence the effective area of BoNTA in the dermis.This study aimed to determine the dermal distribution properties of BoNTA to guide microbotulinum injection.Methods:Ten healthy males aged 18–65 years without BoNTA treatment in the previous year were recruited to receive intradermal injections in the chest and back.Ultrasound was used to ensure the intradermal delivery of injections and measure the dermal thickness.The minor iodine starch test was performed at baseline and 3 days,7 days,21 days,1 month,and 2 months after treatment.Results:All participants received intradermal injections.The dermis was thinner on the chest(thickness,0.20±0.03 cm)than on the back(thickness,0.39±0.07 cm)(P<0.05).An injection in the thicker dermis had a significantly smaller effective area at every follow-up visit.The drug concentration did not affect the effective area except at 3 days after treatment.Injection speed did not influence the effective area at any follow-up visits.Conclusion:An injection in a thicker dermis leads to a smaller effective area for intradermal injections.When the BoNTA dose is the same,the drug concentration and injection speed do not matter.

Clinical effect of botulinum toxin type A combined with autologous fat grafting in patients with nasolabial fold depression

BACKGROUND Nasolabial fold(NLF)depression can affect the facial appearance of patients to some extent and increase their psychological burdens.In recent years,autologous fat grafting(AFG)combined with botulinum toxin A(BTX-A)injection(AFG+BTX-A injection)has been gradually applied in the treatment of patients with NLF depression.Although studies have been conducted on the efficacy and safety of AFG+BTX-A injection in treating NLF depression,the experimental design,observational indicators,and sample enrollment criteria vary remarkably,making it difficult to draw convincing and consistent conclusions.Thus,further relevant research is warranted.AIM To assess the esthetic improvement,efficacy,and safety of AFG+BTX-A injections in patients with NLF depression.METHODS This study included 60 patients with NLF depression who were treated in our hospital from February 2019 to April 2021.These patients were categorized into control(n=30)and observation(n=30)groups.The observation group received AFG+BTX-A injection,whereas the control group underwent AFG only.All patients were evaluated using the wrinkle severity rating scale(WSRS)and global aesthetic improvement scale.The compactness of facial contours,skin evaluation indexes,adverse reactions,and satisfaction of the two groups were evaluated 3 months postoperatively.RESULTS The WSRS scores of the observation group at 1,3,and 6 months postoperatively were lower than those of the control group(P<0.05).Three months postoperatively,facial fine lines and pores showed obvious improvement and the skin index score was higher in the observation group than in the control group(P<0.05).The compactness of facial contours was better in the observation group than in the control group(P<0.05).In addition,no remarkable differences were noted in the incidence of postoperative adverse reactions such as facial stiffness,facial asymmetry,facial bruising,and facial concavity inequality(P>0.05).CONCLUSION AFG+BTX-A injection is a highly safe,cost-effective,effective,and long-lasting treatment for NLF depression with high esthetic value,which should be promoted in the future.

Betulinic acid protects against ovarian impairment by decreasing F-2 toxin-induced oxidative stress and inflammation associated with the downregulation of p38 expression in mice

F-2 toxin is an estrogenic mycotoxin that causes reproductive disorders in animals.Betulinic acid(BA)is a natural pentacyclic lupane-structure triterpenoid that has diverse pharmacological activities.In this study,the antioxidative and anti-inflammatory effects of BA and its underlying mechanism are explored in F-2 toxin-triggered mouse ovarian damage.We found that BA alleviated the F-2 toxin-induced ovarian impairment by stimulating follicle growth,reducing inflammatory cell infiltration,repairing damaged mitochondria and endoplasmic reticulum.Simultaneously,BA not only reversed F-2 toxin-induced reduction of follicle stimulating hormone(FSH)and luteinizing hormone(LH)levels in the serum,but also restrained the protein expression of the estrogen receptors a(ERa)and ERβ.Moreover,BA restored the balance of F-2 toxin-induced ovarian redox system disorders.Subsequently,we found that 0.25 mg/kg BA played an anti-inflammatory role in the F-2 toxin-induced ovarian impairment by decreasing interleukin-1β(IL-1β).IL-6,and tumor necrosis factor-α(TNF-α)mRNA expression,as well as inhibiting p38 protein expression.These data demonstrated that BA exerts its protective effect on F-2 toxin-induced ovarian oxidative impairment and inflammation by inhibiting p38 expression,which implies a natural product-based medicine to ameliorate F-2 toxin-caused female reproductive toxicity and provides a detoxifying method for food contaminated by mycotoxin.

Botulinum toxin type A injection combined with biofeedback in the treatment of spastic pelvic floor syndrome

BACKGROUND Spastic pelvic floor syndrome(SPFS)is a refractory pelvic floor disease characterized by abnormal(uncoordinated)contractions of the external anal sphincter and puborectalis muscle during defecation,resulting in rectal emptation and obstructive constipation.The clinical manifestations of SPFS are mainly characterized by difficult defecation,often accompanied by a sense of anal blockage and drooping.Manual defecation is usually needed during defecation.From physical examination,it is commonly observed that the patient's anal muscle tension is high,and it is difficult or even impossible to enter with his fingers.AIM To investigate the characteristics of anorectal pressure and botulinum toxin A injection combined with biofeedback in treating pelvic floor muscle spasm syndrome.METHODS Retrospective analysis of 50 patients diagnosed with pelvic floor spasm syndrome.All patients underwent pelvic floor surface electromyography assessment,anorectal dynamics examination,botulinum toxin type A injection 100 U intramuscular injection,and two cycles of biofeedback therapy.RESULTS After the botulinum toxin A injection combined with two cycles of biofeedback therapy,the patient's postoperative resting and systolic blood pressure were significantly lower than before surgery(P<0.05).Moreover,the electromyography index of the patients in the resting stage and post-resting stages was significantly lower than before surgery(P<0.05).CONCLUSION Botulinum toxin A injection combined with biofeedback can significantly reduce pelvic floor muscle tension in treating pelvic floor muscle spasm syndrome.Anorectal manometry is an effective method to evaluate the efficacy of treatment objectively.However,randomized controlled trials are needed.

Botulinum toxin type A for treating chronic low back pain:A double blinded randomized control study

BACKGROUND Low back pain(LBP)is a prevalent issue that orthopedic surgeons frequently address in the outpatient setting.LBP can arise from various causes,with stiffness in the paraspinal muscles being a notable contributor.The administration of Botulinum toxin type A(BoNT-A)has been found to alleviate back pain by relaxing these stiff muscles.While BoNT-A is approved for use in numerous conditions,a limited number of randomized clinical trials(RCTs)validate its efficacy specifically for treating LBP.AIM To study the safety and the efficacy of BoNT-A in minimizing pain and improving functional outcomes in patients of chronic LBP(CLBP).METHODS In this RCT,adults aged 18-60 years with mechanical LBP persisting for at least six months were enrolled.Participants were allocated to either the Drug group,receiving 200 Ipsen Units(2 mL)of BoNT-A,or the Control group,which received a 2 mL placebo.Over a 2-month follow-up period,both groups were assessed using the Visual Analog Scale(VAS)for pain intensity and the Oswestry Disability Index(ODI)for disability at the start and conclusion of the study.A decrease in pain by 50%was deemed clinically significant.RESULTS The study followed 40 patients for two months,with 20 in each group.A clinically significant reduction in pain was observed in 36 participants.There was a statistically significant decrease in both VAS and ODI scores in the groups at the end of two months.Nonetheless,when comparing the mean score changes,only the reduction in ODI scores(15 in the placebo group vs 16.5 in the drug group,clinically insignificant)was statistically significant(P=0.012),whereas the change in mean VAS scores was not significant(P=0.45).CONCLUSION The study concludes that BoNT-A does not offer a short-term advantage over placebo in reducing pain or improving LBP scores in CLBP patients.

Severe Botulism after Intragastric Botulinum Toxin-A Injection: A Case Series

Intragastric botulismus toxin-A (BoNT-A) is one of the new approaches in the treatment of obesity. We aimed to contribute to the literature by presenting the clinical features, laboratory findings and treatment responses of iatrogenic botulism cases due to intragastric BoNT-A administered in our clinic. All detailed medical information was obtained by accessing the medical records of the patients who were hospitalized and followed up and treated between September 2022 and December 2022, and the diagnosis of A.05.1 Botulism was entered according to ICD-10, and whose clinical findings were compatible with botulism disease and who underwent intragastric BoNT-A application beforehand. These records were obtained by examining this information. 10 patients who developed botulism after intragastric BoNT-A application between 01/09/2022 and 28/02/2023 were followed up in our clinic. All of the patients were women. The mean age was 35. The mean hospital stay was 9 days. Only 1 of our cases required intensive care. Good response to treatment was accepted as a complete or near-complete improvement in the clinical findings of the patients and all of them had a good response to treatment. Intragastric BoNT-A administration is a procedure that requires careful indication with a profit/loss calculation considering the potential side effects. In addition, attention should be paid to dilution rates and dose amounts.

Increase of β -1, 3-Glucanase and Chitinase Activities in Cotton Callus Cells Treated by Salicylic Acid and Toxin of Verticillium dahliae

The different resistance of cotton (Gossypium hirsutum L.) cultivars to crude toxin of Verticillium dah/iae(VD) was correlated with the activities of chitinase and β-1, 3-glucanase in callus cells. The activities of chitinase and β-1, 3-glucanase in the callus cells treated with the VD-toxin were increased to the higher level at earlier time point in resistant cultivars than these in the susceptible cultivars. Exogenous salicylic acid (SA) induced the accumulation of chitinase and β -1,3-glucanase, which resulted in the resistance of callus cells to the VD. toxin. Western blot using a polyclonal antibody against β -1,3-glucanase identified 28 kD protein that was induced by VD-toxin, SA, or VD-toxin plus SA.

Preliminary Study on the Extraction of Crude Toxin of Rhizoctonia solani and Its Activity

[ Objective] This study was to investigate the pathogenic mechanism of rice sheath blight pathogen （ Rhizoctonia solani） and the bioactive components of toxin. [ Method ] Rice sheath blight pathogen was cultured in the improved Richared medium; the culture filtrate was centrifuged and sterilized, then treated by activated carbon adsorption chromatography, distilled with methanol or water, and all were next concentrated, yielding the crude extracts of culture solution, crude extracts of methanol and crude extracts of water; the activities of these three extracts were determined, [ Result] The three extracts were russet pastes; activity determination showed that they had remarkable inhibitory effects on the growth of rice radicle and plantule, as well as the growth of four-foliage-young seedlings. They could also generate toxic effects on abscisic foliages and spots similar to the symptoms of sheath blight pathogen. [ Conclusion] Bioactive components of rice sheath blight pathogen toxin may be composed of various ingredients.

金黄色葡萄球菌α-toxin(Hla)促进皮肤组织中IL-19表达上调的作用机制研究

目的探究金黄色葡萄球菌α-toxin(Hla)促进皮肤组织中IL-19表达上调的作用机制。方法采用WT S.Aureus、△Hla S.aureus(Hla缺失菌株)以及PBS感染Balb/c小鼠背部皮肤,收集感染后第1、3、7天的皮肤组织,HE染色检测组织炎性病理损伤,q RT-PCR和ELISA分别检测IL-19、IL-1β的m RNA和蛋白水平的表达。分离小鼠骨髓的中性粒细胞,分别用WT S.Aureus、△Hla S.aureus以及meida(不含菌液的培养基)刺激6 h后,q RT-PCR、ELISA和Western blot检测IL-1β的表达。不同浓度IL-1β刺激角质形成细胞PAM 2-12后,q RT-PCR和ELISA分别检测IL-19的表达。结果△Hla S.aureus组与WT S.aureus组相比,其皮肤损伤的面积减小,炎性细胞浸润和脓肿形成减少。同时q RT-PCR和ELISA检测发现,△Hla S.aureus组与WT S.aureus组相比,IL-19的m RNA和蛋白表达水平显著降低(P<0.01)。体外中性粒细胞刺激发现,△Hla S.aureus组与WTS.aureus组相比,IL-1β蛋白表达水平显著降低(P<0.01)。体外IL-1β刺激角质形成细胞PAM 2-12发现,与不刺激组相比,IL-19的m RNA和蛋白表达水平显著增加(P<0.01),并呈剂量依赖性。结论金黄色葡萄球菌分泌的α-toxin能够作用于中性粒细胞,促进了IL-1β的表达,IL-1β的过表达作用于皮肤的角质形成细胞,从而促进了IL-19的上调,可能参与了银屑病的发生与发展。

虾夷扇贝毒素yessotoxins(YTXs),中国沿海贝类中首次发现的一组贝类生物毒素

采用高效液相色谱-串联质谱方法对我国近海贝类中腹泻性贝毒成分进行研究,结果发现采自北黄海大连附近海域的海湾扇贝和虾夷扇贝含有25~41μg/kg的虾夷扇贝毒素（yessotoxin,YTX）,在虾夷扇贝体内还含有37.2μg/kg的45-OH-YTX,并在5种贝中发现微量的Homo-YTX毒素组分,这是首次报道在我国贝中检出此类毒素。虾夷扇贝毒素YTXs是一类含有2个磺酰基的脂溶性多环聚醚类化合物,对小鼠的腹腔注射急性致死毒性很高,毒理作用机制尚不清楚。本研究的结果说明我国贝类体内生物毒素成分复杂,亟需进行毒素成分结构、来源生物、生态毒理效应、分布规律及安全限定标准的研究。

短裸甲藻毒素(Brevetoxin,BTX)研究进展

短裸甲藻毒素(Brevetoxin,BTX)是一类能够引起神经性中毒症状的有害赤潮藻毒素,在世界范围内的分布越来越广,对水产品的质量安全带来严重威胁。本文就该毒素的化学组分与结构、生物转化、致毒机理、分析方法等国内外最新研究进展和政策变化进行系统的论述,并提出我国的应对措施,为我国的赤潮监控和贝类安全监测提供背景参考。

虎纹捕鸟蛛神经毒素Huwentoxin-Ⅰ的二级结构研究

Huwentoxin-Ⅰ是一种小分子量的多肽类毒素,它能阻断脊椎动物的神经肌肉接头传递。该毒素分子内含33个氨基酸残基,有三对二硫键。本文报道用圆二色性光谱分析法对该毒素二级结构的测定和分析,并用Creenfield等介绍的方法计算其二级结构中各种成分的含量。结果表明,此多肽分子中,α螺旋约占22—28％,β折叠约占22—35％,而β转角和无规卷曲约占41—49％。实验还表明,此毒素在不同pH条件下的二级结构均比较稳定,将它加热到80℃保温20分钟后再测定其CD光谱,其二级结构成分变化不大。用各种不同的方法对其二级结构进行了预测,结果表明该分子一级结构序列N-末端有一小段β折叠,C-末端有一段α螺旋,分子中部的大部分残基为β转角和无规卷曲构象。

Establishment and Application of a Real-time PCR Method for Detecting stx2 Gene in Shiga Toxin-producing Escherichia coli(STEC)

[Objective] This study aimed to establish a real-time PCR method for de- tecting stx2 gene in Shiga toxin-producing E. coli （STEC）. [Method] According to the known STEC stx2 gene sequences published in GenBank, PCR primers and probes were designed based on the conserved region to construct recombinant plasmid as a positive template, thus optimizing the reaction conditions and establishing the real- time PCR method. [Result] A standard curve was established based on the opti- mized real-time PCR system, indicting a good linear correlation between the initial template concentration and Ct value, with the correlation coefficient F^e of above 0.995. The established method had a good specificity, without non-specific amplifica- tion for 10 non-STEC intestinal bacterial strains; the detection limit of initial template was 1.0x102 copies/μI, indicating a high sensitivity; furthermore, the coefficients of variation within and among batches were lower than 1% and 5% respectively, sug- gesting a good repeatability. [Conclusion] In this study, a real-time PCR method was successfully established for detecting STEC stx2 gene, which provided technical means for rapid detection of STEC in samples.

重组蜈蚣抗昆虫神经毒素rScolotoxin-Ssm2b对家蚕的经口急性毒性

以家蚕为模式昆虫,进行重组蜈蚣抗昆虫神经毒素r Scolotoxin-Ssm2b的经口急性毒性试验。采用叶片涂抹法分别给2龄起蚕添食质量浓度为0.625、1.250、2.500、5.000、10.000μg/m L的r Scolotoxin-Ssm2b,添食24 h测定的LC50值为4.84μg/m L。幼虫添食质量浓度为5.000μg/m L的r Scolotoxin-Ssm2b后2~5 min,出现口吐消化液、头胸部左右大幅摇摆、躯体扭曲、胸部膨大、头部突出、侧翻倒地等明显的中毒症状;添食后2 h,约80%的幼虫死亡。研究结果表明r Scolotoxin-Ssm2b对家蚕具有经口急性毒性,证明其有口服杀虫活性。

霉菌毒素T-2Toxin酶联免疫吸附测定方法

用T - 2毒素免疫家兔 ,获得了抗T - 2毒素的多克隆抗体 ,运用该抗体建立了检测玉米中T - 2毒素的间接竞争性酶联免疫吸附测定法 .该法最低检出量为 1 0 ppb ,平均回收率为 32 %～43%.

α-toxin调控miR-142表达抑制巨噬细胞吞噬功能的机制研究

目的探讨金黄色葡萄球菌(简称金葡菌)分泌的α-外毒素(Hla)调控miR-142表达并抑制巨噬细胞吞噬功能的分子机制。方法采用野生型金葡菌菌株(WT S.aureus)、Hla缺失金葡菌菌株(△HlaS.aureus)及磷酸盐缓冲液(PBS)感染BALB/C小鼠背部皮肤、RAW264.7鼠源巨噬细胞,检测感染后皮肤组织和巨噬细胞miR-142表达水平。构建荧光素酶报告基因载体,采用荧光素酶活性实验分析miR-142对蛋白激酶Cα(PKCα)表达水平的调控作用。在RAW264.7细胞中过表达miR-142模拟物,分析细胞吞噬能力。结果与PBS处理组相比,△HlaS.aureus与WT S.aureus处理组皮肤组织和巨噬细胞miR-142表达水平下降(P<0.05)。MiR-142模拟物可抑制荧光素酶活性,抑制巨噬细胞RAW264.7细胞的吞噬能力(P<0.05)。结论金葡菌分泌的H1a促进巨噬细胞表达miR-142,进而通过下调PKCα表达水平抑制巨噬细胞的吞噬功能。

Why do we study animal toxins?

Venom （toxins） is an important trait evolved along the evolutionary tree of animals. Our knowledges on venoms, such as their origins and loss, the biological relevance and the coevolutionary patterns with other organisms are greatly helpful in understanding many fundamental biological questions, i.e., the environmental adaptation and survival competition, the evolution shaped development and balance of venoms, and the sophisticated correlations among venom, immunity, body power, intelligence, their genetic basis, inherent association, as well as the cost-benefit and trade-offs of biological economy. Lethal animal envenomation can be found worldwide However, from foe to friend, toxin studies have led lots of important discoveries and exciting avenues in deciphering and fighting human diseases, including the works awarded the Nobel Prize and lots of key clinic therapeutics. According to our survey, so far, only less than 0.1% of the toxins of the venomous animals in China have been explored. We emphasize on the similarities shared by venom and immune systems, as well as the studies of toxin knowledge-based physiological toxin-like proteins/peptides （TLPs）. We propose the natural pairing hypothesis. Evolution links toxins with humans. Our mission is to find out the right natural pairings and interactions of our body elements with toxins, and with endogenous toxin-like molecules. Although, in nature, toxins may endanger human lives, but from a philosophical point of view, knowing them well is an effective way to better understand ourselves. So, this is why we study toxins.