Advantages of NMNH
NMNH: 1. “Bonzyme” Whole-enzymatic method, environmental-friendly, no harmful solvent residues manufacturing powder. 2. Bontac is a very first manufacture in the world to produce the NMNH powder on the level of high purity, stability. 3. Exclusive “Bonpure” seven-step purification technology, high purity（up to 99%) and stability of production of NMNH powder 4. Self-owned factories and obtained a number of international certifications to ensure high quality and stable supply of products of NMNH powder 5. Provide one-stop product solution customization service
Advantages of NADH
NADH: 1. Bonzyme whole-enzymatic method, environmental-friendly, no harmful solvent residues 2. Exclusive Bonpure seven-step purification technology, purity up higher than 98 % 3. Special patented process crystal form, higher stability 4. Obtained a number of international certifications to ensure high quality 5. 8 domestic and foreign NADH patents, leading the industry 6. Provide one-stop product solution customization service
Advantages of NAD
NAD: 1. “Bonzyme” Whole-enzymatic method, environmental-friendly, no harmful solvent residues 2. Stable supplier of 1000+ enterprises around the world 3. Unique “Bonpure” seven-step purification technology, higher product content and higher conversion rate 4. Freeze drying technology to ensure stable product quality 5. Unique crystal technology, higher product solubility 6. Self-owned factories and obtained a number of international certifications to ensure high quality and stable supply of products
Advantages of MNM
NMN: 1. “Bonzyme”Whole-enzymatic method, environmental-friendly, no harmful solvent residues 2. Exclusive“Bonpure”seven-step purification technology, high purity（up to 99.9%) and stability 3. Industrial leading technology: 15 domestic and international NMN patents 4. Self-owned factories and obtained a number of international certifications to ensure high quality and stable supply of products 5. Multiple in vivo studies show that Bontac NMN is safe and effective 6. Provide one-stop product solution customization service 7. NMN raw material supplier of famous David Sinclair team of Harvard University
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Bontac Bio-Engineering (Shenzhen) Co., Ltd. (hereafter referred to as BONTAC) is a high-tech enterprise established in July 2012. BONTAC integrates R&D, production and sales, with enzyme catalysis technology as the core and coenzyme and natural products as main products. There are six major series of products in BONTAC, involving coenzymes, natural products, sugar substitutes, cosmetics, dietary supplements and medical intermediates.
As the leader of the global NMN industry, BONTAC has the first whole-enzyme catalysis technology in China. Our coenzyme products are widely used in health industry, medical & beauty, green agriculture, biomedicine and other fields. BONTAC adheres to independent innovation, with more than 170 invention patents. Different from the traditional chemical synthesis and fermentation industry, BONTAC has advantages of green low-carbon and high-value-added biosynthesis technology. What’s more, BONTAC has established the first coenzyme engineering technology research center at the provincial level in China which also is the sole in Guangdong Province.
In the future, BONTAC will focus on its advantages of green, low-carbon and high-value-added biosynthesis technology, and build ecological relationship with academia as well as upstream/downstream partners, continuously leading the synthetic biological industry and creating a better life for human beings.
NMN powder manufacturing method
NMN powder in general is typically produced via chemical or enzymatic synthesis, or fermentation biosynthesis. There are pros and cons to all three methods.
Chemical synthesis is expensive and labor intensive, and all raw ingredients used are categorized as “unnatural,” i.e., not from biological systems. There are, however, some advantages from the manufacturer’s perspective. The yield is well suited to mass NMN powder production, and all of those unnatural raw ingredients can be carefully controlled. But there are a number of drawbacks as well. Some of the solvents used in the manufacturing process are seriously bad from an environmental standpoint, and impurities and by-products can be challenging to remove from the finished product – that’s seriously bad for the consumer.
Enzymatic production of NMN powder, on the other hand, is considered a “green preparation method.” Like the chemical route, it’s pricey, but it offers a higher yield and impressively high purity. The finished NMN ticks all the boxes – stable, easily absorbed, lightweight, low density, and a low molecular structure.
Fermentation has also been explored as a method of producing NMN, but yield, though high quality, is pretty abysmal, so many supplement companies quite sensibly look to other, more efficacious processes.
NMN powder efficacy in health
NMN was only considered as a source of cellular energy and an intermediate in NAD+ biosynthesis, currently, the attention of the scientific community has been paid on anti-aging activity and a variety of health benefits and pharmacological activities of NMN which are related to the restoring of NAD+. Thus, NMN has therapeutic effects towards a range of diseases, including age-induced type 2 diabetes, obesity, cerebral and cardiac ischemia, heart failure and cardiomyopathies, Alzheimer’s disease and other neurodegenerative disorders, corneal injury, macular degeneration and retinal degeneration, acute kidney injury and alcoholic liver disease.
BONTAC NMN product features and advantages
1、“Bonzyme”Whole-enzymatic method, environmental-friendly, no harmful solvent residues manufacturing powder
2、Exclusive“Bonpure”seven-step purification technology, high purity（up to 99.9%) and stability of production of NMN powder
3、Industrial leading technology: 15 domestic and international NMN patents
4、Self-owned factories and obtained a number of international certifications to ensure high quality and stable supply of products of NMN powder
5、Multiple in vivo studies show that Bontac NMN powder is safe and effective
6、Provide one-stop product solution customization service
7、NMN raw material supplier of famous David Sinclair team of Harvard University.
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Frequently Asked Question
Do you have any question?
Aging, as a natural process is identified by downregulation of energy production in mitochondria of various organs such as brain, adipose tissue, skin, liver, skeletal muscle and pancreas due to the depletion of NAD+ . NAD+ levels in the body decrease as a consequence of increasing NAD+ consuming enzymes when aging There are three different biosynthesis pathways to produce NAD+ in mammalian cells including de novo synthesis from tryptophan, salt and Preiss-Handler pathways. Among these three pathways, NMN is an interproduct by is involved in NAD+ biosynthesis through salt and Preiss-Handler pathways. The salvage pathway is the most efficient and the main route for the NAD+ biosynthesis, in which nicotinamide and 5-phosphoribosyl-1-pyrophosphate are converted to NMN with the enzyme of NAMPT followed by conjugation to ATP and conversion to NAD by NMNAT. Furthermore, NAD+ consuming enzymes are responsible for degradation of NAD+ and consequence nt formation of nicotinamide as a by-product.
The safety of NMN powder cannot be assessed since required clinical and toxicological studies have not been completed yet to establish the recommended safe levels for long term administration. Nevertheless, their safety and efficacy are uncertain and unreliable since most of them have not been back by Rigorous scientific preclinical and clinical testing. This issue has been arisen as manufacturers are hesitant to pay for research and clinical trials due to potential lower profit margin, and there is no authorizing agency to regulate NMN products because it is often product sold as functional food than heavily regulated therapeutic drug. Therefore, more strict approval process has been demanded by consumer advocacy groups requesting regulatory agencies to set standard and restrictions for marketing anti-aging health products, considering safety, health and wellbeing of N red besumers. a panacea for the elderly, because boosting NAD levels when not required may yield some detrimental effects. Therefore, the dose and frequency of NMN supplementation should be carefully prescribed depending on the type of age-related deficiency and all other confronting health conditions of the people. Other NAD precursors over have been studied to diverse age-related deficiencies and they are used for particular deficiencies, only after they are proven for effectiveness and safe to use. Therefore, the same principle should be applied to NMN as well
First, inspect the factory. After some screening, NMN companied that directly face consumers pay more attention to brand building. Therefore, for a good brand, quality is the most important thing, and the first thing to control the quality of raw materials is to inspect the factory. Bontac company actually manufacturing NMN powder of high quality with the caterias of SGS. Secondly, the purity is tested. Purity is one of the most important parameters of NMN powder. If high purity NMN cannot be guaranteed, the remaining substances are likely to exceed the relevant standards. As the attached certificates demonstrates that the NMN powder produced by Bontac reach the purity of 99.9%. Finally, a professional test spectrum is needed to prove it. Magnetic Resonance Spectroscopy (NMR) and high-resolution mass spectrometry (HRMS). Usually through the analysis of these two spectra, the structure of the compound ca n be preliminarily determined.
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The latest research proves: Coenzyme NAD+ can enhance tumor immunity! Expert Comment from Chinese Academy of Sciences
On August 10, 2021, researchers from Shanghai University of Science and Technology published an article titled NAD+ supplement potentiates tumor killing function by rescuing defective TUBBY-mediated NAMPT transcription in tumor infiltrated T cells in Cell Reports, revealing that NAD+ in supplemented during CAR-T therapy and immune checkpoint inhibitor therapy, it can improve the anti-tumor activity of T. At present, the supplementary precursor of NAD+, as a nutritional product,has been verified for human consumption safety.This achievement provides a simply and feasible new method for improving the anti-tumor activity of T cells. Cancer immunotherapies including the adoptive transfer of naturally occurring tumor-infiltrating lymphocytes (TILs) and genetically engineered T cells, as well as the use of immune checkpoint blockade (ICB) to boost the function of T cells, have emerged as promising approaches to achieve durable clinical responses of otherwise treatment-refractory cancers (Lee et al., 2015; Rosenberg and Restifo, 2015; Sharma and Allison, 2015). Although immunotherapies have been successfully used in the clinic, the number of patients benefiting from them is still limited (Fradet et al., 2019; Newick et al., 2017). Tumor microenvironment (TME)-related immunosuppression has emerged as the major reason for low and/or no response to both immunotherapies (Ninomiya et al., 2015; Schoenfeld and Hellmann, 2020). Therefore, efforts to investigate and overcome TME-related limitations in immune therapies are of great urgency. The fact that immune cells and cancer cells share many fundamental metabolic pathways implies an irreconcilable competition for nutrients in TME (Andrejeva and Rathmell, 2017; Chang et al., 2015). During uncontrolled proliferation, cancer cells hijack alternative pathways for more rapid metabolite generation (Vander Heiden et al., 2009). As a consequence, nutrient depletion, hypoxia, acidity, and generation of metabolites that can be toxic in the TME may hinder successful immunotherapy (Weinberg et al., 2010). Indeed, TILs often experience mitochondrial stress within growing tumors and become exhausted (Scharping et al., 2016). Interestingly, multiple studies also indicate that metabolic changes in TME could re-shape T cell differentiation and functional activity (Bailis et al., 2019; Chang et al., 2013; Peng et al., 2016). All these evidences inspired us to hypothesize that metabolic reprogramming in T cells might rescue them from a stressed metabolic environment, thereby reinvigorating their anti-tumor activity (Buck et al., 2016; Zhang et al., 2017). In this current study, by integrating both genetic and chemical screens, we identified that NAMPT, a key gene involved in NAD+ biosynthesis, was essential for T cell activation. NAMPT inhibition led to robust NAD+ decline in T cells, thereby disrupting glycolysis regulation and mitochondrial function, blocking ATP synthesis, and dampening the T cell receptor (TCR) downstream signaling cascade. Building on the observation that TILs have relatively lower NAD+ and NAMPT expression levels than T cells from peripheral blood mononuclear cells (PBMCs) in ovarian cancer patients, we performed genetic screening in T cells and identified that Tubby (TUB) is a transcription factor for NAMPT. Finally, we applied this basic knowledge in the (pre) clinic and showed very strong evidence that supplementation with NAD+ dramatically improves the anti-tumor killing activity both in adoptively transferred CAR-T cells therapy and immune check point blockade therapy, indicating their promising potential for targeting NAD+ metabolism to better treat cancers. 1.NAD+ regulates the activation of T cells by affecting energy metabolism After antigen stimulation, T cells undergo metabolic reprogramming, from mitochondrial oxidation to glycolysis as the main source of ATP. While maintaining sufficient mitochondrial functions to support cell proliferation and effector functions.Given that NAD+ is the main coenzyme for redox, the researchers verified the effect of NAD+ on the level of metabolism in T cells through experiments such as metabolic mass spectrometry and isotope labeling. The results of in vitro experiments show that NAD+ deficiency will significantly reduce the level of glycolysis, TCA cycle and electron transport chain metabolism in T cells. Through the experiment of replenishing ATP, the researchers found that the lack of NAD+ mainly inhibits the production of ATP in T cells, thereby reducing the level of T cell activation. 2.The NAD+ salvage synthesis pathway regulated by NAMPT is essential for T cell activation The metabolic reprogramming process regulates the activation and differentiation of immune cells. Targeting T cell metabolism provides an opportunity to modulate the immune response in a cellular way. Immune cells in the tumor microenvironment, their own metabolic level will also be correspondingly affected. The researchers in this article have discovered the important role of NAMPT in the activation of T cells through genome-wide sgRNA screening and metabolism-related small molecule inhibitor screening experiments. Nicotinamide adenine dinucleotide (NAD+) is a coenzyme for redox reactions and can be synthesized through the salvage pathway, de novo synthesis pathway, and Preiss-Handler pathway. The NAMPT metabolic enzyme is mainly involved in the NAD+ salvage synthesis pathway. Analysis of clinical tumor samples found that in tumor-infiltrating T cells, their NAD+ levels and NAMPT levels were lower than other T cells. Researchers speculate that NAD+ levels may be one of the factors that affect the anti-tumor activity of tumor-infiltrating T cells. 3.Supplement NAD+ to enhance the anti-tumor activity of T cells Immunotherapy has been exploratory research in cancer treatment, but the main problem is the best treatment strategy and the effectiveness of immunotherapy in the overall population. Researchers want to study whether enhancing the activation ability of T cells by supplementing NAD+ levels can enhance the effect of T cell-based immunotherapy. At the same time, in the anti-CD19 CAR-T therapy model and anti-PD-1 immune checkpoint inhibitor therapy model, it was verified that supplementation of NAD+ significantly enhanced the tumor-killing effect of T cells. The researchers found that in the anti-CD19 CAR-T treatment model, almost all mice in the CAR-T treatment group supplemented with NAD+ achieved tumor clearance, while the CAR-T treatment group without NAD+ supplemented only about 20 % Of mice achieved tumor clearance. Consistent with this, in the anti-PD-1 immune checkpoint inhibitor treatment model, B16F10 tumors are relatively tolerant to anti-PD-1 treatment, and the inhibitory effect is not significant. However, the growth of B16F10 tumors in the anti-PD-1 and NAD+ treatment group could be significantly inhibited. Based on this, NAD+ supplementation can enhance the anti-tumor effect of T cell-based immunotherapy. 4.How to supplement NAD+ The NAD+ molecule is large and cannot be directly absorbed and utilized by the human body. The NAD+ directly ingested orally is mainly hydrolyzed by brush border cells in the small intestine. In terms of thinking, there is indeed another way to supplement NAD+, which is to find a way to supplement a certain substance so that it can synthesize NAD+ autonomously in the human body. There are three ways to synthesize NAD+ in the human body: Preiss-Handler pathway, de novo synthesis pathway and salvage synthesis pathway. Although the three ways can synthesize NAD+, there is also a primary and secondary distinction. Among them, the NAD+ produced by the first two synthetic pathways only accounts for about 15% of the total human NAD+, and the remaining 85% is achieved through the way of remedial synthesis. In other words, the salvage synthesis pathway is the key to the human body to supplement NAD+. Among the precursors of NAD+, nicotinamide (NAM), NMN and nicotinamide ribose (NR) all synthesize NAD+ through a salvage synthesis pathway, so these three substances have become the body's choice for supplementing NAD+. Although NR itself has no side effects, in the process of NAD+ synthesis, most of it is not directly converted into NMN, but needs to be digested into NAM first, and then participate in the synthesis of NMN, which still cannot escape the limitation of rate-limiting enzymes. Therefore, the ability to supplement NAD+ through oral administration of NR is also limited . As a precursor for supplementing NAD+, NMN not only bypasses the restriction of rate-limiting enzymes, but is also absorbed very quickly in the body and can be directly converted into NAD+. Therefore, it can be used as a direct, rapid and effective method to supplement NAD+. Expert Reviews: Xu Chenqi (Excellence and Innovation Center of Molecular Cell Science, Chinese Academy of Sciences, Immunology Research Expert) Cancer treatment is a problem in the world. The development of immunotherapy has made up for the limitations of traditional cancer treatment and expanded the treatment methods of doctors. Cancer immunotherapy can be divided into immune checkpoint blocking therapy, engineered T cell therapy, tumor vaccine, etc. These treatment methods have played a certain role in the clinical treatment of cancer. At the same time, this also makes the current focus of immunotherapy research on how to further enhance the effect of immunotherapy and expand the beneficiaries of immunotherapy.
Quantification NAD+ and its Metabolites in Mouse Sciatic Nerves
Introduction The crucial parts of nicotinamide adenine dinucleotide (NAD+) and its metabolites in aging and neurodegeneration have been widely recognized. To spur progress toward biochemical research and interventions targeting aging and neurodegenerative diseases, it is of great significance to accurately quantify NAD+ and its metabolite levels in the NAD+ salvage pathway. Here, a robust and accurate LC-MS/MS method is applied to quantify NAD+ and its metabolites levels in normal and injured mouse sciatic nerve. Limitations of existing methods for quantifying NAD+ and its metabolites Traditional methods for quantifying NAD+ and its metabolites, such as HPLC-UV, NMR, capillary zone electrophoresis, or colorimetric enzymatic assays, face various challenges in sensitivity, selectivity, and indirect measurement. As for existing LC-MS/MS assays for cellular or tissue NAD+ and its metabolites measurements, there are still many difficulties to overcome, such as extended run times, poor chromatographic retention behavior, and unsatisfactory peak shapes. Moreover, only one to three substances in the NAD+ salvage pathway can be covered by these methods. The modifications of LC-MS/MS method On the basis of existing LC-MS/MS assays, the modifications regarding the chromatographic conditions, surrogate matrix and MS/MS conditions are conducted. Specifically, 5 μM of methylene phosphonic acid is employed as the mobile phase additive, which explicitly promotes the signal intensity and peak shape. Given the relatively clean and simple nature of never samples and their small size, ultrapure water is tested as a substitute matrix. Instead of hydrophilic interaction liquid chromatography column and hypercarb column, the Waters Atlantis Premier BEH C18 AX column is utilized, whose unique MaxPeak HPS high-performance surface technology (passivating the column inner wall, eliminating metal surface) enables the high reproducibility, peak symmetry, and baseline separation of all analytes. Besides, MS conditions are optimized to minimize the NAD+ interference signal in the cyclic adenosine diphosphate ribose (cADPR) channel while maintaining the response of cADPR and nicotinamide mononucleotide (NMN), with 4000V for ion spray voltage, 450℃ for turbo heater temperature, 50 psi for Gas 1, 50 psi for Gas 2, 30 psi for curtain gas, and 12 psi for collision gas. Representative chromatogram of nerve samples (normal vs injured) All five analytes achieve baseline separation, where cADPR is a sensitive biomarker in the neurodegeneration model. Herein, sciatic nerve axotomy induces axonal degeneration, leading to reduced NAD+ level and elevated NMN level in the injured nerves, resulting in about a 2-fold increase in the NMN/NAD+ ratio. Simultaneously, the levels of nicotinamide (NAM) and adenosine diphosphate ribose (ADPR), are decreased by about 2-fold, while cADPR level is increased by more than 8-fold. These results are consistent with those of previously reported research, verifying the accuracy of this modified LS-MS/MS method in quantifying NAD+ and its metabolites. Conclusion This modified LC-MS/MS method enables effective baseline separation of NAD+, NMN, NAM, ADPR, and cADPR within a brief runtime of 5 min, which is contributive to early diagnoses of various neurological disorders and drug development for aging and neurodegenerative diseases. Reference Ma Y, Deng L, Du Z. Development and validation of an LC-MS/MS method for quantifying NAD+ and related metabolites in mice sciatic nerves and its application to a nerve injury animal model. J Chromatogr A. doi:10.1016/j.chroma.2024.464821 BONTAC NAD BONTAC has been dedicated to the R&D, manufacture and sale of raw materials for coenzyme and natural products since 2012, with self-owned factories, over 170 global patents as well as strong R&D team. BONTAC has rich R&D experience and advanced technology in the biosynthesis of NAD and its precursors (eg. NMN and NR). There are various types of NAD to be selected, encompassing NAD ER Grade (endoxin removal), NAD Grade I (IVD/dietary supplement/cosmetics raw powder), NAD Grade II (API/intermediates) and NAD Grade IV (if any higher requirement on the solubility), which can be provided in the form of lyophilized powder or crystalline powder. The purity of BONTAC NAD can reach above 98%. Disclaimer This article is based on the reference in the academic journal. The relevant information is provided for sharing and learning purposes only, and does not represent any medical advice purposes. If there is any infringement, please contact the author for deletion. The views expressed in this article do not represent the position of BONTAC. Under no circumstances will BONTAC be held responsible or liable in any way for any claims, damages, losses, expenses or costs resulting or arising directly or indirectly from your reliance on the information and material on this website.
Potential Treatment for Glaucoma: NAD+ Precursor NR
Introduction Glaucoma is regarded as the second dominant cause of blindness across the world. With the amounting number and proportion of elderly people, it is estimated that 111.8 million people will have glaucoma by 2040. Nicotinamide riboside (NR) has been attested to protect retinal ganglion cells from the stress of elevated intraocular pressure and optic nerve crush. Glaucoma patients can protect their optic nerves by oral administration of NR at a dose of 300 mg (approximately 1.18 mM). The abovementioned protective effects of NR may be achieved by its antioxidant and antifibrotic properties. About glaucoma Glaucoma is a typical ocular disease characterized by atrophy and depression of the optic nerve head, visual field defects, and diminution of vision. The pathologically increased intraocular pressure and insufficient blood supply to the optic nerve are deemed as the primary risk factors for the development of the disease. In addition to those with family history of glaucoma, people with severe myopia/hyperopia, hypertension, hyperlipidemia, hyperglycemia and long-term use of corticosteroid medications, especially eye drops, are at high risk for glaucoma. Extraordinary role of NR in protecting HTMs against oxidative stress In glaucoma, oxidative stress can trigger TM degeneration, thereby resulting in intraocular hypertension. Herein, an oxidative damage model is established in vitro by incubation of human trabecular meshwork (HTM) cells with 200 μM H2O2 for 24 h. As expected, NR hampers H2O2-induced apoptosis in HTM cells, as evidenced by the upregulation of the anti-apoptotic protein Bcl-2 and downregulation of apoptotic protein Bax. Conversely, NR boosts the viability of oxidative-damaged HTM cells. In addition, NR can shield HTM cells from oxidative stress by lowering ROS and superoxide anion levels. Apart from this, NR overtly improves the H2O2-induced decrease in the mitochondrial membrane potential (MMP) in HTM cells, hinting its antioxidant effect possibly achieved by maintaining mitochondrial homeostasis. Underlying mechanism regarding the antioxidant role of NR in HTM cells MAPK and JAK2/Stat3 pathways are related to NR-alleviated HTM cell apoptosis during oxidative stress. In the MAPK pathway, H2O2 leads to the downregulation of p-P38/P38 ratio and upregulation of p-ERK1/2 protein expression, which are offset by intervention with NR. In the JAK2/Stat3 pathway, H2O2 induces downregulation of p-JAK2 protein expression, while NR runs oppositely. Potential antifibrotic role of NR in HTM cells Considering that transforming growth factor-beta 2 (TGF-β2), a profibrotic cytokine, is also a major contributor to glaucomatous HTM dysfunction, an HTM cell model of fibrosis is constructed by induction of TGF-β2 at 10 ng/mL for 48 h. Remarkably, NR prevents TGF-β2-induced fibrosis by reducing extracellular matrix (ECM) deposition in HTM cells. Concretely, the mRNA and protein levels of fibronectin (FN) are elevated in the TGF-β2-treated HTM cells, which however are counteracted by NR. Conclusion NR can boost the viability, proliferation and MMP oxidative damage in H2O2-induced HTM cells, and hamper TGF-β2-induced fibrosis, which is linked to the MAPK and JAK2/Stat3 pathways. NR may be a potential therapeutic agent for glaucoma by inhibiting oxidative damage and fibrosis in HTM cells. Reference Zeng Y, Lin Y, Yang J, et al. The Role and Mechanism of Nicotinamide Riboside in Oxidative Damage and a Fibrosis Model of Trabecular Meshwork Cells. Transl Vis Sci Technol. 2024;13(3):24. doi:10.1167/tvst.13.3.24 BONTAC NR BONTAC is one of the few suppliers in China that can launch mass production of raw materials for NR, with self-owned factory and professional R&D team. Up till now, there are 173 BONTAC patents. BONTAC provides one-stop service for customized products. Both malate and chloride salt forms of NR are available. By dirt of unique Bonpure seven-step purification technology and Bonzyme Whole-enzymatic method, the product content and conversion rate can be maintained in a higher level. The purity of BONTAC NR can reach above 97%. Our products are subjected to strict third-party self-inspection, which are worth of trustworthy. Disclaimer This article is based on the reference in the academic journal. The relevant information is provided for sharing and learning purposes only, and does not represent any medical advice purposes. If there is any infringement, please contact the author for deletion. The views expressed in this article do not represent the position of BONTAC. Under no circumstances will BONTAC be held responsible or liable in any way for any claims, damages, losses, expenses, or costs resulting or arising directly or indirectly from your reliance on the information and material on this website.