This work was financially supported by the National Natural Science Foundation of China (No. 82130113), the China Postdoctoral Science Foundation (No. 2021MD703800), the Science Foundation for Youths of Science &#38; Technology Department of Sichuan Province (No. 2022NSFSC1449), and the &#34;Xinglin Scholars&#34; Research Promotion Program of Chengdu University of Traditional Chinese Medicine (No. BSH2021009).

In this study, the processing technology of TBC processed with highland barley wine was optimized with a Box-Behnken design combined with the entropy method. DDA and MDA content were used as evaluation indicators, and the weight coefficient of each evaluation index was determined by the entropy method.
1. Experimental preparation
<ol>
	<li>Prepare highland barley wine15.
	<ol>
		<li>Take 500.00 g of black highland barley rice and add five times the amount of water. Cook the rice until the remaining water is absorbed (~2 h). Pour it out, wait until the temperature falls to 37 &#176;C, add 4 g of Jiuqu (see Table of Materials), mix well, seal the can, wrap the container with cotton wool, and let it stew for 7 days.</li>
		<li>Add 300 mL of water on the 7th day and seal again. On the 8th day, begin removing the wine and replace with 300 mL of water afterward. Seal and ferment for 1 day, take the wine, and add 300 mL of water again. Repeat this procedure three times and combine the liquors.</li>
		<li>Bring to a boil, then reduce the heat to a simmer, and continue cooking until the remaining water is absorbed.</li>
	</ol>
	</li>
	<li>To prepare processed products, accurately weigh the TBC in a container, add highland barley wine, and soak for 1 day. Then, dry in a constant temperature electric drying oven. 
	NOTE: The drying temperature should be less than 40 &#176;C to avoid changes in the alkaloid composition.</li>
	<li>Prepare test sample solution.
	<ol>
		<li>Accurately weigh TBC processed product powder (2 g) in a conical flask, add 40% ammonia solution, and perform ultrasound-assisted extraction with isopropanol-ethyl acetate (1:1) mixed solvents (50 mL) (power: 200 W; frequency: 40 kHz; temperature: 40 &#176;C) for 30 min. 
		NOTE: To prepare 40% ammonia solution, transfer 40 mL of ammonia to a 100 mL volumetric flask and then dilute with pure water.</li>
		<li>Adjust the extracted solution to the original weight by adding an isopropanol-ethyl acetate mixture (1:1 v/v).</li>
		<li>Accurately transfer the extracted solution (25 mL) to a round-bottom flask for the recovery of the solvent under reduced pressure until dry.</li>
		<li>Finally, transfer 0.05% hydrochloric acid-methanol solution to dissolve the residue from step 1.3.3 in a 5 mL volumetric flask and dilute with 0.05% methanol hydrochloride solution. Filter the solution through a 0.22 &#181;m microporous membrane filter prior to injection into the high-performance liquid chromatography (HPLC) systems. 
		NOTE: Prepare 0.05% methanol hydrochloride acid by adding 0.05 mL of hydrochloric acid to a 100 mL volumetric flask, then dilute with methanol.</li>
	</ol>
	</li>
	<li>Prepare a standard solution by weighing 5.18 mg of benzoylaconine, 13.13 mg of aconitine, 10.05 mg of 3-deoxyaconitine, and 10.09 mg of 3-acetylaconitine accurately, and then place the solids in a 5 mL volumetric flask individually. Dilute with 0.05% methanol hydrochloride solution.</li>
</ol>
2. Chromatographic condition
<ol>
	<li>Set up the chromatographic conditions as shown in Table 1 for HPLC. Details of the instruments used are provided in the Table of Materials.</li>
</ol>
3. System adaptability test
<ol>
	<li>Range of linearity 
	NOTE: First, we used HPLC to determine the peak areas of benzoylaconitine, aconitine, 3-deoxyaconitine, and 3-acetylaconitine in the sample, and then randomly determined the peak area of one known concentration of standard solution. Next, we compared the difference between two peak areas (sample solution and standard solution) to estimate the concentration of benzoylaconitine, aconitine, 3-deoxyaconitine, and 3-acetylaconitine in different samples, and then adjusted the standard solution into a linear range to include the concentration of the sample in the curve. The standard curve concentrations are shown in Table 2.
	<ol>
		<li>Prepare benzoylaconitine reference solutions containing 1.036 mg/mL, 0.518 mg/mL, 0.2072 mg/mL, 0.1036 mg/mL, and 0.0518 mg/mL.</li>
		<li>Prepare aconitine reference solutions containing 1.313 mg/mL, 0.5252 mg/mL, 0.2626 mg/mL, 0.1313 mg/mL, and 0.05252 mg/mL.</li>
		<li>Prepare 3-deoxyaconitine reference solutions containing 1.005 mg/mL, 0.5025 mg/mL, 0.201 mg/mL, 0.1005 mg/mL, and 0.402 mg/mL.</li>
		<li>Prepare 3-acetylaconitine reference solutions containing 0.2018 mg/mL, 0.1009 mg/mL, 0.04036 mg/mL, 0.02018 mg/mL, and 0.01009 mg/mL.</li>
		<li>Investigate the linearity of each compound by plotting the peak area versus injection concentration.</li>
	</ol>
	</li>
	<li>To perform the precision test, inject 10 &#181;L of each reference solution into the HPLC system six times daily and employ the same HPLC conditions described in step 2.1 to run the samples Record the peak area of each component.</li>
	<li>Perform intraday stability testing by injecting 10 &#181;L of the prepared sample solution via step 1.3 and determine the peak areas after 0 h, 2 h, 4 h, 8 h, 14 h, 12 h, and 24 h16.</li>
	<li>Perform a reproducibility test by taking six samples of the same batch of TBC to prepare the test sample solution, according to step 1.3. Inject 10 &#181;L of each sample into the HPLC system and run the samples as described in step 2.1.</li>
	<li>Perform the recovery test to evaluate the accuracy of the method. Add 100% of the standard solution of each index component (benzoylaconitine, aconitine, 3-deoxyaconitine, and 3-acetylaconitine) in the test solution to calculate the recovery rate, respectively. For example, as the content of benzoylaconitine is 0.1524 mg/mL in the TBC sample, accurately weigh 0.1524 mg of benzoylaconitine standards and add to the TBC sample, then prepare the test sample solution according to step 1.3. Run these samples with the same HPLC conditions described in step 2.1. Calculate the recovery rate using Equation (1): 
	<img alt="Equation 1" src="/files/ftp_upload/65154/65154eq01.jpg" style="margin: auto;" />&#160; &#160; (1) 
	Here, A is the amount of component (benzoylaconitine, aconitine, 3-deoxyaconitine, or 3-acetylaconitine) to be measured in the sample solution, B is the amount of standard added (benzoylaconitine, aconitine, 3-deoxyaconitine, or 3-acetylaconitine), and C is the measured value of the solution containing the standard solution and the sample solution (see Table 3). Refer to step 2.1 for the chromatographic conditions to perform the above steps. The recovery rate reflects the degree of loss of the target component (benzoylaconitine, aconitine, 3-deoxyaconitine, or 3-acetylaconitine) during the sample analysis; the higher the recovery rate, the lower the loss of the target component.</li>
</ol>
4. Single factor test of TBC processed with highland barley wine
NOTE: The ratio between highland barley wine and TBC, slice thickness of TBC, and soaking time will affect the dissolution of more toxic components (aconitine, 3-deoxyaconitine, and 3-acetylaconitine) in TBC during the TBC processed with highland barley wine17. The single factor test and Box-Behnken design were used to investigate the influence of the ratio of highland barley wine to TBC, slice thickness of TBC, and soaking time.
<ol>
	<li>Perform the highland barley wine addition test (A) by setting up five groups of tests, each with 30 g of TBC, where the amount of highland barley wine is two, three, four, five, and six times the amount of TBC in the recipe. The soaking time is 12 h, and the slices are 1.0 cm thick18. 
	NOTE: Each group of the same condition test should be processed in three parallel groups.</li>
	<li>Perform the soaking time test (B) by setting up five groups of tests, each with 30 g of TBC. The soaking times are 12 h, 24 h, 36 h, and 48 h. The amount of highland barley wine is five times that of TBC, and the slices are 1.0 cm thick19. 
	NOTE: Each group of the same condition experiment should be processed in three parallel groups.</li>
	<li>Perform the slicing thickness test (C) by setting up five groups of tests, each with 30 g of TBC. The slices are 0.5, 1.0, 1.5, 2.0, and 2.5 cm thick, the soaking time is 24 h, and the amount of highland barley wine is five times that of TBC20. 
	NOTE: Each group of the same condition experiment should be processed in three parallel groups.</li>
	<li>Accurately weigh processed products for each test group to prepare test sample solution according to step 1.3. Determine the peak area of each sample by HPLC and use the standard curve to estimate the amounts of MDAs and DDAs. In the standard curve, y is the peak area and x is the content. The content of MDAs is benzoyl aconitine, and the content of DDAs is the sum of aconitine, 3-deoxyaconitine, and 3-acetylaconitine.</li>
	<li>Use the total content of DDAs and the content of MDAs as evaluation indicators, and determine the weight coefficient of each evaluation index and the comprehensive scoring via the entropy method (section 5). 
	CAUTION: TBC is toxic, and thus protective measures should be taken during processing.</li>
</ol>
5. Entropy method to calculate the comprehensive scoring
NOTE: We use the experimental data of the slicing thickness test in the single factor test as an example to illustrate the calculation process in detail. We use the peak area of the components in each sample in Supplementary Table S1 and the standard curve in Table 2 to calculate the content of MDAs and DDAs (see Supplementary Table S2). In the linear equation, y is the peak area and x is the content. In this study, the moderately toxic MDA (benzoylaconitine) was used as the positive indicator, and the total content of DDAs (aconitine, 3-deoxyaconitine, and 3-acetylaconitine) with high toxicity was used as the negative indicator. The content of MDAs is benzoyl aconitine, and the content of DDAs is the sum of aconitine, 3-deoxyaconitine, and 3-acetylaconitine. Each sample has two evaluation indicators: i = 1,2,&#8230;,n, and j = 1,2,&#8230;m21.
<ol>
	<li>Use Equation (2) to standardize the content of MDAs22. 
	<img alt="Equation 2" src="/files/ftp_upload/65154/65154eq02.jpg" style="margin: auto;" />&#160; &#160; &#160;(2) 
	Thus, <img alt="Equation 3" src="/files/ftp_upload/65154/65154eq03.jpg" style="margin: auto;" /> 
	NOTE: Xij is the value of the j-th indicator of the i-th sample. Xij* is the standardized value of Xij. For example, i = 3 and j = 1, X31 represents the value of the first indicator of the third sample, and <img alt="Equation 4" src="/files/ftp_upload/65154/65154eq04.jpg" style="margin: auto;" /> is the standardized value of the first indicator in the third sample. <img alt="Equation 5" src="/files/ftp_upload/65154/65154eq05.jpg" style="margin: auto;" /> are shown in Supplementary Table S3.</li>
	<li>Use Equation (3) to standardize the total content of the DDAs23. 
	<img alt="Equation 6" src="/files/ftp_upload/65154/65154eq06.jpg" style="margin: auto;" />&#160; &#160; &#160;(3) 
	<img alt="Equation 7" src="/files/ftp_upload/65154/65154eq07.jpg" style="margin: auto;" /> 
	NOTE: Here, i = 3, j = 2, represents the second indicator of the third sample. <img alt="Equation 8" src="/files/ftp_upload/65154/65154eq08.jpg" style="margin: auto;" /> is the standardized value of the second indicator in the third sample. <img alt="Equation 9" src="/files/ftp_upload/65154/65154eq09.jpg" style="margin: auto;" /> are shown in Supplementary Table S3.</li>
	<li>Use Equations (4) and (5) to define the entropy value (Hj) of each indicator23.
	<ol>
		<li>Calculate the probability of the j-th trial under the i-th evaluation indicator Pij using equation (4). 
		<img alt="Equation 10" src="/files/ftp_upload/65154/65154eq10.jpg" style="margin: auto;" />&#160; &#160; &#160;(4) 
		For number 3, 
		<img alt="Equation 11" src="/files/ftp_upload/65154/65154eq11.jpg" style="margin: auto;" /> 
		<img alt="Equation 12" src="/files/ftp_upload/65154/65154eq12.jpg" style="margin: auto;" /> 
		&#8203;NOTE: The probability values for the first indicator and second indicator of the third sample are 0.2374 and 0.2812, respectively. <img alt="Equation 13" src="/files/ftp_upload/65154/65154eq13.jpg" style="margin: auto;" /> are shown in Supplementary Table S3.</li>
		<li>Calculate the information entropy Hj. 
		<img alt="Equation 14" src="/files/ftp_upload/65154/65154eq14.jpg" style="margin: auto;" />&#160; &#160; &#160;(5) 
		<img alt="Equation 15" src="/files/ftp_upload/65154/65154eq15.jpg" style="margin: auto;" /> 
		<img alt="Equation 16" src="/files/ftp_upload/65154/65154eq16.jpg" style="margin: auto;" /> 
		NOTE: H1 is the entropy of the first indicator (MDAs) and H2 is the entropy of the second indicator (DDAs) in the slicing thickness test.</li>
	</ol>
	</li>
	<li>Use Equation (6) to calculate the indicator weights (Wj)23. 
	<img alt="Equation 17" src="/files/ftp_upload/65154/65154eq17.jpg" style="margin: auto;" /> (6) 
	<img alt="Equation 18" src="/files/ftp_upload/65154/65154eq18.jpg" style="margin: auto;" />&#160; &#160;= 33.3% 
	<img alt="Equation 19" src="/files/ftp_upload/65154/65154eq19.jpg" style="margin: auto;" />&#160; &#160;= 66.7% 
	NOTE: Wj is the weight coefficient of each indicator. In the slicing thickness test, the weight coefficient of the positive indicator (MDAs) and negative indicator (DDAs) are 33.3% and 66.7%, respectively.</li>
	<li>Use Equation (7) to calculate the comprehensive scoring of the indicators23. 
	<img alt="Equation 20" src="/files/ftp_upload/65154/65451eq20v2.jpg" style="margin: auto;" /> (7) 
	For number 3, <img alt="Equation 21" src="/files/ftp_upload/65154/65154eq21.jpg" style="margin: auto;" /> 
	<img alt="Equation 22" src="/files/ftp_upload/65154/65154eq22.jpg" style="margin: auto;" /> 
	NOTE: Si is the comprehensive scoring of each sample. We need to obtain the highest score as the central point in the Box-Behnken design. S1, S2, S3, S4, and S5 are show in Supplementary Table S3.</li>
</ol>
6. Box-Behnken design
<ol>
	<li>Through the single factor test, use the condition with the highest comprehensive scoring (see Table 4, Table 5, Table 6, and Figure 2) as the center point of the response surface. Use the amount of highland barley wine (A), soaking time (B), and slice thickness of TBC (C) as the influencing factors and the comprehensive scoring as the response value24. 
	NOTE: Based on the single factor data in Table 4, Table 5, and Table 6, the highest comprehensive scoring is calculated by equations (2), (3), (4), (5), (6), and (7) in section 5, and the best point is obtained. The amount of highland barley wine was five times that of TBC, the soaking time was 36 h, and the slicing thickness was 1.0 cm.</li>
</ol>
7. Box-Behnken design software operation steps
<ol>
	<li>Open the software (see Table of Materials) and select New Design | Box-Behnken Design (see step 5.1; Supplementary File 1).
	<ol>
		<li>Input the number of influencing factors and input the level information (three-level-three-factor; see Table 7). The Box-Behnken design is composed of 17 experiments in this study. Finally, click Continue (see step 5.2; Supplementary File 1).</li>
		<li>Set the comprehensive scoring (Y) by equations (2), (3), (4), (5), (6), and (7) in section 5 as the response. Input the number of response values (image shows only one response value) and click Finish (see step 5.3; Supplementary File 1).</li>
		<li>Process the TBC with highland barley wine according to the design results and complete the experiment based on the 17 scenarios designed for the response surface.</li>
		<li>Prepare the sample solutions by following step 1.3 and calculate the total content of the MDAs and DDAs by the HPLC system.</li>
		<li>Calculate the comprehensive scoring for each group by equations (2), (3), (4), (5), (6), and (7) in step 5, and input the score results (see step 5.4; Supplementary File 1).</li>
	</ol>
	</li>
	<li>Click analyze to analyze the date and model information (see step 5.4.1; Supplementary File 1).
	<ol>
		<li>Perform statistical validation of polynomial equations and response surface analysis plotted in 3D model plots obtained by the software.</li>
		<li>Click on ANOVA in the top menu and observe the results table.</li>
	</ol>
	</li>
	<li>Click Optimization to view the predicted optimal process conditions (see step 5.4.2; Supplementary File 1).</li>
</ol>
8. Validation test
<ol>
	<li>According to the results predicted from the Box-Behnken response surface design, in step 7.3, identify the optimal processing condition of TBC. Here, it is as follows: TBC is soaked for 24 h in five times the amount of highland barley wine, and the thickness of the TBC is 1.5 cm. Take the optimal level of influencing factors as processing conditions and set up three parallel sets of experiments to verify the stability of the processing technology.</li>
</ol>

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C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Box-Behnken+design:+an+alternative+for+the+optimization+of+analytical+methods.">Box-Behnken design: an alternative for the optimization of analytical methods.</a> Analytica Chimica Acta. 597 (2), 179-186 (2007).</li><li>Dong, R., Lu, Y., Wang, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+process+optimization+of+vinegar+roasting+of+Bupleurum+chinense+by+entropy+weight+method+combined+with+Box-Behnken+response+surface+method+and+its+protective+effect+on+mice+liver+injury.">The process optimization of vinegar roasting of Bupleurum chinense by entropy weight method combined with Box-Behnken response surface method and its protective effect on mice liver injury.</a> Science and Technology of Food Industry. 42 (23), 209-217 (2021).</li><li>Li, W. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Analysis+on+the+times+of+Polygonati+Rhizoma+steamed+by+multiple+times+based+on+entropy+weight+and+gray+relative+analysis+method.">Analysis on the times of Polygonati Rhizoma steamed by multiple times based on entropy weight and gray relative analysis method.</a> China Journal of Traditional Chinese Medicine and Pharmacy. 36 (11), 6764-6769 (2021).</li><li>Huang, B. J., Liu, X. T., Mao, Y. M., Qi, B., Liu, L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Response+surface+methodology+combined+with+analytic+hierarchy+process+to+optimize+the+processing+technology+of+Custutae+semen+with+wine.">Response surface methodology combined with analytic hierarchy process to optimize the processing technology of Custutae semen with wine.</a> Lishizhen Medicine and Materia Medica Research. 33 (8), 1890-1894 (2022).</li><li>Wang, J., Meng, X. H., Chai, T., Yang, J. L., Shi, Y. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Diterpenoid+alkaloids+and+one+lignan+from+the+roots+of+Aconitum+pendulum+Busch.">Diterpenoid alkaloids and one lignan from the roots of Aconitum pendulum Busch.</a> Natural Products and Bioprospecting. 9 (6), 419-423 (2019).</li><li>Xie, H. H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Metabolomics+study+of+aconitine+and+benzoylaconine+induced+reproductive+toxicity+in+Be+Wo+cell.">Metabolomics study of aconitine and benzoylaconine induced reproductive toxicity in Be Wo cell.</a> Chinese Journal of Analytical Chemistry. 43 (12), 1808-1813 (2015).</li><li>Han, Y. F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Optimization+of+extraction+process+for+Yangyin+Runmu+granules+by+Box-Behnken+design+based+on+entropy+weight+method-analytic+hierarchy+process+method.">Optimization of extraction process for Yangyin Runmu granules by Box-Behnken design based on entropy weight method-analytic hierarchy process method.</a> Chinese Journal of Modern Applied Pharmacy. 39 (7), 896-903 (2022).</li><li>Chen, F. G., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Optimization+of+the+baked+drying+technology+of+Clinamomi+Ramulus+based+on+CRITIC+combined+with+Box-Behnken+response+surface+method.">Optimization of the baked drying technology of Clinamomi Ramulus based on CRITIC combined with Box-Behnken response surface method.</a> Journal of Chinese Medicinal Materials. 2022 (8), 1838-1842 (2022).</li><li>Pan, Y. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Optimization+of+stir-baking+process+of+Coix+lacryma-Jobi+Var.Mayuen+Kernel+by+Box-Behnken+response+surface+methodology.">Optimization of stir-baking process of Coix lacryma-Jobi Var.Mayuen Kernel by Box-Behnken response surface methodology.</a> Shandong Chemical Industry. 51 (14), 73-75 (2022).</li></ol>

The authors have no conflicts of interest to disclose.

As a commonly used Tibetan medicine with toxic effects, the toxicity-attenuating effect of processing is extremely important for TBC&#39;s clinical application25. In this study, the processing technology of TBC processed with highland barley wine was optimized. By reviewing the main active ingredients and relating the pharmacological effects of TBC, we found that TBC alkaloids have anti-inflammatory and analgesic effects and can be used to treat rheumatoid arthritis. In this study, a moderate toxi...

Tiebangchui (TBC), the dried root of Aconitum pendulum Busch, is a well-known Tibetan medicine and was initially recorded in the classic Tibetan medical book &#34;Four Medical Tantra&#34;1,2. According to &#34;Drug Standards of the Ministry of Health of the People&#39;s Republic of China (Tibetan Medicine)&#34;, TBC is effective in expelling cold, relieving pain, dispelling wind, and calming shock, and is commonly used to treat rheumatoid arthritis in clinics3,4,5.
TBC mainly contains alkaloids, including highly toxic diester-diterpenoid alkaloids (DDAs), and the moderately toxic monoester-diterpenoid alkaloids (MDAs)6,7,8. These chemical components are active ingredients with medicinal effects but are toxic. One of the most famous active and toxic ingredients, aconitine, causes poisoning when it exceeds 1 mg9. Therefore, improper or excessive use of TBC might result in poisoning and even death, and the toxicity attenuation and efficacy reservation of TBC is crucial for its safe clinical application10,11.
Processing is an effective method for detoxifying TBC. According to ancient Tibetan medicine books, processing with highland barley wine is an efficient way to attenuate toxicity and preserve the efficacy of TBC. TBC is soaked in highland barley wine, stored for one night, dried, and added to medicines12. However, the specific processing technology and potential influencing factors are rarely reported, and the traditional processing process often relies on experience and lacks standardized methods. Hence, modern scientific and technological methods for optimizing and standardizing the processing process are needed.
The Box-Behnken design method is used in investigating interactions among different factors and their influence on comprehensive scoring through quadratic polynomial fitting. This design allows the intuitive observation of optimal conditions and has been widely used in the field of pharmacy13. For example, the Box-Behnken design method, based on the entropy method, successfully optimized the processing technology of stir-frying with vinegar of Curcuma Longa Radix14. In this study, the Box-Behnken response surface experimental design combined with the entropy method was used in optimizing the processing technology of TBC processed with highland barley wine. The optimized processing technology is expected to ensure quality control and safe clinical use.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Aconitine</td>
			<td>Chengdu Push Biotechnology Co.,Ltd</td>
			<td>PS000905</td>
			<td></td>
		</tr>
		<tr>
			<td>3-Acetylaconitine</td>
			<td>Chengdu Push Biotechnology Co.,Ltd</td>
			<td>PS010552</td>
			<td></td>
		</tr>
		<tr>
			<td>3-Deoxyaconitine</td>
			<td>Chengdu Push Biotechnology Co.,Ltd</td>
			<td>PS011258</td>
			<td></td>
		</tr>
		<tr>
			<td>Benzoylaconine</td>
			<td>Chengdu Push Biotechnology Co.,Ltd</td>
			<td>PS010300</td>
			<td></td>
		</tr>
		<tr>
			<td>Circulating water vacuum pump</td>
			<td>Gongyi City Yuhua Instrument Co., Ltd</td>
			<td>SHZ-DIII</td>
			<td></td>
		</tr>
		<tr>
			<td>Design-Expert&#160;</td>
			<td>State-East Corporation</td>
			<td>8.0.6</td>
			<td></td>
		</tr>
		<tr>
			<td>Electric constant temperature drying oven</td>
			<td>Shanghai Yuejin Medical Equipment Co., Ltd</td>
			<td>101-3-BS</td>
			<td></td>
		</tr>
		<tr>
			<td>Electronic analytical balance</td>
			<td>Shanghai Liangping Instruments Co., Ltd.</td>
			<td>FA1004</td>
			<td></td>
		</tr>
		<tr>
			<td>High performance liquid chromatography</td>
			<td>Shimadzu Enterprise Management (China) Co., Ltd</td>
			<td>shimadzu 2030</td>
			<td></td>
		</tr>
		<tr>
			<td>Highland barley rice</td>
			<td>Kangding City, Ganzi Tibetan Autonomous Prefecture, Sichuan Province</td>
			<td>20221015</td>
			<td></td>
		</tr>
		<tr>
			<td>Millipore filter</td>
			<td>Tianjin Jinteng Experimental Equipment Co., Ltd</td>
			<td>&#966;13 0.22 Nylon66</td>
			<td></td>
		</tr>
		<tr>
			<td>Rotary evaporator</td>
			<td>Shanghai Yarong Biochemical Instrument Factory</td>
			<td>RE-2000A</td>
			<td></td>
		</tr>
		<tr>
			<td>Starter of liquor-making</td>
			<td>Angel Yeast CO., Ltd</td>
			<td>BJ22-104</td>
			<td></td>
		</tr>
		<tr>
			<td>Ultra pure water systemic</td>
			<td>Merck Millipore Ltd.</td>
			<td>Milli-Q</td>
			<td></td>
		</tr>
		<tr>
			<td>Ultrasonic cleansing machine</td>
			<td>Ningbo Xinyi Ultrasonic Equipment Co., Ltd</td>
			<td>SB-8200 DTS</td>
			<td></td>
		</tr>
	</tbody>
</table>

optimization of processing of tiebangchui with highland barley wine based on the box-behnken design combined with the entropy method

The processing of toxic ethnomedicines is of great significance for their safe clinical application. Thus, the limitations of traditional processing should be addressed, and the processing method of ethnomedicines should be standardized using modern research methods. In this study, the processing technology of a commonly used Tibetan medicine Tiebangchui (TBC), the dried root of Aconitum pendulum&#160;Busch, processed with highland barley wine was optimized. Diester-diterpenoid alkaloid (DDA) (aconitine, 3-deoxyaconitine, 3-acetylaconitine) and monoester-diterpenoid alkaloid (MDA) (benzoylaconine) content were used as evaluation indicators, and the weight coefficient of each evaluation index was determined by the entropy method.
The single factor test and Box-Behnken design were used in investigating the influence of the ratio between highland barley wine and TBC, slice thickness of TBC, and processing time. Comprehensive scoring was performed according to the objective weight of each index determined by the entropy method. The optimal processing conditions of TBC with highland barley wine were as follows: the amount of highland barley wine is five times that of TBC, a soaking time of 24 h, and a TBC thickness of 1.5 cm. The results showed that the relative standard deviation between the verification test and predicted value was less than 2.55% and the optimized processing technology of TBC processed with highland barley wine is simple, feasible, and stable, and so can provide a reference for industrial production.

In this study, the precision, stability, repeatability, and sample recovery of TBC indicated that the method is feasible. The four index components in TBC had a good linear relationship within a specific concentration range. Typical chromatograms are shown in Figure 1. The precision test results (Table 8) showed that the relative standard deviation (RSD) of the peak areas were 2.56%, 1.49%, and 2.03% for benzoylaconine, aconitine, and 3-deoxyaconitine, respectively, and 0.21...

Watch this Scientific Journal Video about Optimization of Processing of Tiebangchui with Highland Barley Wine Based on the Box-Behnken Design Combined with the Entropy Method at JoVE.com

Optimization of Processing of Tiebangchui with Highland Barley Wine Based on the Box-Behnken Design Combined with the Entropy Method

The present protocol describes an efficient method for optimization of the processing technology of Tiebangchui processed with highland barley wine based on a Box-Behnken design response surface combined with the entropy method.

The processing of toxic ethnomedicines is of great significance for their safe clinical application. Thus, the limitations of traditional processing ...

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542 Views.  Chengdu University of Traditional Chinese Medicine. The present protocol describes an efficient method for optimization of the processing technology of Tiebangchui processed with highland barley wine based on a Box-Behnken design response surface combined with the entropy method.

Video: Optimization of Processing of Tiebangchui with Highland Barley Wine Based on the Box-Behnken Design Combined with the Entropy Method

Techniques for Processing Eyes Implanted with a Retinal Prosthesis for Localized Histopathological Analysis: Part 2 Epiretinal Implants with Retinal Tacks

Retinal prostheses for the treatment of certain forms of blindness are gaining traction in clinical trials around the world with commercial devices currently entering the market. In order to evaluate the safety of these devices, in preclinical studies, reliable techniques are needed. However, the hard metal components utilised in some retinal implants are not compatible with traditional histological processes, particularly in consideration for the delicate nature of the surrounding tissue. Here we describe techniques for assessing the health of the eye directly adjacent to a retinal implant secured epiretinally with a metal tack.
Retinal prostheses feature electrode arrays in contact with eye tissue. The most commonly used location for implantation is the epiretinal location (posterior chamber of the eye), where the implant is secured to the retina with a metal tack that penetrates all the layers of the eye. Previous methods have not been able to assess the proximal ocular tissue with the tack in situ, due to the inability of traditional histological techniques to cut metal objects. Consequently, it has been difficult to assess localized damage, if present, caused by tack insertion.
Therefore, we developed a technique for visualizing the tissue around a retinal tack and implant. We have modified an established technique, used for processing and visualizing hard bony tissue around a cochlear implant, for the soft delicate tissues of the eye. We orientated and embedded the fixed eye tissue, including the implant and retinal tack, in epoxy resin, to stabilise and protect the structure of the sample. Embedded samples were then ground, polished, stained, and imaged under various magnifications at incremental depths through the sample. This technique allowed the reliable assessment of eye tissue integrity and cytoarchitecture adjacent to the metal tack.

Here we describe histological techniques for visualising ocular tissue directly adjacent to a metal epiretinal tack and retinal prosthesis.

Retinal prostheses for the treatment of certain forms of blindness are gaining traction in clinical trials around the world with commercial devices ...

Application of Laparoscopic Hepatectomy Combined with Intraoperative Microwave Ablation in Colorectal Cancer Liver Metastasis

Laparoscopic hepatectomy is a common treatment for colorectal cancer liver metastasis. Previously, a sufficient number of functional liver masses had to be maintained during laparoscopic hepatectomy, with a residual liver volume of &gt;40% in cirrhotic patients and &gt;30% in non-cirrhotic patients. The high incidence of complications such as bleeding, bile leakage, or liver failure due to the exposure and difficulty of the resection of specific liver segments such as S2 and S7 reduces the success rate of liver resection. At present, microwave ablation is mainly applied in the treatment of liver metastasis using a percutaneous approach, which makes it difficult to identify hidden parts or small lesions. For some liver segments, the percutaneous puncture of liver segment 7 (S7) is likely to pass through the thoracic cavity, and the percutaneous puncture of liver segment 2 (S2) adjacent to the diaphragm is likely to injure the diaphragm and heart; these issues restrict the application of percutaneous ablation in colorectal cancer liver metastasis. Considering multiple lesions, laparoscopic microwave ablation combined with hepatectomy was performed in this study. The location of the lesions was determined by contrast-enhanced ultrasound under laparoscopy, and small lesions that were difficult to detect before the operation were identified. For the scattered lesions, which had diameters less than 3 cm and were difficult to resect, ablation was adopted to substitute hepatectomy. This technique helped to more explicitly locate the tumors, simplified the operation procedures, reduced the risk of complications such as bleeding and bile leakage, shortened the operation time, accelerated the postoperative recovery, significantly improved the success rate of operation, and enhanced the clinical prognosis of colorectal cancer liver metastasis by surgical resection.

This protocol describes the laparoscopic resection of colorectal cancer liver metastases combined with ultrasound-guided microwave ablation. This technique can safely, effectively, and accurately treat refractory liver metastases &lt;3 cm, reduce postoperative complications, and accelerate the postoperative rehabilitation of patients.

Laparoscopic hepatectomy is a common treatment for colorectal cancer liver metastasis. Previously, a sufficient number of functional liver masses had to ...

Optimization of the Epimedii Folium Mutton-Oil Processing Technology and Testing Its Effect on Zebrafish Embryonic Development

As a traditional Chinese medicine (TCM), Epimedii folium (EF) has a history in medicine and food that is &#62; 2,000 years old. Clinically, EF processed with mutton oil is often used as a medicine. In recent years, reports of safety risks and adverse reactions of products that use EF as a raw material have gradually increased. Processing can effectively improve the safety of TCM. According to TCM theory, mutton-oil processing can reduce the toxicity of EF and enhance its tonifying effect on the kidneys. However, there is a lack of systematic research and evaluation of EF mutton-oil processing technology. In this study, we used the Box-Behnken experimental design-response surface methodology to optimize the key parameters of the processing technology by assessing the contents of multiple components. The results showed that the optimal mutton-oil processing technology of EF was as follows: heating the mutton oil at 120 &#176;C &#177; 10 &#176;C, adding the crude EF, stir-frying it gently to 189 &#176;C &#177; 10 &#176;C until it is evenly shiny, and then removing it and cool. For every 100 kg of EF, 15 kg of mutton oil should be used. The toxicities and teratogenicities of an aqueous extract of crude and mutton-oil processed EF were compared in a zebrafish embryo developmental model. The results showed that the crude herb group was more likely to cause zebrafish deformities, and its half-maximal lethal EF concentration was lower. In conclusion, the optimized mutton-oil processing technology was stable and reliable, with good repeatability. At a certain dose, the aqueous extract of EF was toxic to the development of zebrafish embryos, and the toxicity was stronger for the crude drug than for the processed drug. The results showed that mutton-oil processing reduced the toxicity of crude EF. These findings can be used to improve the quality, uniformity, and clinical safety of mutton oil-processed EF.

In this protocol, the mutton-oil processing technology of Epimedii folium (EF) was optimized by applying a Box-Behnken experimental design-response surface methodology, and the effect of crude and optimized water-extracted EF on zebrafish embryonic development was preliminarily investigated.

As a traditional Chinese medicine (TCM), Epimedii folium (EF) has a history in medicine and food that is &#62; 2,000 years old. Clinically, EF processed ...

A Method for Zanba-Stir-Fried Tiebangchui Process Optimization

Optimization of Processing Technology for Tiebangchui with Zanba Based on CRITIC Combined with Box-Behnken Response Surface Method

The dried root of Aconitum pendulum Busch., called Tiebangchui (TBC) in Chinese, is one of the most famous Tibetan medicines. It is a widely used herb in northwest China. However, many cases of poisoning have occurred because of TBC's intense toxicity and because its therapeutic and toxic doses are similar. Therefore, finding a safe and effective method to reduce its toxicity is an urgent task. A search through the Tibetan medicine classics shows that the processing method of TBC stir-fried with Zanba was recorded in the "Processing specification of Tibetan medicine of Qinghai Province (2010)". However, the specific processing parameters are not yet clear. Thus, this study aims to optimize and standardize the processing technology of Zanba-stir-fried TBC.
First, a single-factor experiment was conducted on four factors: the slice thickness of TBC, amount of Zanba, processing temperature, and time. With monoester and diester alkaloid contents in Zanba-stir-fried TBC as indexes, CRITIC combined with the Box-Behnken response surface method was used to optimize the processing technology of Zanba-stir-fried TBC. The optimized processing conditions of Zanba-stir-fried TBC were a TBC slice thickness of 2 cm, three times more Zanba than TBC, a processing temperature of 125 &#176;C, and 60 min of stir-frying. This study determined the optimized and standard processing conditions for the usage of Zanba-stir-fried TBC, thus providing an experimental basis for the safe clinical use and industrial production of Zanba-stir-fried TBC.

Author Spotlight: Optimization of Processing Technology for Tiebangchui with Zanba Based on CRITIC Combined with Box-Behnken Response Surface Method  

The present protocol describes an efficient and standard detoxification processing method for Zanba-stir-fried Tiebangchui using CRITIC combined with the Box-Behnken response surface method.

The dried root of Aconitum pendulum Busch., called Tiebangchui (TBC) in Chinese, is one of the most famous Tibetan medicines. It is a widely used herb in ...

Modified Laparoscopic Anatomic Hepatectomy: Two-Surgeon Technique Combined with the Simple Extracorporeal Pringle Maneuver

Laparoscopic anatomic hepatectomy (LAH) has become increasingly prevalent worldwide in recent years. However, LAH remains a challenging procedure due to the anatomical characteristics of the liver, with intraoperative hemorrhage being a primary concern. Intraoperative blood loss is the leading cause of conversion to open surgery; therefore, effective management of bleeding and hemostasis is crucial for a successful LAH.
The two-surgeon technique is proposed as an alternative to the traditional single-surgeon approach, with potential benefits in reducing intraoperative bleeding during laparoscopic hepatectomy. However, there remains a lack of evidence to determine which mode of the two-surgeon technique yields superior patient outcomes. Besides, to our knowledge, the LAH technique, which involves the use of a cavitron ultrasonic surgical aspirator (CUSA) by the primary surgeon while an ultrasonic dissector by the second surgeon, has been rarely reported before.
Herein, we present a modified, two-surgeon LAH technique, wherein one surgeon employs a CUSA while the other uses an ultrasonic dissector. This technique is combined with a simple extracorporeal Pringle maneuver and low central venous pressure (CVP) approach. In this modified technique, the primary and secondary surgeons utilize a laparoscopic CUSA and an ultrasonic dissectorconcurrently to achieve precise and expeditious hepatectomy. A simple extracorporeal Pringle maneuver, combined with the maintenance of low CVP, is employed to regulate the hepatic inflow and outflow in order to minimize intraoperative bleeding. This approach facilitates the attainment of a dry and clean operative field, which allows for the precise ligation and dissection of blood vessels and bile ducts. The modified LAH procedure is simpler and safer due to its effective control over bleeding as well as the seamless transition between the roles of primary and secondary surgeons. It holds great promise for future clinical applications.

Here, we present a protocol to perform a modified laparoscopic anatomic hepatectomy using improved techniques and instruments.

Laparoscopic anatomic hepatectomy (LAH) has become increasingly prevalent worldwide in recent years. However, LAH remains a challenging procedure due to ...

Quantitative Analysis of Liver Stiffness Distribution

A Three-Dimensional Digital Model for Early Diagnosis of Hepatic Fibrosis Based on Magnetic Resonance Elastography

Hepatic fibrosis is an early stage of liver cirrhosis, and there are no better non-invasive and convenient methods for the detection and evaluation of the disease. Despite the good progress made with the liver stiffness map (LSM) based on magnetic resonance elastography (MRE), there are still some limitations that need to be overcome, including manual focus determination, manual selection of regions of interest (ROIs), and discontinuous LSM data without structural information, which makes it impossible to evaluate the liver as a whole. In this study, we propose a novel three-dimensional (3D) digital model for the early diagnosis of hepatic fibrosis based on MRE.
MRE is a non-invasive imaging technique that employs magnetic resonance imaging (MRI) to measure the liver stiffness at the scanning site through human-computer interaction. Studies have indicated a significant positive correlation between the LSM obtained through MRE and the degree of hepatic fibrosis. However, for clinical purposes, a comprehensive and precise quantification of the degree of hepatic fibrosis is necessary. To address this, the concept of Liver Stiffness Distribution (LSD) was proposed in this study, which refers to the 3D stiffness volume of each liver voxel obtained by the alignment of 3D liver tissue images and MRE indicators. This provides a more effective clinical tool for the diagnosis and treatment of hepatic fibrosis.

Author Spotlight: Advancing Hepatic Fibrosis Diagnosis Using Magnetic Resonance Elastography and AI 

The objective of this study was to develop a novel three-dimensional digital model for the early diagnosis of hepatic fibrosis, which includes the stiffness of each voxel in the patient's liver and can thus, be used to calculate the distribution ratio of the patient's liver at different fibrosis stages.

Hepatic fibrosis is an early stage of liver cirrhosis, and there are no better non-invasive and convenient methods for the detection and evaluation of the ...

Preparing Zanba-Stir-Fried Tiebangchui (TBC) Sample for Processing Technology Optimization

Response Surface Methodology (RSM) for Processing Technology Optimization of Zanba-Stir-Fried Tiebangchui (TBC)

Enhancing Pulmonary Nodule Diagnosis Using Whole-Lung 3D Reconstruction

Three-Dimensional Reconstruction for the Whole Lung with Early Multiple Pulmonary Nodules

For patients with early multiple pulmonary nodules, it is essential, from a diagnostic perspective, to determine the spatial distribution, size, location, and relationship with surrounding lung tissue of these nodules throughout the entire lung. This is crucial for identifying the primary lesion and developing more scientifically grounded treatment plans for doctors. However, pattern recognition methods based on machine vision are susceptible to false positives and false negatives and, therefore, cannot fully meet clinical demands in this regard. Visualization methods based on maximum intensity projection (MIP) can better illustrate local and individual pulmonary nodules but lack a macroscopic and holistic description of the distribution and spatial features of multiple pulmonary nodules.
Therefore, this study proposes a whole-lung 3D reconstruction method. It extracts the 3D contour of the lung using medical image processing technology against the background of the entire lung and performs 3D reconstruction of the lung, pulmonary artery, and multiple pulmonary nodules in 3D space. This method can comprehensively depict the spatial distribution and radiological features of multiple nodules throughout the entire lung, providing a simple and convenient means of evaluating the diagnosis and prognosis of multiple pulmonary nodules.

Author Spotlight: Advancing 3D Modeling for Enhanced Diagnosis and Treatment of Pulmonary Nodules in Early-Stage Lung Cancer 

This study introduces a three-dimensional (3D) reconstruction method for the entire lung in patients with early multiple pulmonary nodules. It offers a comprehensive visualization of nodule distribution and their interplay with lung tissue, simplifying the assessment of diagnosis and prognosis for these patients.

For patients with early multiple pulmonary nodules, it is essential, from a diagnostic perspective, to determine the spatial distribution, size, location, ...

Establishment of the KOA Model in Rabbits Using the Modified Videman Method

Application of Acupotomy in a Knee Osteoarthritis Model in Rabbit

Knee osteoarthritis (KOA) is one of the most frequently encountered diseases in the orthopedic department, which seriously reduces the quality of life of people with KOA. Among several pathogenic factors, the biomechanical imbalance of the knee joint is one of the main causes of KOA. Acupotomology believes that restoring the mechanical balance of the knee joint is the key to treating KOA. Clinical studies have shown that acupotomy can effectively reduce pain and improve knee mobility by reducing adhesion, contracture of soft tissues, and stress concentration points in muscles and tendons around the knee joint. 
In this protocol, we used the modified Videman method to establish a KOA model by immobilizing the left hindlimb in a straight position. We have outlined the method of operation and the precautions related to acupotomy in detail and evaluated the efficacy of acupotomy in conjunction with the theory of "Modulating Muscles and Tendons to Treat Bone Disorders" through the detection of the mechanical properties of quadriceps femoris and tendon, as well as cartilage mechanics and morphology. The results show that acupotomy has a protective effect on cartilage by adjusting the mechanical properties of the soft tissues around the knee joint, improving the cartilage stress environment, and delaying cartilage degeneration.

Author Spotlight: Investigating the Mechanism of Action of Acupotomy in Treating Knee Osteoarthritis

In this protocol, a knee osteoarthritis model was prepared using the modified Videman method, and the operation procedures and precautions of acupotomy are detailed. The effectiveness of acupotomy has been demonstrated by testing the mechanical properties of quadriceps femoris and tendon and the mechanical and morphological properties of cartilage.

Knee osteoarthritis (KOA) is one of the most frequently encountered diseases in the orthopedic department, which seriously reduces the quality of life of ...