Computed tomography-based multi-organ radiomics nomogram model for predicting the risk of esophagogastric variceal bleeding in cirrhosis.

BACKGROUND: Radiomics has been used in the diagnosis of cirrhosis and prediction of its associated complications. However, most current studies predict the risk of esophageal variceal bleeding (EVB) based on image features at a single level, which results in incomplete data. Few studies have explored the use of global multi-organ radiomics for non-invasive prediction of EVB secondary to cirrhosis. AIM: To develop a model based on clinical and multi-organ radiomic features to predict the risk of first-instance secondary EVB in patients with cirrhosis. METHODS: In this study, 208 patients with cirrhosis were retrospectively evaluated and randomly split into training (n = 145) and validation (n = 63) cohorts. Three areas were chosen as regions of interest for extraction of multi-organ radiomic features: The whole liver, whole spleen, and lower esophagus-gastric fundus region. In the training cohort, radiomic score (Rad-score) was created by screening radiomic features using the inter-observer and intra-observer correlation coefficients and the least absolute shrinkage and selection operator method. Independent clinical risk factors were selected using multivariate logistic regression analyses. The radiomic features and clinical risk variables were combined to create a new radiomics-clinical model (RC model). The established models were validated using the validation cohort. RESULTS: The RC model yielded the best predictive performance and accurately predicted the EVB risk of patients with cirrhosis. Ascites, portal vein thrombosis, and plasma prothrombin time were identified as independent clinical risk factors. The area under the receiver operating characteristic curve (AUC) values for the RC model, Rad-score (liver + spleen + esophagus), Rad-score (liver), Rad-score (spleen), Rad-score (esophagus), and clinical model in the training cohort were 0.951, 0.930, 0.801, 0.831, 0.864, and 0.727, respectively. The corresponding AUC values in the validation cohort were 0.930, 0.886, 0.763, 0.792, 0.857, and 0.692. CONCLUSION: In patients with cirrhosis, combined multi-organ radiomics and clinical model can be used to non-invasively predict the probability of the first secondary EVB.

Sampling of N-methyl-N-nitrosourea-induced Rat's Retina Damage and Multi-index Evaluation of Pathological Changes.

Retinopathy can be observed in most ocular diseases and the late complications of diabetes mellitus. The specific pigment epithelial cells and optic cells' damage and degeneration are the main features of retinopathy. Many traditional medicines have shown substantial clinical efficacy in treating retinopathy. How to obtain a retina quickly and completely is a key step in traditional medicine research for the treatment of retinopathy. In this study, we aim to provide a standardized and exercisable procedure for sampling of N-methyl-N-nitrosourea (MNU)-induced rat's retina damage and multi-index evaluation of pathological changes. Rats were injected intraperitoneally with 60 mg/kg MNU once to induce retina damage, and retina samples were obtained after 7 days. Additionally, we performed hematoxylin-eosin staining to assess retinal pathological changes. Determination of the apoptosis rate and apoptosis protein by TUNEL and Western blot. These standardized protocols for retinal sampling and evaluation of pathological changes are helpful in promoting the exploration of the mechanism of retinopathy and the discovery of novel and effective traditional herbs.

Research progress of traditional Chinese medicine in the treatment of ischemic stroke by regulating mitochondrial dysfunction.

Ischemic stroke (IS) is a severe cerebrovascular disease with increasing incidence and mortality rates in recent years. The pathogenesis of IS is highly complex, with mitochondrial dysfunction playing a critical role in its onset and progression. Thus, preserving mitochondrial function is a pivotal aspect of treating ischemic brain injury. In response, there has been growing interest among scholars in the regulation of mitochondrial function through traditional Chinese medicine (TCM), including herb-derived compounds, individual herbs, and herbal prescriptions. This article reviews recent research on the mechanisms of mitochondrial dysfunction in IS and explores the potential of TCM in treating this condition by targeting mitochondrial dysfunction.

Discovery of novel 5-phenyl-1H-pyrrole-2-carboxylic acids as Keap1-Nrf2 inhibitors for acute lung injury treatment.

Oxidative stress is intricately linked to acute lung injury (ALI) and cerebral ischemic/reperfusion (I/R) injury. The Keap1 (Kelch-like ECH-Associating protein 1)-Nrf2 (nuclear factor erythroid 2-related factor 2)-ARE (antioxidant response element) signaling pathway, recognized as a crucial regulatory mechanism in oxidative stress, holds immense potential for the treatment of both diseases. In our laboratory, we initially screened a compound library and identified compound 3, which exhibited a dissociation constant of 5090 nM for Keap1. To enhance its binding affinity, we developed a novel 5-phenyl-1H-pyrrole-2-carboxylic acid Keap1-Nrf2 inhibitor through scaffold hopping from compound 3. Structure-activity relationship studies identified compound 19 as the most potent, with a KD2 of 42.2 nM against Keap1. Furthermore, compound 19 showed significant protection against LPS-induced injury in BEAS-2B cells and promoted Nrf2 nuclear translocation. Subsequently, we investigated its therapeutic effects in mouse models of ALI injury. Compound 19 effectively alleviated symptoms at doses of 15 mg/kg for ALI injury. Additionally, it facilitated Nrf2 translocation to the nucleus, increased Nrf2 levels, and upregulated the expression of HO-1 and NQO1 in affected tissues.

Research progress of circular RNAs in myocardial ischemia.

Circular RNAs (circRNAs) are a type of single-stranded RNA that forms a covalently closed continuous loop. Its structure, stability, properties, and cell- and tissue-specificity have gained considerable recognition in the research and clinical sectors, as its role has been observed in different diseases, such as cardiovascular diseases, cancers, and central nervous system diseases, etc. Cardiovascular disease is still named as the number one cause of death globally, with myocardial ischemia (MI) accounting for 15 % of mortality annually. A number of circRNAs have been identified and are being studied for their ability to reduce MI by inhibiting the molecular mechanisms associated with myocardial ischemia reperfusion injury, such as inflammation, oxidative stress, autophagy, apoptosis, and so on. CircRNAs play a significant role as crucial regulatory elements at transcriptional levels, regulating different proteins, and at posttranscriptional levels, having interactions with RNA-binding proteins, ribosomal proteins, micro-RNAS, and long non-coding RNAS, making it possible to exert their effects through the circRNA-miRNA-mRNA axis. CircRNAs are a potential novel biomarker and therapeutic target for myocardial ischemia and cardiovascular diseases in general. The purpose of this review is to summarize the relationship, function, and mechanism observed between circRNAs and MI injury, as well as to provide directions for future research and clinical trials.

Study on the anti-mitochondrial apoptosis mechanism of Erigeron breviscapus injection based on UPLC-Q-TOF-MS metabolomics and molecular docking in rats with cerebral ischemia-reperfusion injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Erigeron breviscapus is a common medicine of eight ethnic minorities, including Miao, Naxi, and Yi. As early as the Ming Dynasty (AD 1368-1644), Lanmao's Materia Medica of Southern Yunnan (AD 1436) recorded that the medicine is used for the treatment of "Zuo tan you huan." In modern pharmacological research, Erigeron breviscapus injection is the most commonly used preparation in the treatment of ischemic stroke caused by acute cerebral infarction, but its mechanism of action in the treatment of ischemic stroke is not well understood. AIM OF THE STUDY: In this study, a metabonomics study based on ultraperformance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-QTOF-MS) was used in investigating the effect of a traditional Chinese medicine preparation Erigeron breviscapus injection on the rat model of focal cerebral ischemia-reperfusion and the affinity of its main components with the targets of mitochondrial apoptotic pathways. MATERIALS AND METHODS: This study used molecular docking technology to verify the effective binding ability of main effective components of Erigeron breviscapus injection to target proteins related to mitochondrial apoptosis pathway. This study developed a metabonomics method based on the ultra-performance liquid chromatography combined with quadrupole time-of-flight tandem mass spectrometry (UPLC Q-TOF MS) to evaluate the efficacy and study the mechanism of traditional Chinese medicine preparation. With pattern recognition analysis (principal component analysis and partial least squares-discriminate analysis) of urinary metabolites, a clear separation of focal cerebral ischemia-reperfusion model group and healthy control group was achieved. RESULTS: Erigeron breviscapus injection can significantly reduce the area of cerebral infarction, improve tissue morphological lesion in rats, and can increase the number of Nissl bodies. It may be a promoting factor by inhibiting hippocampal nerve cell apoptosis and Bax protein expression and by exerting effects against ischemia reperfusion after the induction of apoptosis. Thus, it plays a role in brain protection. Moreover, it can considerably promote the recovery of neurological deficiency signs in advance. Meanwhile, Erigeron breviscapus decreased malondialdehyde content and T-NOS activity. Its curative effect from strong to weak order: low dose > high dose > medium dose. The representative components of Erigeron breviscapus have good affinity with the active sites of mitochondrial apoptosis-related proteins. Metabolomics found that the potential biomarkers regulated by breviscapine are kynurequinolinic acid, succinylornithine, and leucine proline. It is speculated that it may participate in TRP-kynurequinolinic acid and succinylornithine-urea cycle-NO metabolic pathways. CONCLUSIONS: This paper revealed the potential biomarkers and metabolic pathways regulated by Erigeron breviscapus. It was speculated that the mechanism is related to its inhibition of mitochondrion-mediated apoptosis. Erigeron breviscapus could restore the metabolic profiles of the model animals to normal animal levels. The mechanism may be related to the potential biomarkers of quinolinic acid, succinylornithine, and leucine proline and the metabolic pathways involved. However, the exact mechanism by which Erigeron breviscapus inhibits mitochondrion-mediated apoptosis remains to be further explored.

Barrier Functional Integrity Recording on bEnd.3 Vascular Endothelial Cells via Transendothelial Electrical Resistance Detection.

The blood-brain barrier (BBB) is a dynamic physiological structure composed of microvascular endothelial cells, astrocytes, and pericytes. By coordinating the interaction between restricted transit of harmful substances, nutrient absorption, and metabolite clearance in the brain, the BBB is essential in preserving central nervous system homeostasis. Building in vitro models of the BBB is a valuable tool for exploring the pathophysiology of neurological disorders and creating pharmacological treatments. This study describes a procedure for creating an in vitro monolayer BBB cell model by seeding bEnd.3 cells into the upper chamber of a 24-well plate. To assess the integrity of cell barrier function, the conventional epithelial cell voltmeter was used to record the transmembrane electrical resistance of normal cells and CoCl2-induced hypoxic cells in real-time. We anticipate that the above experiments will provide effective ideas for the creation of in vitro models of BBB and drugs to treat disorders of central nervous system diseases.

Observation of the Systolic Function of Isolated Right Atria from Guinea Pigs.

Common chronic heart failure (CHF) is characterized by impaired ventricular filling and/or ejection function, which leads to insatiable cardiac output and increased incidence. The decline in cardiac systolic function is a key factor in the pathogenesis of CHF. Systolic function is simply the filling of oxygenated blood in the left ventricle, followed by the blood being pumped throughout the body during a heartbeat. A weak heart and the inability of the left ventricle to contract appropriately as the heart beats indicate poor systolic function. Many traditional herbs have been suggested to strengthen the systolic function of the heart in patients. However, stable and efficient experimental methods for screening compounds that enhance myocardial contractility are still lacking in the process of ethnic medicine research. Here, taking digoxin as an example, a systematic and standardized protocol is provided for screening compounds that enhance myocardial contractility by using isolated right atria from guinea pigs. The results showed that digoxin could markedly enhance the contractility of the right atrium. This systematic and standardized protocol is intended to serve as a methodological reference for screening the active ingredients of ethnic medicines in the treatment of CHF.

Corrigendum: Review of phytomedicine, phytochemistry, ethnopharmacology, toxicology, and pharmacological activities of Cymbopogon genus.

[This corrects the article DOI: 10.3389/fphar.2022.997918.].

Therapeutic targets by traditional Chinese medicine for ischemia-reperfusion injury induced apoptosis on cardiovascular and cerebrovascular diseases.

Traditional Chinese medicine (TCM) has a significant role in treating and preventing human diseases. Ischemic heart and cerebrovascular injuries are two types of diseases with different clinical manifestations with high prevalence and incidence. In recent years, it has been reported that many TCM has beneficial effects on ischemic diseases through the inhibition of apoptosis, which is the key target to treat myocardial and cerebral ischemia. This review provides a comprehensive summary of the mechanisms of various TCMs in treating ischemic cardiovascular and cerebrovascular diseases through anti-apoptotic targets and pathways. However, clinical investigations into elucidating the pharmacodynamic ingredients of TCM are still lacking, which should be further demystified in the future. Overall, the inhibition of apoptosis by TCM may be an effective strategy for treating ischemic cardio-cerebrovascular diseases.

Review of phytomedicine, phytochemistry, ethnopharmacology, toxicology, and pharmacological activities of Cymbopogon genus.

The Cymbopogon genus belongs to the Andropoganeae family of the family Poaceae, which is famous for its high essential oil concentration. Cymbopogon possesses a diverse set of characteristics that supports its applications in cosmetic, pharmaceuticals and phytotherapy. The purpose of this review is to summarize and connect the evidence supporting the use of phytotherapy, phytomedicine, phytochemistry, ethnopharmacology, toxicology, pharmacological activities, and quality control of the Cymbopogon species and their extracts. To ensure the successful completion of this review, data and studies relating to this review were strategically searched and obtained from scientific databases like PubMed, Google Scholar, ResearchGate, ScienceDirect, and Elsevier. Approximately 120 acceptable reviews, original research articles, and other observational studies were included and incorporated for further analysis. Studies showed that the genus Cymbopogon mainly contained flavonoids and phenolic compounds, which were the pivotal pharmacological active ingredients. When combined with the complex ß-cyclodextrin, phytochemicals such as citronellal have been shown to have their own mechanism of action in inhibiting the descending pain pathway. Another mechanism of action described in this review is that of geraniol and citral phytochemicals, which have rose and lemon-like scents and can be exploited in soaps, detergents, mouthwash, cosmetics, and other products. Many other pharmacological effects, such as anti-protozoal, anti-bacterial, anti-inflammatory and anti-cancer have been discussed sequentially, along with how and which phytochemicals are responsible for the observed effect. Cymbopogon species have proven to be extremely valuable, with many applications. Its phytotherapy is proven to be due to its rich phytochemicals, obtained from different parts of the plant like leaves, roots, aerial parts, rhizomes, and even its essential oils. For herbs of Cymbopogon genus as a characteristic plant therapy, significant research is required to ensure their efficacy and safety for a variety of ailments.

Molecular Mechanisms Involved in Supersaturation of Emodin Ternary Solid Dispersions Based on Bonding Agents.

The use of solid dispersions (SDs) is an established method for improving the dissolution rate of poorly water-soluble drugs. However, there have been few studies on the molecular mechanisms contributing to SD supersaturation. Emodin ternary SDs (TSDs) were prepared by hot melt extrusion (HME) using Kollidon® VA64 as the polymer carrier and nicotinamide as the bonding agent. Molecular docking and solubility tests were used to assist screening of polymer carriers, and in vitro dissolution and dissociation constant data were used to optimize the formulation. A variety of analytical methods and molecular dynamics simulations were used to investigate the mechanism of SD supersaturation at the molecular level. The results showed that molecular migration, intermolecular interactions, drug crystal transformation and dissociation constant were particularly important factors in SD supersaturation. This study proposes a new strategy to improve solubility of poorly water-soluble drugs and explore the molecular mechanisms of TSD supersaturation, which could provide a basis for the rational selection of excipients for pharmaceutical preparations.

Lycium barbarum polysaccharides attenuates high glucose-induced diabetic retinal angiogenesis by rescuing the expression of miR-15a-5p in RF/6A cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Lycium barbarum L., a classical traditional Chinese Medicine, has long been used to treat ocular diseases. Lycium barbarum polysaccharides (LBP) is an effective component of Lycium barbarum L. with a wide range of pharmacological activities. This research aims to investigate the inhibition of high glucose-induced angiogenesis by LBP in RF/6A cells. MATERIALS AND METHODS: A high-glucose-induced angiogenesis model was established using monkey retinal vascular endothelial (RF/6A) cells. Different dosages administration times of LBP and glucose concentrations were tested. Under the optimized conditions, RF/6A cells were treated with LBP for 48 h, followed by another 48-h culture in high glucose (25 mmol/L) medium. The effect and mechanism of LBP were investigated following the treatment. RESULTS: The expression of miR-15a-5p and miR-15a-3p in RF/6A cells decreased significantly after 48 h of 25 or 50 mmol/L high glucose treatment. The expression of miR-15a-5p was higher than that of miR-15a-3p. Mimic-miR-15a-5p or 600 mg/L LBP could increase the apoptosis of cells and the total length of vascular branches. The expression of VEGFA, VEGFR2, and ANG2 proteins was reduced, while the expression of ANG1 protein was elevated. Expression of ASM mRNA and protein was also inhibited. CONCLUSIONS: LBP attenuates diabetic retinal angiogenesis by rescuing the expression of miR-15a-5p in RF/6A cells.

Dehydrocostuslactone attenuated oxygen and glucose deprivation/reperfusion-induced PC12 cell injury through inhibition of apoptosis and autophagy by activating the PI3K/AKT/mTOR pathway.

The purpose of this study is to investigate the protective effect of dehydrocostuslactone (DHL) on PC12 cells injury induced by oxygen and glucose deprivation/reperfusion (OGD/R) and its possible mechanism on the PI3K/AKT/mTOR pathway. The maestro 11.1 software was used to predict the binding sites of DHL with LC3, Beclin-1, PI3K, AKT, mTOR, Bax, Bcl-2, Caspase-3, Caspase-9, and Caspase-7. We used a cellular model of 2 h of OGD and 24 h of reperfusion to mimic cerebral ischemia-reperfusion injury. Cells were treated with DHL during the reperfusion phase. The docking results showed that DHL had binding sites with LC3, Beclin-1, PI3K, AKT, mTOR, Bax, Bcl-2, Caspase-3, Caspase-9, and Caspase-7. The expression levels of autophagy-related proteins, LC3 and Beclin-1 increased while P-PI3K, P-AKT, and P-mTOR decreased. Apoptosis-related proteins, namely, Bax, Cyto-c, Caspase-3, Caspase-7, Caspase-9 increased, but the anti-apoptosis Bcl-2 protein decreased. However, DHL effectively inhibited these undesirable changes induced by OGD/R in PC12 cells. Our results suggested that DHL attenuated OGD/R-induced neuronal injury by inhibiting apoptosis and autophagy by activating PI3K/AKT/mTOR signaling. This inhibition can improve cell survival and offer evidence for the beneficial effects of DHL on the nervous system.

Improved transdermal permeability of tanshinone IIA from cataplasms by loading onto nanocrystals and porous silica.

Novel transdermal cataplasms have been designed to improve permeability of poorly soluble drugs by different pretreatments. Nanocrystal and porous silica solid dispersions were loaded with Tanshinone IIA and incorporated into a cross-linked hydrogel matrix of cataplasm. It was shown that the small particle size and improved dissolution would increase dermal bioavailability. The adhesion, rheological properties, drug release, skin permeation, skin deposition and in vivo skin absorption of the different formulations were investigated. In an in vitro experiment using mouse skin, cumulative amount of drug permeated within 24 h was 7.32 ± 0.98 µg/cm2 from conventional cataplasm, 13.14 ± 0.70 µg/cm2 from nanocrystal-loaded cataplasm and 11.40 ± 0.13 µg/cm2 from porous silica solid dispersion-loaded cataplasm. In vitro dissolution profiles showed that drug release was 76.5% and 74.9% from two optimized cataplasms within 24 h, while conventional cataplasm was 55.0%. The cross-linking characteristics of the cataplasms were preserved after incorporation of different drug forms, while the elastic and viscous behaviors of the hydrogel layers increased. In vivo evaluation by CLSM showed the more favorable skin permeation for two optimized cataplasms. These findings suggest that applications of nanocrystal and porous silica systems on cataplasms enable effective transdermal delivery of poorly soluble drugs. The resulting drug delivery and rheological properties are desirable for transdermal application.AbbreviationAll the abbreviations that appear in this article are shown in Table 1.

The role of traditional Chinese medicine in the treatment of cognitive dysfunction in type 2 diabetes.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetic cognitive dysfunction (DCD) is mainly one of the complications of type 2 diabetes mellitus (T2DM) with complex and obscure pathogenesis. Extensive evidence has demonstrated the effectiveness and safety of traditional Chinese medicine (TCM) for DCD management. AIM OF THE STUDY: This review attempted to systematically summarize the possible pathogenesis of DCD and the current Chinese medicine on the treatment of DCD. MATERIALS AND METHODS: We acquired information of TCM on DCD treatment from PubMed, Web of Science, Science Direct and CNKI databases. We then dissected the potential mechanisms of currently reported TCMs and their active ingredients for the treatment of DCD by discussing the deficiencies and giving further recommendations. RESULTS: Most TCMs and their active ingredients could improve DCD through alleviating insulin resistance, microvascular dysfunction, abnormal gut microbiota composition, inflammation, and the damages of the blood-brain barrier, cerebrovascular and neurons under hyperglycemia conditions. CONCLUSIONS: TCM is effective in the treatment of DCD with few adverse reactions. A large number of in vivo and in vitro, and clinical trials are still needed to further reveal the potential quality markers of TCM on DCD treatment.

Nanovoid-Enhanced Thin-Film Composite Reverse Osmosis Membranes Using ZIF-67 Nanoparticles as a Sacrificial Template.

In this work, nanovoid-enhanced thin-film composite (TFC) membranes have been successfully fabricated using ZIF-67 nanoparticles as the sacrificial template. By incorporating different amounts of ZIF-67 during interfacial polymerization, the resultant TFC membranes can have different degrees of nanovoids after self-degradation of ZIF-67 in water, consequently influencing their physiochemical properties and separation performance. Nanovoid structures endow the membranes with additional passages for water molecules. Thus, all the newly developed TFC membranes exhibit better separation performance for brackish water reverse osmosis (BWRO) desalination than the pristine TFC membrane. The membrane made from 0.1 wt % ZIF-67 shows a water permeance of 2.94 LMH bar-1 and a salt rejection of 99.28% when being tested under BWRO at 20 bar. This water permeance is 53% higher than that of the pristine TFC membrane with the salt rejection well maintained.

Costunolide attenuates oxygen­glucose deprivation/reperfusion­induced mitochondrial­mediated apoptosis in PC12 cells.

The present study investigated the effect of costunolide (CT), a compound extracted from Aucklandia lappa Decne, to attenuate oxygen­glucose deprivation/reperfusion (OGD/R)­induced mitochondrial­mediated apoptosis in PC12 cells. The present study used molecular docking technology to detect the binding of CT with mitochondrial apoptotic protein targets. A model of oxygen­glucose deprivation for 2 h and reperfusion for 24 h in PC12 cells was used to mimic cerebral ischemic injury. Cell viability and damage were measured using the Cell Counting kit­8 and lactate dehydrogenase (LDH) cytotoxicity assay kits. Cellular apoptosis was analyzed using flow cytometry. A fluorescence microscope determined intracellular [Ca2+] and mitochondrial membrane potential. Furthermore, immunofluorescence and Western blot analyses were used to detect the expression of apoptosis­associated proteins. CT contains binding sites with Caspase­3, Caspase­9 and Caspase­7. CT markedly enhanced cell viability, inhibited LDH leakage, increased intracellular [Ca2+], stabilized the mitochondrial membrane potential, increased the expression of Bcl­2 and inhibited the expression of Apaf­1, Bax, cleaved­caspase­7, cleaved­caspase­9 and cleaved­caspase­3. CT may markedly protect PC12 cells from damage caused by OGD/R, and its mechanism is associated with blocking the calcium channel and inhibiting mitochondrial­mediated apoptosis.

Prediction of the physical stability of amorphous solid dispersions: relationship of aging and phase separation with the thermodynamic and kinetic models along with characterization techniques.

Introduction: Solid dispersion has been considered to be one of the most promising methods for improving the solubility and bioavailability of insoluble drugs. However, the physical stability of solid dispersions (SDs), including its aging and recrystallization, or phase separation, has always been one of the most challenging problems in the process of formulation development and storage.Areas covered: The high energy state of SDs is one of the primary reasons for the poor physical stability. The factors affecting the physical stability of SDs have been described from the perspective of thermodynamics and kinetics, and the corresponding theoretical model is put forward. We briefly summarize several commonly used techniques to characterize the thermodynamic and kinetic properties of SDs. Specific measures to improve the physical stability of SDs have been proposed from the perspective of prescription screening, process parameters, and storage conditions.Expert opinion: The separation of the drug from the polymer, the formation, and migration of drug crystals will cause the SDs to shift toward the direction of energy reduction, which is the intrinsic cause of instability. Furthermore, computational simulation can be used for efficient and rapid screening suitable for the excipients to improve the physical stability of SDs.