Methamphetamine (METH) is a powerful stimulant drug that can cause addiction and serious health problems. It is one of the most widely abused drugs in the world. However, the mechanisms of how METH affects the brain and leads to addiction are still unclear, and there are no effective treatments for METH addiction in clinical practice. Therefore, it is important to explore the new addiction mechanisms and treatment strategies of METH. METH addiction is a complex and chronic brain disorder that involves multiple brain regions and neurotransmitter systems. Neurotransmitters are chemical messengers that transmit signals between neurons (nerve cells) in the brain. Some of the main neurotransmitters involved in METH addiction are dopamine (DA), glutamate (Glu), norepinephrine (NE), and serotonin (SNRIS). These neurotransmitters regulate various aspects of brain function, such as reward, reinforcement, motivation, cognition, emotion, and behavior. When a person takes METH, it causes a surge of these neurotransmitters in the brain, especially in the prefrontal cortex (mPFC), ventral tegmental area (VTA), and nucleus accumbens (NAc). These brain regions form a circuit called the mesocorticolimbic system, which is responsible for mediating the rewarding and reinforcing effects of drugs and natural stimuli. The increased levels of neurotransmitters in this circuit make the person feel euphoric, alert, confident, and energetic. However, repeated or chronic use of METH can also cause negative effects, such as anxiety, paranoia, psychosis, depression, and cognitive impairment. The effects of METH on the brain are not only due to the changes in neurotransmitter levels, but also to the changes in gene expression. Gene expression is the process by which genes are turned on or off to produce proteins that perform various functions in the cells. Gene expression can be influenced by environmental factors, such as drugs, stress, diet, etc. One way that environmental factors can affect gene expression is through epigenetic mechanisms. Epigenetics is a branch of genetics that studies the heritable changes in gene expression that are not caused by changes in DNA sequence. Epigenetic mechanisms include histone modifications, DNA methylation, and non-coding RNA regulation. These mechanisms can modulate the chromatin structure and accessibility, thereby affecting the transcriptional activity of genes. Chromatin is a complex of DNA and proteins that forms the chromosomes in the nucleus of the cell. The chromatin structure can be altered by adding or removing chemical groups to histones (proteins that wrap around DNA) or DNA itself. These chemical groups can either activate or repress gene expression by changing the affinity of transcription factors (proteins that bind to DNA and initiate transcription) or other regulatory molecules. Non-coding RNAs are RNA molecules that do not code for proteins but can regulate gene expression by interacting with DNA, RNA, or proteins. Epigenetic mechanisms provide a link between environmental stimuli and gene expression, and play an important role in various physiological and pathological processes, including drug addiction. Recent studies have shown that epigenetic mechanisms are involved in the regulation of neurotransmitter systems and neural plasticity in response to METH exposure. Neural plasticity is the ability of neurons to change their structure and function in response to experience or injury. Neural plasticity is essential for learning, memory, adaptation, and recovery. The expression of some genes related to METH addiction is altered by epigenetic modifications, such as histone acetylation, methylation, ubiquitination, and non-coding RNA regulation. These epigenetic changes may affect the synaptic function and morphology, neuronal connectivity, and circuitry formation in the brain regions implicated in METH addiction. Moreover, some epigenetic modifications may persist for a long time after METH withdrawal, suggesting that they may contribute to the development and maintenance of METH addiction. In this article, we review the current literature on the epigenetic mechanisms of METH addiction. We will first introduce METH and its pharmacological effects, and then discuss the epigenetic regulation of neurotransmitter systems and neural plasticity by METH. We will focus on the changes of histone, DNA, and RNA during METH addiction, and the possible causes and consequences of their relationship with METH addiction. We will also provide some perspectives on the potential applications of epigenetic interventions for METH addiction treatment.

Orodispersible films (oral dispersible films), a novel form of oral solid dosage forms, are widely used for patients with dysphagia and those with uncontrollable autonomic behavior. In this study, suvorexant orodispersible film was prepared by hot melt extrusion technology, and the disintegration time, mechanical properties, in vitro dissolution and pharmacokinetics were evaluated, compared with other orodispersible films and commercially available tablets Belsomra. All experiments were approved by the Committee on the Management and Use of Laboratory Animals of Academy of Military Medical Sciences (IACUC-DWZX-2024-504). The results showed that the dissolution rate of suvorexant orodispersible film was faster and the mechanical strength was better than that of other commercially available orodispersible film, which could meet the needs of storage and transportation. Differential scanning calorimetry and X-ray diffraction results showed that suvorexant was dispersed within the orodispersible film in an amorphous state. The in vitro dissolution of the film was observed to be four times faster than that of the commercial tablets, achieving complete dissolution within five minutes. Pharmacokinetic evaluations in Beagle dogs revealed that the self-formulated orodispersible film exhibited no significant differences in the area under the blood concentration-time curve when compared with Belsomra. However, the film showed a faster onset of action, with a peak time that was twice as rapid, and a maximum blood concentration that was twice as high as that of Belsomra. Leveraging hot melt extrusion technology, the suvorexant orodispersible film offers a straightforward, continuous production process with consistent quality. It serves as an excellent platform for the development of solvent-free film preparations tailored for patients with special needs.

The rheological properties of drug and carrier materials have a wide range of guiding significance for the formulation and process development of solid dispersions. In this study, the rheological properties of materials with different drug carrier ratios were systematically studied with suvorexant as the model drug and copovidone as the carrier material, which provided a sufficient basis for determining the formulation and process of solid dispersions. The optimal suvorexant-copovidone ratio obtained by oscillating temperature scanning was 1∶4. If the ratio is greater than 1∶ 4, the glass transformation temperature of the material will increase significantly, and the solubilization effect of the solid dispersion will show a downward trend. The results of oscillation temperature scanning and oscillation temperature sweep can show that when the extrusion temperature is greater than 150 ℃, the viscosity of the material is less than 10 000 Pa·s, and the melt can be extruded smoothly, and the best extrusion temperature of 160-180 ℃ can be obtained by combining the dissolution results. Finally, the dissolution of suvorexant tablets guided by rheological property studies in multiple media is similar to that of the commercially available tablets Belsomra. Therefore, rheological studies can screen and optimize the formulation and process of suvorexant solid dispersions at the mechanism level, which is of great significance to improve the success rate of R&D and shorten the R&D cycle of solid dispersions prepared by hot melt extrusion.

Separation and determination of chiral and achiral impurities in glimepiride tablets by supercritical fluid chromatography. Chiral and achiral impurities were separated on a ACQUITY UPC² Trefoil^TM CEL1 column (150 mm × 3.0 mm, 2.5 μm) maintained at 30 ℃ with the mobile phase containing a mixture of CO₂ and methanol-isopropanol (1∶1) at 1 mL·min^-1, and the detection wavelength was set at 228 nm. The back pressure was set at 13.8 MPa. The injection volume was 5 μL. In the chromatogram of the system suitability solution, the peaks elute in the following order: impurity Ⅳ, impurity Ⅴ, glimepiride, impurity Ⅲ, impurity Ⅰ and impurity Ⅱ. The six substances were separated successfully in 6 min using the proposed method with a resolution factor of 2.9, 1.6, 3.0, 2.0, 6.4. The impurity Ⅰ-Ⅴ detection limit (S/N = 3) was 0.17, 0.10, 0.06, 0.15, 0.10 μg·mL^-1, respectively. Good linear relationship was established between the peak response and the concentration in the range of 0.48-51.30 μg·mL^-1 for all impurities. The spiked recovery of impurity Ⅰ-Ⅴ was found to be acceptable for 99.9%, 98.9%, 102.1%, 100.1%, 96.3% (n = 9), respectively. The related substance and assay results of 11 sample batches are consistent with the results obtained using the HPLC method in the Chinese Pharmacopoeia. Compared to the two HPLC methods in the Chinese Pharmacopoeia, the established supercritical fluid chromatography method can simultaneously separate glimepiride and its 5 impurities in a single run, and it has the following advantages: simplified sample preparation, greatly reducing the volumes of organic solvents, environmentally friendly, high accuracy and good reproducibility. It can be employed for the quality control of the chiral and achiral impurities in glimepiride tablets.

MADS-box protein family are important transcriptional regulatory factors in plant growth and development. The AGAMOUS 12 (AGL12) subfamily is believed to play an important regulatory role in the process of plant flowering transition. To explore the potential mechanism of AGL12 subfamily involved in regulating the flower development of Lonicera macranthoides, quantitative real-time polymerase chain reaction (qRT-PCR), prokaryotic expression and yeast two-hybrid techniques were used to analyze the expression pattern, protein expression, and protein-protein interaction pattern of LmAGL12 based on transcriptome data. The results showed that the LmAGL12 gene contains a 603 bp open reading frame (ORF), encoding 200 amino acids, and the encoded protein was stable and hydrophilic without a transmembrane region and signal peptide. Through homologous sequence alignment and phylogenetic analysis, it was confirmed that LmAGL12 protein belongs to the MADS-box protein family and is closely related to the AGL12 protein of Heracleum sosnowskyi and Daucus carota subsp. sativus. The LmAGL12 gene was cloned into prokaryotic expression vector pET-28a and the recombinant constructs were transformed into Escherichia coli BL21 (DE3), which inducing the target protein successfully. The yeast two-hybrid results showed that LmAGL12 protein interacts with LmSVP protein, LmSOC1 protein and LmAP1 protein, respectively. The qRT-PCR results showed that LmAGL12 gene were differentially expressed in different development stages of flower bud, stem, and leaves of 'Longhua' and 'Baiyun' in L. macranthoides. The LmAGL12 gene showed the highest expression level in the middle stage of the 'Longhua' floral bud; For the 'Baiyun' variety, the relative expression level of LmAGL12 gene is the highest in the stem. This study cloned the LmAGL12 gene in L. macranthoides and analyzed it expression for the first time, enriching the research on flower organ development and providing a research basis for further exploring the molecular mechanisms of long bud stage and non-unfolded corolla in L. macranthoides, as well as for variety improvement.

Sodium-glucose co-transporter protein 2 inhibitor(SGLT2i)has steadily demonstrated benefits in the treatment of type 2 diabetes complicated with cardiovascular diseases based on evidence-based medicine,but its precise mechanism is yet unknown.We identified type 2 diabetes patients with HFpEF by searching PubMed,Web of Science,China knowledge network(CNKI),and other databases.We then summarized the pathological mechanism of HFpEF caused by type 2 diabetes.At the same time,to link to evidence-based medical,we explored the future of SGLT2i in clinical application.

Background::Cardiovascular disease (CVD) has emerged as the leading cause of death from prostate cancer (PCa) in recent decades, bringing a great disease burden worldwide. Men with preexisting CVD have an increased risk for major adverse cardiovascular events when treated with androgen deprivation therapy (ADT). The present study aimed to explore the prevalence and risk evaluation of CVD among people with newly diagnosed PCa in China.Methods::Clinical data of newly diagnosed PCa patients were retrospectively collected from 34 centers in China from 2010 to 2022 through convenience sampling. CVD was defined as myocardial infarction, arrhythmia, heart failure, stroke, ischemic heart disease, and others. CVD risk was estimated by calculating Framingham risk scores (FRS). Patients were accordingly divided into low-, medium-, and high-risk groups. χ2 or Fisher’s exact test was used for comparison of categorical variables. Results::A total of 4253 patients were enrolled in the present study. A total of 27.0% (1147/4253) of patients had comorbid PCa and CVD, and 7.2% (307/4253) had two or more CVDs. The enrolled population was distributed in six regions of China, and approximately 71.0% (3019/4253) of patients lived in urban areas. With imaging and pathological evaluation, most PCa patients were diagnosed at an advanced stage, with 20.5% (871/4253) locally progressing and 20.5% (871/4253) showing metastasis. Most of them initiated prostatectomy (46.6%, 1983/4253) or regimens involving ADT therapy (45.7%, 1944/4253) for prostate cancer. In the present PCa cohort, 43.1% (1832/4253) of patients had hypertension, and half of them had poorly controlled blood pressure. With FRS stratification, as expected, a higher risk of CVD was related to aging and metabolic disturbance. However, we also found that patients with treatment involving ADT presented an originally higher risk of CVD than those without ADT. This was in accordance with clinical practice, i.e., aged patients or patients at advanced oncological stages were inclined to accept systematic integrative therapy instead of surgery. Among patients who underwent medical castration, only 4.0% (45/1118) received gonadotropin releasing hormone antagonists, in stark contrast to the grim situation of CVD prevalence and risk.Conclusions::PCa patients in China are diagnosed at an advanced stage. A heavy CVD burden was present at the initiation of treatment. Patients who accepted ADT-related therapy showed an original higher risk of CVD, but the awareness of cardiovascular protection was far from sufficient.

Secondary organic aerosol(SOA)produced by photooxidation of styrene and other aromatic compounds is a major part of fine particles in urban atmosphere.In this study,the measurement of component and content of SOA formed from photooxidation of styrene in smog chamber using synchronous radiation vacuum-ultraviolet photoionization aerosol mass spectrometer(VUV-PIAMS)was conducted.Photoionization mass spectra of styrene SOA was detected by synchrotron radiation photon with 10.5 eV,and the proportion of main components was quantified based on the peak area of each ion peak.The photoionization efficiency curve of ion peak was obtained under synchrotron radiation photons in the range from 7.5 to 11.5 eV,and then the ionization potential was acquired for qualitative analysis of the component structure.The results showed that the photoionization mass spectra of styrene SOA mainly contained ion peaks at m/z 106,108,120 and 122,and the ionization potentials of each peak were(9.41±0.03)eV,(8.93±0.03)eV,(9.24±0.03)eV and(9.25±0.03)eV,respectively.Combined with quantum chemistry calculation and off-line measurement verification of infrared absorption spectra and electrospray ionization mass spectra,it was determined that benzaldehyde,benzyl alcohol,4-vinylphenol and benzoic acid were main components of styrene SOA,accounting for 32.5%,17.5%,25%and 15%of the measured components,respectively,and the generated quantity ratio was 13∶7∶10∶6.VUV-PIAMS could overcome the disadvantages of off-line method,and could on-line detect component and content of SOA,proving a useful tool to measure the chemical components and reveal the formation process of SOA particles.

In recent years,the development of acupuncture and moxibustion(shortened as acup-moxibustion)has flourished.With the verification of clinical efficacy of acup-moxibustion,its basic research has gradually drawn the attention of the practitioners accordingly.But how to scientifically perform the basic research of acup-moxibustion and to serve the clinic effectively has become a major problem for the contemporary Chinese medicine practitioners.By analyzing the characteristics of acup-moxibustion-related research projects funded by the National Natural Science Foundation of China,this paper outlined the current status of domestic research of acup-moxibustion,and proposed four suggestions after analyzing the problems and weaknesses of acup-moxibustion basic research in China:①the clinical evidence-based system in the current acup-moxibustion should be further constructed and the basic research should be focused on the area of advantages;② the key problems of acup-moxibustion basic research should be clarified,and the proportion of original researches should be increased;③ the integration of production,teaching and research of acup-moxibustion should be enhanced to adapt to the era of big science;④ the funding system and its polity and structure needed to be reformed.This study will help to increase the discipline ranking of acup-moxibustion,enhance its high-quality development,and promote its internationalization.

Objective To explore the influence factors and predictors of treatment response after adrenocorticotropic hormone(ACTH)in infantile epileptic spasms syndrome(IESS).Methods A retrospective analysis was conducted on 80 cases of IESS infants(50 males and 30 females)who were diagnosed and treated with ACTH in Chengdu Women's and Children's Central Hospital from January 2016 to December 2020.Patients were divided into effective group(n=39)and ineffective group(n=41)based on their response of ACTH treatment after 28 days,and their clinical data including the patients'basic information,etiology,treatment programmer,per-and post-treatment Kramer scores of electroencephalogram(EEG)hypsarrhythmia severity and so on,were collected to compare and analyze between the two groups.A modified Poisson regression model was constructed to discover predictors of outcome,and the receiver operating characteristic(ROC)curves were used to assess the prognosis evaluation of the positive predictive value.Results The ages at seizure onset ranged from one month and seven days to one year and nine months.Seizure types included simple epileptic spasms in 66 cases and combined with other types(focal and secondarily generalized seizures)in 14 cases.Thirty-two cases had been given anti-seizure medications(ASMs)before ACTH treatment.The median Kramer scores per-treatment and at 14 days post-treatment were 10.0(8.3,12.0)and 6.0(4.0,7.0),respectively.After ACTH treatment,39(48.8%)cases were effective.Compared with the effective group,the ineffective group had significantly higher proportion of abnormal perinatal conditions,unknown aetiology with normal development,ASMs given before ACTH treatment,the dosages of ACTH greater than 2 U/(kg·d),combinations of two or more ASMs,poor control,and still seizure attack after ACTH treatment of 14 days(P<0.05).Additionally,the Kramer scores after ACTH treatment of 14 days in the ineffective group were also significantly higher(P<0.05).The modified Poisson regression model showed that there were significant statistic differences between the two groups on ASMs given before ACTH treatment(RR=0.546,95%CI 0.357-0.833,P=0.005)and Kramer scores of hypsarrhythmia severity(RR=0.701,95%CI 0.620-0.792,P<0.001),while there were no significant differences between the two groups in term of ages,gender,perinatal conditions,etiologies,seizure types,Kramer scores before treatment,time lag between onset and treatment,duration of ACTH treatment,kinds of ASMs combination.ROC curve analysis showed that only Kramer scores at 14 days after ACTH treatment could predict the treatment response with sensitivity and specificity of 92.7%and 84.6%,respectively,with Youden index of 0.773.The area under the ROC curve was 0.930(95%CI 0.873-0.987,P<0.001)and the cut-point of the score was 6,indicating that the higher the Kramer scores at 14 days after ACTH treatment,the worse the treatment response.The treatment response rate would reduce by about 30.0%if the Kramer score increased by one point.Conclusion ASMs given before ACTH treatment may influence the treatment response.Kramer scores greater than 6 at day 14 after ACTH treatment may be used as a predictor of treatment response after ACTH in IESS patients.