Conventional therapeutic agents are no longer adequate against leishmaniasis. This complex condition continues to have a high mortality rate and public health impact. The present study aimed to explore an extensive array of experiments to monitor the biological activities of 6-shogaol, a major component of ginger, and meglumine antimoniate (MA or Glucantime®). The binding affinity of 6-shogaol and inducible nitric oxide synthase (iNOS), a major enzyme catalyzing nitric oxide (NO) from L-arginine was the source for the docking outline. The inhibitory effects of 6-shogaol, MA, and mixture were assessed using colorimetric and macrophage assays. Antioxidant activity was inferred by UV-visible spectrophotometry. Variably expressed genes were measured by quantifiable real-time polymerase chain reaction. Apoptotic and cell cycle profiles were analyzed by flow cytometry. Moreover, a DNA fragmentation assay was performed by electrophoresis and antioxidant metabolites include superoxide dismutase (SOD), catalase (CAT), and also nitric oxide (NO) by enzyme-linked immunosorbent assay. 6-shogaol and MA exhibited multiple synergistic mechanisms of action. These included a remarkable leishmanicidal effect, potent antioxidative activity, a high safety index, upregulation of M1 macrophages/Th1-associated cytokines (including, γ-interferon, interleukin-12p40, tumor necrotizing factor-alpha, and associated iNOS), significant cell division capture at the sub-G0/G1 phase, a high profile of apoptosis through DNA fragmentation of the nuclear components. In addition, the activity of NO was substantially elevated by treated intracellular amastigotes, while SOD and CAT activities were significantly diminished. This study is exclusive because no similar investigation has inclusively been conducted before. These comprehensive mechanistic actions form a logical foundation for additional advanced study.

Parkinson\'s disease (PD) is a neurodegenerative disease caused by the death of dopaminergic neurons in the nigrostriatal pathway, leading to motor and non-motor dysfunctions, such as depression, olfactory dysfunction, and memory impairment. Although levodopa (L-dopa) has been the gold standard PD treatment for decades, it only relieves motor symptoms and has no effect on non-motor symptoms or disease progression. Prior studies have reported that 6-shogaol, the active ingredient in ginger, exerts a protective effect on dopaminergic neurons by suppressing neuroinflammation in PD mice. This study investigated whether cotreatment with 6-shogaol and L-dopa could attenuate both motor and non-motor symptoms and dopaminergic neuronal damage. Both 6-shogaol (20 mg/kg) and L-dopa (80 mg/kg) were orally administered to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid- induced PD model mice for 26 days. The experimental results showed that L-dopa alleviated motor symptoms, but had no significant effect on non-motor symptoms, loss of dopaminergic neuron, or neuroinflammation. However, when mice were treated with 6-shogaol alone or in combination L-dopa, an amelioration in both motor and non-motor symptoms such as depression-like behavior, olfactory dysfunction and memory impairment was observed. Moreover, 6-shogaol-only or co-treatment with 6-shogaol and L-dopa protected dopaminergic neurons in the striatum and reduced neuroinflammation in the striatum and substantia nigra. Overall, these results suggest that 6-shogaol can effectively complement L-dopa by improving non-motor dysfunction and restoring dopaminergic neurons via suppressing neuroinflammation.

Colorectal cancer (CRC) poses a significant global health burden, being the third most prevalent cancer and the second most significant contributor to cancer-related deaths worldwide. Preventive strategies are crucial to combat this rising incidence. 6-shogaol, derived from ginger, has shown promise in preventing and treating various cancers. This study investigated the preventive effects of 6-shogaol on azoxymethane (AOM) and dextran sulfate sodium (DSS)-induced CRC in mice. Forty male BALB/c mice were randomly divided into control, 6-shogaol, AOM + DSS, and 6-shogaol + AOM + DSS. Mice in the control group received corn oil for 16 weeks, while those in the 6-Shogaol group were administered 20 mg/kg of 6-shogaol for 16 weeks. The AOM + DSS group received a single intraperitoneal dose (ip) of 10 mg/kg of AOM, followed by three cycles of 2.5% DSS in drinking water. The 6-shogaol + AOM + DSS group received both 6-shogaol for 16 weeks and a single ip of 10 mg/kg of AOM, followed by three cycles of 2.5% DSS in drinking water. The AOM + DSS-treated mice exhibited reduced food consumption, colon weight, and colon length, along with increased tumor formation. Co-administration of 6-shogaol effectively reversed these changes, inhibiting CRC development. Histopathological analysis revealed protective effects of 6-shogaol against colonic insults and modulation of inflammatory responses. 6-shogaol significantly reduced Carcinoembryonic antigen and Kiel 67 levels, indicating inhibition of tumor cell proliferation. Mechanistically, 6-shogaol promoted apoptosis by upregulating protein 53 and caspase-3 expression, and it effectively restored the balance of the Wingless-related integration site signaling pathway by regulating β-catenin and adenomatous polyposis coli levels. Moreover, 6-shogaol demonstrated anti-inflammatory effects, reducing myeloperoxidase, Tumor necrosis factor alpha, and cyclooxygenase-2 levels in AOM/DSS-treated mice. Additionally, 6-shogaol restored redox homeostasis by reducing lipid peroxidation and nitrosative stress and enhancing antioxidant enzyme activities. The findings suggest that 6-shogaol inhibits cell proliferation, induces apoptosis, regulates Wnt signaling, suppresses inflammation, and restores redox homeostasis, providing comprehensive insights into its potential therapeutic benefits for CRC.

The purpose of this study is to investigate the mechanism by which 6-shogaol ameliorates hepatic steatosis via miRNA-mRNA interaction analysis. C57BL/6 J mice were fed a high-fat diet (HFD) for 12 weeks, during which 6-shogaol was administered orally. The liver lipid level, liver function and oxidative damage in mice were evaluated. mRNA sequencing, miRNA sequencing, and RT-qPCR were employed to compare the expression profiles between the HFD group and the 6-shogaol-treated group. High-throughput sequencing was used to construct the mRNA and miRNA libraries. Target prediction and integration analysis identified eight potential miRNA-mRNA pairs involved in hepatic steatosis, which were subsequently validated in liver tissues and AML12 cells. The findings revealed that 6-shogaol modulates the miR-3066-5p/Grem2 pathway, thereby improving hepatic steatosis. This study provides new insights into the mechanisms through which 6-shogaol alleviates hepatic steatosis, establishing a foundation for future research on natural active compounds for the treatment of metabolic diseases.

Sunitinib (SUN) is the first-line targeted therapeutic drug for advanced renal cell carcinoma (RCC). However, SUN resistance is frequently observed to result in tumor metastasis, with a poor survival rate. Therefore, finding an effective and safe adjuvant to reduce drug resistance is important for RCC treatment. Pterostilbene (PTE) and 6-shogaol (6-S) are natural phytochemicals found in edible sources and have potential applications against various cancers. However, the biological mechanisms of PTE and 6-S in SUN-resistant RCC are still unclear. Accordingly, this study investigated the regulatory effects of PTE and 6-S on cell survival, drug resistance, and cell invasion in 786-O and SUN-resistant 786-O (786-O SUNR) cells, respectively. The results demonstrated that PTE and 6-S induced apoptosis in both cell lines by upregulating the Bax/Bcl-2 ratio. Additionally, PTE and 6-S increased SUN sensitivity by inhibiting the expression of the RLIP76 transport protein, reduced cell invasion and downregulated MMP expression in both 786-O and 786-O SUNR cells. Mechanistically, PTE, and 6-S significantly and dose-dependently suppressed the RLIP76-initiated Ras/ERK and Akt/mTOR pathways. In summary, PTE and 6-S induce apoptosis, enhance SUN sensitivity, and inhibit migration in both 786-O and 786-O SUNR cells. These novel findings demonstrate the potential of PTE and 6-S as target therapeutic adjuvants for RCC treatment.

The dynamically evolving science of pharmacology requires AI technology to advance a new path for drug development. The author proposes generative AI for future drugs, identifying suitable drug molecules, uncharacteristically to previous generations of medicines, incorporating the wisdom, experience, and intuit of traditional materia medica and the respective traditional medicine practitioners. This paper describes the guiding principles of the new drug development, springing from the tradition and practice of Tibetan medicine, defined as the Interactive Nutrient Process (INP). The INP provides traditional knowledge and practitioner\'s experience, contextualizing and teaching the new drug therapy. An illustrative example of the outcome of the INP is a potential small molecule drug, 6-Shogaol and related shogaol derivatives, from ginger roots (Zingiber officinalis fam. Zingiberaceae) evaluated clinically for 12 months for biological markers of iron homeostasis in patients with the myelodysplastic syndromes (MDS). The study\'s preliminary results indicate that 6-Shogaol and related shogaols may improve iron homeostasis in low-risk/intermediate-1 MDS patients without objective or subjective side effects.

Non-alcoholic steatohepatitis (NASH) is becoming an increasingly serious global health threat, distinguished by hepatic lipid accumulation, inflammation, and fibrosis. There is a lack of approved pharmaceutical interventions for this disease, highlighting the urgent need for effective treatment. This study explores the hepatoprotective potential of 6-shogaol, a natural compound derived from ginger, in a methionine- and choline-deficient (MCD) dietary mouse model of NASH. Male C57BL/6J mice were subjected to the MCD diet for 4 weeks to induce NASH, with concurrent intraperitoneal administration of 6-shogaol (20 mg/kg) three times a week. While 6-shogaol did not impact body weight, liver weight, or hepatic lipid accumulation, it effectively mitigated liver injury, inflammation, and fibrosis in MCD diet-fed mice. Mechanistically, 6-shogaol inhibited lipid and DNA oxidation, restored hepatic glutathione levels, and regulated the expression of pro-oxidant and antioxidant enzymes. Furthermore, 6-shogaol inhibited apoptosis and necroptosis, as indicated by a decrease in TUNEL-stained cells and downregulation of apoptosis- and necroptosis-associated proteins. Additionally, 6-shogaol alleviated endoplasmic reticulum (ER) stress, as demonstrated by decreased expression of molecules associated with unfolded protein response pathways. These findings underscore the potential of 6-shogaol as a therapeutic intervention for NASH by targeting pathways related to oxidative stress, cell death, and ER stress.

Ginger (Zingiber officinale Roscoe, Zingeberaceae) is a medicinal plant widely used as food, spice, or flavoring agent worldwide. 6-Shogaol is a compound of prime interest in exhibiting anti-inflammatory, antioxidant and chemopreventive effects. The objective of the study is to investigate the effect of microwave-assisted drying (MAD) followed by microwave-assisted extraction (MAE) so as to produce 6-Shogaol enriched Ginger with improved therapeutic benefits. Various drying techniques viz. shade drying, tray drying, microwave-assisted drying and osmotic dehydration as a pretreatment were used for drying Ginger rhizomes. The dried rhizomes were extracted by conventional solvent extraction and microwave-assisted extraction techniques and tested for content of 6-Shogaol using the newly developed HPLC method whereas total flavonoid and polyphenol content were determined using the UV spectrophotometric method. Subjecting the microwave dried Ginger to microwave-assisted extraction for 45 min at constant power level of 284 W resulted in a significant rise in the extractability of 6-Shogaol (1.660 ± 0.018), total polyphenols (855.46 ± 5.33) and flavonoids (617.97 ± 6.40) compared to the conventional method of extraction. The proposed Ginger processing method of microwave drying followed by microwave extraction outperforms traditional methods in terms of speed, convenience, and performance thus can be scaled up to industrial levels.

[This corrects the article DOI: 10.3389/fmolb.2022.808162.].

Cancer is a malignant disease that has plagued human beings all the time, but the treatment effect of commonly used anticancer drugs in clinical practice is not ideal by reason of their drug tolerance and Strong adverse reactions to patients. Therefore, it is imperative to find effective and low-toxic anticancer drugs. Many research works have shown that natural products in Chinese herbal medicine have great anticancer potential, such as 6-shogaol, a monomer composition obtained from Chinese herbal ginger, which has been confirmed by numerous in vitro or vivo studies to be an excellent anti-cancer active substance. In addition, most notably, 6-shogaol has different selectivity for normal and cancer cells during treatment, which makes it valuable for further research and clinical development. Therefore, this review focus on the anti-cancer attributes, the mechanism and the regulation of related signaling pathways of 6-shogaol. In addition, its synergy with commonly used anticancer drugs, potential drug delivery systems and prospects for future research are discussed. This is the first review to comprehensively summarize the anti-cancer mechanism of 6-shogaol, hoping to provide a theoretical basis and guiding significance for future anti-cancer research and clinical development of 6-shogaol.