Plants with cosmetic uses.

The use of plants as a source of active principles for cosmetics has significantly increased in the last few years. Safety, compatibility with all types of skin, fewer side effects, and availability are among the advantages of herbal cosmetics above synthetic ingredients. The present review aims to explore the most important plants used in cosmetics. A literature search was carried out in several electronic databases with the following phrases: skincare and plants; cosmetics and plants; natural and cosmetics; and natural and skincare. Furthermore, more detailed filters such as clinical studies, meta-analyses, and systemic reviews were applied to positive results. Various plants and plant extracts currently used in skin care, scaring, whitening, and aging, as well as in sun protection, acne, eczema, and others, have been included in this review. The effectiveness of these plants is based mainly on preclinical research, and to a lesser extent on clinical studies. Some plant extracts or oils have been tested clinically, such as onions, aloe, and tea tree oil, more than other plant extracts. Despite many studies on natural products to improve dermal needs, proper clinical cosmeceutical trials are much fewer than expected. Therefore, more clinical trials are needed to evaluate appropriate efficacy. Furthermore, new formulation technologies might enhance the cosmeceutical benefits, but more work is warranted.

Sex shapes cell-type-specific transcriptional signatures of stress exposure in the mouse hypothalamus.

Stress-related psychiatric disorders and the stress system show prominent differences between males and females, as well as strongly divergent transcriptional changes. Despite several proposed mechanisms, we still lack the understanding of the molecular processes at play. Here, we explore the contribution of cell types to transcriptional sex dimorphism using single-cell RNA sequencing. We identify cell-type-specific signatures of acute restraint stress in the paraventricular nucleus of the hypothalamus, a central hub of the stress response, in male and female mice. Further, we show that a history of chronic mild stress alters these signatures in a sex-specific way, and we identify oligodendrocytes as a major target for these sex-specific effects. This dataset, which we provide as an online interactive app, offers the transcriptomes of thousands of individual cells as a molecular resource for an in-depth dissection of the interplay between cell types and sex on the mechanisms of the stress response.

Contribution of the co-chaperone FKBP51 in the ventromedial hypothalamus to metabolic homeostasis in male and female mice.

OBJECTIVE: Steroidogenic factor 1 (SF1) expressing neurons in the ventromedial hypothalamus (VMH) have been directly implicated in whole-body metabolism and in the onset of obesity. The co-chaperone FKBP51 is abundantly expressed in the VMH and was recently linked to type 2 diabetes, insulin resistance, adipogenesis, browning of white adipose tissue (WAT) and bodyweight regulation. METHODS: We investigated the role of FKBP51 in the VMH by conditional deletion and virus-mediated overexpression of FKBP51 in SF1-positive neurons. Baseline and high fat diet (HFD)-induced metabolic- and stress-related phenotypes in male and female mice were obtained. RESULTS: In contrast to previously reported robust phenotypes of FKBP51 manipulation in the entire mediobasal hypothalamus (MBH), selective deletion or overexpression of FKBP51 in the VMH resulted in only a moderate alteration of HFD-induced bodyweight gain and body composition, independent of sex. CONCLUSIONS: Overall, this study shows that animals lacking and overexpressing Fkbp5 in Sf1-expressing cells within the VMH display only a mild metabolic phenotype compared to an MBH-wide manipulation of this gene, suggesting that FKBP51 in SF1 neurons within this hypothalamic nucleus plays a subsidiary role in controlling whole-body metabolism.

Ketamine exerts its sustained antidepressant effects via cell-type-specific regulation of Kcnq2.

A single sub-anesthetic dose of ketamine produces a rapid and sustained antidepressant response, yet the molecular mechanisms responsible for this remain unclear. Here, we identified cell-type-specific transcriptional signatures associated with a sustained ketamine response in mice. Most interestingly, we identified the Kcnq2 gene as an important downstream regulator of ketamine action in glutamatergic neurons of the ventral hippocampus. We validated these findings through a series of complementary molecular, electrophysiological, cellular, pharmacological, behavioral, and functional experiments. We demonstrated that adjunctive treatment with retigabine, a KCNQ activator, augments ketamine's antidepressant-like effects in mice. Intriguingly, these effects are ketamine specific, as they do not modulate a response to classical antidepressants, such as escitalopram. These findings significantly advance our understanding of the mechanisms underlying the sustained antidepressant effects of ketamine, with important clinical implications.

Mediobasal hypothalamic FKBP51 acts as a molecular switch linking autophagy to whole-body metabolism.

The mediobasal hypothalamus (MBH) is the central region in the physiological response to metabolic stress. The FK506-binding protein 51 (FKBP51) is a major modulator of the stress response and has recently emerged as a scaffolder regulating metabolic and autophagy pathways. However, the detailed protein-protein interactions linking FKBP51 to autophagy upon metabolic challenges remain elusive. We performed mass spectrometry-based metabolomics of FKBP51 knockout (KO) cells revealing an increased amino acid and polyamine metabolism. We identified FKBP51 as a central nexus for the recruitment of the LKB1/AMPK complex to WIPI4 and TSC2 to WIPI3, thereby regulating the balance between autophagy and mTOR signaling in response to metabolic challenges. Furthermore, we demonstrated that MBH FKBP51 deletion strongly induces obesity, while its overexpression protects against high-fat diet (HFD)-induced obesity. Our study provides an important novel regulatory function of MBH FKBP51 within the stress-adapted autophagy response to metabolic challenges.

Enzyme Replacement Therapy with Pabinafusp Alfa for Neuronopathic Mucopolysaccharidosis II: An Integrated Analysis of Preclinical and Clinical Data.

Enzyme replacement therapy (ERT) improves somatic manifestations in mucopolysaccharidoses (MPS). However, because intravenously administered enzymes cannot cross the blood-brain barrier (BBB), ERT is ineffective against the progressive neurodegeneration and resultant severe central nervous system (CNS) symptoms observed in patients with neuronopathic MPS. Attempts to surmount this problem have been made with intrathecal and intracerebroventricular ERT in order to achieve CNS effects, but the burdens on patients are inimical to long-term administrations. However, since pabinafusp alfa, a human iduronate-2-sulfatase fused with a BBB-crossing anti-transferrin receptor antibody, showed both central and peripheral efficacy in a mouse model, subsequent clinical trials in a total of 62 patients with MPS-II (Hunter syndrome) in Japan and Brazil substantiated this dual efficacy and provided an acceptable safety profile. To date, pabinafusp alfa is the only approved intravenous ERT that is effective against both the somatic and CNS symptoms of patients with MPS-II. This article summarizes the previously obtained preclinical and clinical evidence related to the use of this drug, presents latest data, and discusses the preclinical, translational, and clinical challenges of evaluating, ameliorating, and preventing neurodegeneration in patients with MPS-II.

The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus of male mice.

Disturbed activation or regulation of the stress response through the hypothalamic-pituitary-adrenal (HPA) axis is a fundamental component of multiple stress-related diseases, including psychiatric, metabolic, and immune disorders. The FK506 binding protein 51 (FKBP5) is a negative regulator of the glucocorticoid receptor (GR), the main driver of HPA axis regulation, and FKBP5 polymorphisms have been repeatedly linked to stress-related disorders in humans. However, the specific role of Fkbp5 in the paraventricular nucleus of the hypothalamus (PVN) in shaping HPA axis (re)activity remains to be elucidated. We here demonstrate that the deletion of Fkbp5 in Sim1+ neurons dampens the acute stress response and increases GR sensitivity. In contrast, Fkbp5 overexpression in the PVN results in a chronic HPA axis over-activation, and a PVN-specific rescue of Fkbp5 expression in full Fkbp5 KO mice normalizes the HPA axis phenotype. Single-cell RNA sequencing revealed the cell-type-specific expression pattern of Fkbp5 in the PVN and showed that Fkbp5 expression is specifically upregulated in Crh+ neurons after stress. Finally, Crh-specific Fkbp5 overexpression alters Crh neuron activity, but only partially recapitulates the PVN-specific Fkbp5 overexpression phenotype. Together, the data establish the central and cell-type-specific importance of Fkbp5 in the PVN in shaping HPA axis regulation and the acute stress response.

Kava (Piper methysticum) Extract for the Treatment of Nervous Anxiety, Tension and Restlessness.

AIM: Prior to the kava ban of 2002, the indication for kava (Piper methysticum) extracts defined by the German Commission E was "nervous anxiety, tension and restlessness". In 2000, an observational trial was started in Germany with the aim of defining symptoms of these indications best treated with kava extract. The trial was interrupted and archived "unevaluated" in 2001 due to the upcoming safety debate on kava. The data from this study has now been analyzed in order to identify symptoms best treated with kava. METHODS: Documentation was available from 156 patients. Twelve typical symptoms of nervous anxiety, tension and restlessness were assessed on a five-item rating scale, together with the therapeutic context, the perceived time of onset of effects and the safety of application. RESULTS: The median duration of treatment was 28 days. All individual symptoms showed significant and clinically relevant improvements. The most effective results were seen for nervous tension and restlessness, with better effects in patients with acute versus chronic complaints. The safety of the treatment was found to be excellent, which included the assessment of laboratory data. CONCLUSIONS: Overall, the study confirms the effective and safe short-term use of kava in the Commission E-defined indication of "nervous anxiety, tension and restlessness", especially in other than chronic cases. The clinical use of kava might be translated into context-related phobias according to ICD-10 F40, or to nervous tension (ICD10 R45.0) or restlessness and excitation (ICD-10 R45.1).

Health policy versus kava (Piper methysticum): Anxiolytic efficacy may be instrumental in restoring the reputation of a major South Pacific crop.

ETHNOPHARMACOLOGICAL RELEVANCE: Kava (Piper methysticum G. Forst. f.) is by far the most important plant used in the islands of Melanesia, Polynesia and Micronesia for its relaxing effects. Kava drinking is a pillar of South Pacific societies and is also the foundation of their economies. Preparations of kava extract as herbal medicinal drugs were banned in Germany in 2002 and again in 2019, with dramatic consequences for the South Pacific economies. In 2002, the major regulatory argument for the ban of kava was safety issues. In 2019, the assessment report of the European Medicines Agency's Herbal Medicinal Product Committee (HMPC) justified a negative benefit-to-risk ratio by a supposed lack of efficacy of ethanolic extracts for an indication of which kava extract preparations never had an approval. In this HMPC report the efficacy in the approved indications 'nervous anxiety, tension and restlessness' was attributed to the extract branded as 'WS 1490', which was assumed to have been prepared with acetone as an extraction solvent. In addition to this change of indication and the attribution of efficacy to acetone kava extract alone, the German health authorities and the HMPC still refuse to discuss quality issues as a likely factor impacting drug safety. The first case reports of liver toxicity were observed with an acetone extract in a timely relationship with the introduction of 'two-day kava' instead of 'noble kava' as used in ethanolic kava extracts. AIM OF THE STUDY: The correlation between clinical benefits and the type of extract preparation was examined. METHODS: In order to identify the types of kava material and extracts used in clinical trials, the respective publications were compared with regulatory databases and protocols of a German regulatory advisory board. RESULTS AND CONCLUSIONS: The comparison reveals inconsistencies in the regulatory decisions. In all studies with WS 1490, the evidence points to the use of an ethanolic extract. The efficacy of kava extract for the approved indication was clearly demonstrated. The HMPC report and the recent renewed German regulatory ban of kava therefore require major revision, which should include the impact of the use of "two-day kava" on drug safety. Such a revision could contribute to restoring the reputation of "noble kava" on the international markets.

Safety of medicinal comfrey cream preparations (Symphytum officinale s.l.): The pyrrolizidine alkaloid lycopsamine is poorly absorbed through human skin.

European Union guidelines indiscriminately discuss a permitted daily exposure (PDE) for pyrrolizidine alkaloids (PA) of up to 0.007 µg/kg body weight for oral and for topical exposure to herbal medicinal products. In this study, lycopsamine served as a model substance for measuring the extent of skin permeation of PAs following the application of a spiked comfrey cream (Symphytum officinale s.l.) to abdominal skin from human donors in Franz diffusion cells. PAs could be excluded in the non-spiked cream with a limit of detection of 8 µg/kg. Only small amounts of the applied quantity of lycopsamine had migrated through the skin sample into the receptor cell side of the diffusion cell after 24 h. In five of six diffusion cells, there was no detectable lycopsamine within the skin and only 0.6 ± 0.4% of the applied dose in the receptor fluid. The theoretical skin penetration of 4.9% of the applied quantity of lycopsamine largely resulted from the worst case approach of assuming the presence of at least a quantity corresponding to the limit of detection - the true penetration is probably considerably lower. Even with the worst-case calculation, the currently discussed guidelines on PA overestimate the risk related to topical preparations.

Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity.

Recent genome-wide association studies (GWAS) identified DUSP8, encoding a dual-specificity phosphatase targeting mitogen-activated protein kinases, as a type 2 diabetes (T2D) risk gene. Here, we reveal that Dusp8 is a gatekeeper in the hypothalamic control of glucose homeostasis in mice and humans. Male, but not female, Dusp8 loss-of-function mice, either with global or corticotropin-releasing hormone neuron-specific deletion, had impaired systemic glucose tolerance and insulin sensitivity when exposed to high-fat diet (HFD). Mechanistically, we found impaired hypothalamic-pituitary-adrenal axis feedback, blunted sympathetic responsiveness, and chronically elevated corticosterone levels driven by hypothalamic hyperactivation of Jnk signaling. Accordingly, global Jnk1 ablation, AAV-mediated Dusp8 overexpression in the mediobasal hypothalamus, or metyrapone-induced chemical adrenalectomy rescued the impaired glucose homeostasis of obese male Dusp8-KO mice, respectively. The sex-specific role of murine Dusp8 in governing hypothalamic Jnk signaling, insulin sensitivity, and systemic glucose tolerance was consistent with functional MRI data in human volunteers that revealed an association of the DUSP8 rs2334499 risk variant with hypothalamic insulin resistance in men. Further, expression of DUSP8 was increased in the infundibular nucleus of T2D humans. In summary, our findings suggest the GWAS-identified gene Dusp8 as a novel hypothalamic factor that plays a functional role in the etiology of T2D.

Epidermal Regeneration Induced by Comfrey Extract: A Study by Light and Electron Microscopy.

INTRODUCTION: An accelerated healing of superficial wounds was demonstrated in clinical trials with a topical comfrey preparation (Symphytum × uplandicum Nyman). The effect has previously not been examined in skin models. METHODS: An established in vitro model of epidermal cells with the typical strata was used for the observation of effects of applied substances on skin regeneration. Damage corresponding to a typical abrasion was created on day 1 by punching an opening into the epidermal fine structure down to the stratum basale. Samples were either untreated (controls) or exposed to comfrey cream on days 2, 3, 5, and 6. Tissue samples were taken for light and electron microscopy on days 1, 4, and 7. RESULTS AND CONCLUSIONS: Application of comfrey cream led to a quicker regeneration of skin cells and to an earlier differentiation of the cells towards a normal fine structure with a visible distinction of epidermal strata, keratin, and corneocyte formation within 4-7 days. The study covered the early days of skin regeneration and confirms the benefits observed in published clinical trials and non-interventional studies in patients with abrasions.

[Marshmallow Root Extract for the Treatment of Irritative Cough: Two Surveys on Users' View on Effectiveness and Tolerability].

BACKGROUND: Cough preparations containing aqueous marshmallow root extracts (Althaea officinalis) have a long history as medicinal products in Germany. The aim of the 2 prospective, non-interventional surveys reported here was to create a better documentation of the users' impression of the effectiveness and tolerability, and user satisfaction. METHODS: Consumers (n = 822) buying either lozenges or syrup of the aqueous marshmallow root extract STW42 to treat their dry cough were recruited in pharmacies in 2 independently performed surveys. They were asked to fill in a questionnaire covering a treatment duration of 7 days so that the course of symptoms could be documented, and the overall effectiveness, tolerability and satisfaction assessed. RESULTS: This consumer-reported outcome shows that both preparations showed a good effect with respect to the symptomatic treatment of oral or pharyngeal irritation and associated dry cough with a very rapid onset of effects, in the majority of cases within 10 min. The tolerability was very good (with only 3 minor adverse events for the syrup). CONCLUSION: The results of the surveys justify the long-established use of both marshmallow preparations for symptomatic treatment of dry cough.

Soy germ extract alleviates menopausal hot flushes: placebo-controlled double-blind trial.

BACKGROUND/OBJECTIVES: A double-blind, placebo-controlled study was performed to assess the potency of a soy germ preparation for the alleviation of menopausal hot flushes. SUBJECTS/METHODS: Caucasian women with at least seven hot flushes daily were treated with soy germ extract (100 mg isoflavone glycosides) daily or with placebo for 12 weeks, followed by 12 weeks of open treatment with soy. Outcome parameters were the number of hot flushes and the evaluation of the Greene Climacteric Scale. RESULTS: A total of 192 women were included. As the hot flush diaries from one study centre were lost, the assessment of hot flushes was based on 136 participants (soy: 54 women; placebo: 82 women). After 12 weeks, 180 women were available for the analysis of Greene Scale and safety (soy and placebo: each 90 women). Hot flushes were reduced by 43.3% (-3.5 hot flushes) with soy and by 30.8% with placebo (-2.6; p < 0.001). After the open treatment phase with soy, both original groups showed a reduction of 68% of hot flushes. A subgroup analysis showed better effects for soy when symptoms were classified as "severe" at baseline. After 12 weeks of double-blind treatment, there was an improvement from baseline values of 71 and 78% with soy with the items "hot flushes" and "sweating", compared with 24% for both items with placebo. Hormonal safety parameters remained uninfluenced. CONCLUSIONS: Soy germ extract with 100 mg of isoflavone glycosides was shown to modestly, but significantly reduce menopausal hot flushes.

An open prospective pilot study of a herbal combination "Relief" as a supportive dietetic measure during alcohol withdrawal.

OBJECTIVE: A herbal combination (saffron extract, passion flower herb extract, cocoa seed extract, radish extract and black cumin extract) called "Relief" was designed as a supportive therapy of alcohol withdrawal syndrome (AWS). This combination was based on the scientific evidence of each constituent effect on AWS-like symptoms. In addition, our preclinical studies have shown the effectiveness of Relief on AWS detoxification. The rationale of the study was to document whether the oral intake of the designed content of Relief could have a positive effect on the course of alcohol detoxification by reducing some of the AWS in hospitalized patients. METHODS: This pilot study was performed as non-interventional, open, single-armed, prospective on 32 hospitalized patients entered for detoxification of alcohol withdrawal syndrome. Each patient received daily three capsules of Relief for 15 days, and AWS parameters were monitored, in addition to serum liver enzymes and quality of life which was evaluated using the Befindlichkeits-Skala (Bf-SR) scaling system. RESULTS: Relief administration significantly reduced the percentage of patients with hyperhidrosis (r=0.815, p<0.001), reduced serum liver enzymes by ~50-80% (p<0.05), and increased normalization of appetite (r=0.777, p<0.001). Besides, before the treatment began the Bf-SR scale was 28.3±4.3, which was typical for neurological syndromes such as depression or insomnia, and during Relief administration the Bf-SR scale significantly dropped to 15.6±2.4 (p<0.001). As for the safety, four, but not serious, adverse events were observed; two of them may be product related. Finally, 84.4% of patients' assessed Relief treatment as good to excellent and 87.5% of the patients declared an interest in reusing Relief for the next detoxification period. CONCLUSIONS: Despite the limitations of the present study, the findings showed the potential of Relief for the improvement of the clinical situation of patients with symptoms of alcohol withdrawal and therefore, justify a full-scale well-controlled study design to be implemented.

Prenatal Exposure to Maternal Obesity Alters Anxiety and Stress Coping Behaviors in Aged Mice.

BACKGROUND: There is growing evidence that maternal obesity and prenatal exposure to a high-fat diet program fetal development to regulate the physiology and behavior of the offspring in adulthood. Yet the extent to which the maternal dietary environment contributes to adult disease vulnerability remains unclear. In the current study we tested whether prenatal exposure to maternal obesity increases the offspring's vulnerability to stress-related psychiatric disorders. METHODS: We used a mouse model of maternal diet-induced obesity to investigate whether maternal obesity affects the response to adult chronic stress exposure in young adult (3-month-old) and aged adult (12-month-old) offspring. RESULTS: Long-lasting, delayed impairments to anxiety-like behaviors and stress coping strategies resulted on account of prenatal exposure to maternal obesity. Although maternal obesity did not change the offspring's behavioral response to chronic stress per se, we demonstrate that the behavioral outcomes induced by prenatal exposure to maternal obesity parallel the deleterious effects of adult chronic stress exposure in aged male mice. We found that the glucocorticoid receptor (GR, Nr3c1) is upregulated in various hypothalamic nuclei on account of maternal obesity. In addition, gene expression of a known regulator of the GR, FKBP51, is increased specifically within the paraventricular nucleus. CONCLUSIONS: These findings indicate that maternal obesity parallels the deleterious effects of adult chronic stress exposure, and furthermore identifies GR/FKBP51 signaling as a novel candidate pathway regulated by maternal obesity.

German Kava Ban Lifted by Court: The Alleged Hepatotoxicity of Kava (Piper methysticum) as a Case of Ill-Defined Herbal Drug Identity, Lacking Quality Control, and Misguided Regulatory Politics.

Kava, the rhizome and roots of Piper methysticum, are one of the most important social pillars of Melanesian societies. They have been used for more than 1000 years in social gatherings for the preparation of beverages with relaxing effects. During the colonial period, extract preparations found their way into Western medicinal systems, with experience especially concerning the treatment of situational anxiety dating back more than 100 years. It therefore came as a surprise when the safety of kava was suddenly questioned based on the observation of a series of case reports of liver toxicity in 1999 and 2000. These case reports ultimately led to a ban of kava products in Europe - a ban that has been contested because of the poor evidence of risks related to kava. Only recently, two German administrative courts decided that the decision of the regulatory authority to ban kava as a measure to ensure consumer safety was inappropriate and even associated with an increased risk due to the higher risk inherent to the therapeutic alternatives. This ruling can be considered as final for at least the German market, as no further appeal has been pursued by the regulatory authorities. However, in order to prevent further misunderstandings, especially in other markets, the current situation calls for a comprehensive presentation of the cardinal facts and misconceptions concerning kava and related drug quality issues.

The mechanisms of action of St. John's wort: an update.

Pharmacological research confirms and supports the clinically observed antidepressant efficacy of St. John's wort (Hypericum perforatum L., SJW). This contribution is an update of a former review by the authors in 2007. Positive evidence of antidepressant effects has been found with SJW preparations, extract fractions, and single constituents. The efficacy of SJW is obviously defined by a range of parallel mechanisms of action, triggered by different constituents. In vitro research showed, among other tests, positive effects in neurotransmitter regulation (in beta adrenergic systems and glutamate receptors) and ion channel conductance. Antidepressant effects were confirmed in typical in vivo models such as the forced swimming test, the open field test, the tail suspension test, or a model of stress-impaired memory. The overall effect cannot be attributed to a single constituent or fraction. SJW is therefore an outstanding example of the total extract being defined as the active constituent of herbal medicines.

Interplay between diet-induced obesity and chronic stress in mice: potential role of FKBP51.

While it is known that stress promotes obesity, the effects of stress within an obesogenic context are not so clear and molecular targets at the interface remain elusive. The FK506-binding protein 51 (FKBP51, gene: Fkbp5) has been identified as a target gene implicated in the development of stress-related psychiatric disorders and is a possible candidate for involvement in stress and metabolic regulation. The aims of the current study are to investigate the interaction between chronic stress and an obesogenic context and to additionally examine whether FKBP51 is involved in this interaction. For this purpose, male C57BL/6 mice were exposed to a high-fat diet for 8 weeks before being challenged with chronic social defeat stress. Herein, we demonstrate that chronic stress induces hypophagia and weight loss, ultimately improving features arising from an obesogenic context, including glucose tolerance and levels of insulin and leptin. We show that Fkbp5 expression is responsive to diet and stress in the hypothalamus and hippocampus respectively. Furthermore, under basal conditions, higher levels of hypothalamic Fkbp5 expression were related to increased body weight gain. Our data indicate that Fkbp5 may represent a novel target in metabolic regulation.